Chromosomal Abnormalities in Offspring of Young Cancer Survivors: A Population-Based Cohort Study in Denmark

Chromosomal Abnormalities in Offspring of Young Cancer Survivors: A Population-Based Cohort Study... Abstract To examine whether cancer survivors diagnosed before age 35 years are more likely to have offspring with chromosomal abnormalities than their siblings, chromosomal abnormalities were determined in a population-based cohort of 14 611 offspring (14 580 live-born children and 31 fetuses) of 8945 Danish cancer survivors and 40 859 offspring (40 794 live-born children and 65 fetuses) of 19 536 siblings. Chromosomal abnormalities include numeric and structural abnormalities. Odds ratios were estimated by multiple logistic regression models comparing the risk of chromosomal abnormalities among survivors’ offspring with that in siblings’ offspring. In a subgroup of survivors with gonadal radiation doses (mean = 0.95 Gy for males and 0.91 Gy for females), no indication of a dose response was found. Overall, no increased risk of chromosomal abnormalities among survivors’ offspring was observed compared with their siblings’ offspring (odds ratio = 0.99, 95% confidence interval = 0.67 to 1.44, two-sided P = .94), with similar risk between male and female survivors. Cancer survivors were not more likely than their siblings to have children with a chromosomal abnormality. The overall five-year survival rate among cancer survivors diagnosed before age 35 years has increased as a consequence of improved cancer treatment and now approaches 80% (1,2). The growing cohort of cancer survivors worry about whether their children will be healthy or be born with a congenital malformation or a genetic condition related to their cancer or treatment (3). These concerns are plausible as radiation and certain chemotherapeutics are potent germ cell mutagens, which in mice lead to genetic disease in the next generation (4,5). In a nationwide population-based cohort study, we evaluated whether preconception cancer treatments in childhood, adolescence, and young adulthood cause transgenerational germ cell mutations seen as chromosomal abnormalities in offspring (defined as a fetus or a live-born child) conceived after treatment. In the nationwide and population-based Danish Cancer Registry, we identified 8945 cancer survivors (56.2% males) diagnosed before age 35 years in 1943–2002 (80.3% were older than age 20 years) who were alive on or born after April 1, 1968, when the national Central Population Register (CPR) was established, and who had a child in Denmark conceived at least nine months after diagnosis. A total of 14 580 live-born children (7468 boys, 7112 girls) were identified from the CPR. Similar linkages identified 19 536 siblings of survivors (48.6% males) and their 40 794 live-born children (20 850 boys, 19 944 girls), providing the comparison cohort. A search for chromosomal abnormalities in the Danish Cytogenetic Registry from 1960 through 2007, including data on all abnormal karyotypes for fetuses or live-born children and their parents, if tested, resulted in 52 live-born children and 31 fetuses of 8945 survivors and 123 children and 65 fetuses of 19 536 siblings identified with a chromosomal abnormality. Adding the number of fetuses to the live-born children in each of the two cohorts resulted in 14 611 offspring of cancer survivors and 40 859 offspring of siblings. Information on radiotherapy (yes/no) was extracted from the Danish Cancer Registry on the entire survivor cohort. In a subgroup of 860 cancer survivors, it was possible to estimate gonadal radiation doses at the MD Anderson Cancer Center (Houston, TX) based on information from medical records including radiation beam energies and position and documented procedures to reduce gonadal dose. Radiation dose outside the treatment beam was measured using a three-dimensional water phantom simulating the size of a person at the age of radiotherapy (6). If the same karyotype was known to be present in one or both parents, the case was classified as hereditary. To include the prenatally diagnosed and terminated cases (ie, fetuses) when estimating the proportion of live-born children, these cases were adjusted for viability using the following survival probabilities: 0.74 for Down syndrome, 0.35 for Turner syndrome, 0.36 for Edward syndrome, 0.63 for Patau syndrome (7). These estimates were calculated to compare the adjusted proportion of live-born children affected in survivor families with sibling families. A logistic regression model estimating odds ratios (ORs) with 95% confidence intervals (CIs) was used to compare the risk of chromosomal abnormalities among survivors’ offspring with that in siblings’ offspring adjusting for maternal age and sex of the child. Statistical significance was defined as a two-sided P value of less than .05. In 860 survivors with gonadal radiation doses estimated, a dose-response analysis was conducted to evaluate the association between gonadal radiation dose and the risk of chromosomal abnormalities. We computed a Ptrend by treating radiation dose to the gonads as a continuous variable. After excluding 56 hereditary cytogenetic cases, 63 survivors’ offspring and 152 siblings’ offspring were identified with a chromosomal abnormality (Table 1). The viability-adjusted live-born proportions of offspring with abnormalities were similar between survivors (0.37%) and siblings (0.33%). The adjusted OR did not indicate an increased risk of abnormalities among survivors’ offspring compared with that in siblings’ offspring (OR = 0.99, 95% CI = 0.67 to 1.44, P = .94). The risk of Klinefelter syndrome was increased among cancer survivors’ offspring (ORadj = 2.72, 95% CI = 0.99 to 7.47, P = .05). No indication of a dose response was found between gonadal radiation dose (mean = 0.95 Gy for males and 0.91 Gy for females) and risk of chromosomal abnormalities in the offspring (Table 2). The risk of having an offspring affected was similar between male and female survivors (OR = 1.25, 95% CI = 0.80 to 1.95, P = .33; not shown). Table 1. Crude and adjusted odds ratios of chromosomal abnormalities among offspring of 8945 survivors vs offspring of 19 536 siblings (with and without hereditary cases) Abnormal karyotypes Hereditary cases excluded* Hereditary cases included Chromosomal abnormalities Crude analysis Adjusted analysis† Chromosomal abnormalities Crude analysis Adjusted analysis† Offspring of survivors, No. (%) Offspring of siblings, No. (%) OR (95% CI) P‡ OR (95% CI) P‡ Offspring of survivors, No. (%) Offspring of siblings, No. (%) OR (95% CI) P‡ OR (95% CI) P‡ Total/overall risk 63 (100) 152 (100) 1.16 (0.86 to 1.56) .32 0.99 (0.67 to 1.44) .94 83 (100) 188 (100) 1.24 (0.95 to 1.60) .11 1.09 (0.80 to 1.50) .58 Numeric abnormalities 52 (82.5) 119 (78.3) 1.22 (0.88 to 1.70) .23 1.03 (0.67 to 1.57) .91 52 (62.7) 121 (64.4) 1.20 (0.87 to 1.67) .27 1.00 (0.66 to 1.53) .98  Autosomal abnormalities   Down syndrome§ 25 (39.6) 57 (37.5) 1.23 (0.77 to 1.97) .39 1.04 (0.62 to 1.78) .88 25 (30.2) 59 (31.4) 1.19 (0.74 to 1.89) .48 1.00 (0.60 to 1.67) .34   Patau syndrome‖ 3 (4.8) 5 (3.3) 1.68 (0.40 to 7.03) .48 1.56 (0.36 to 6.77) .55 3 (3.6) 5 (2.7) 1.68 (0.40 to 7.02) .48 1.58 (0.36 to 6.85) .55   Edward syndrome¶ 7 (11.1) 13 (8.6) 1.51 (0.60 to 3.78) .38 1.00 (0.35 to 2.84) 1.00 7 (8.4) 13 (6.9) 1.51 (0.60 to 3.78) .38 0.98 (0.35 to 2.77) .98   Trisomy 16 0 (0.0) 1 (0.7) — — — — 0 (0.0) 1 (0.5) — — — —   Trisomy 14# 0 (0.0) 1 (0.7) — — — — 0 (0.0) 1 (0.5) — — — —  Sex chromosome abnormalities   Klinefelter syndrome** 9 (14.3) 7 (4.6) 3.60 (1.34 to 9.66) .01 2.72 (0.99 to 7.47) .05 9 (10.9) 7 (3.7) 3.60 (1.34 to 9.66) .01 2.70 (0.98 to 7.41) .05   Turner syndrome†† 5 (7.9) 16 (10.5) 0.87 (0.32 to 2.39) .79 0.98 (0.35 to 2.78) .97 5 (6.0) 16 (8.5) 0.87 (0.32 to 2.39) .79 1.00 (0.40 to 2.83) 1.00   Triple X syndrome 1 (1.6) 2 (1.3) — — — — 1 (1.2) 2 (1.1) — — — —   Double Y syndrome 0 (0.0) 8 (5.2) — — — — 0 (0.0) 8 (4.3) — — — —   Male turner‡‡ 1 (1.6) 2 (1.3) — — — — 1 (1.2) 2 (1.1) — — — —   XX-male§§ 0 (0.0) 1 (0.7) — — — — 0 (0.0) 1 (0.5) — — — —   Triploidy 1 (1.6) 6 (3.9) — — — — 1 (1.2) 6 (3.2) — — — — Structural abnormalities 11 (17.5) 33 (21.7) 0.93 (0.47 to 1.85) .84 0.90 (0.45 to 1.81) .77 31 (37.3) 67 (35.6) 1.30 (0.85 to 1.98) .23 1.19 (0.77 to 1.84) .43  Reciprocal translocation 3 (4.8) 6 (3.9) — — — — 13 (15.7) 21 (11.2) — — — —  Robertsonian translocation 1 (1.6) 1 (0.7) — — — — 5 (6.0) 7 (3.7) — — — —  Deletion 3 (4.8) 13 (8.6) — — — — 4 (4.8) 13 (6.9) — — — —  Ring chromosome 1 (1.6) 3 (2.0) — — — — 1 (1.2) 3 (1.6) — — — —  Duplication 0 (0.0) 6 (3.9) — — — — 0 (0.0) 6 (3.2) — — — —  Inversion 2 (3.1) 2 (1.3) — — — — 7 (8.4) 12 (6.4) — — — —  Marker chromosome 0 (0.0) 1 (0.7) — — — — 0 (0.0) 4 (2.1) — — — —  Derivative chromosome 0 (0.0) 1 (0.7) — — — — 0 (0.0) 1 (0.5) — — — —  Isochromosome 1 (1.6) 0 (0.0) — — — — 1 (1.2) 0 (0.0) — — — — Abnormal karyotypes Hereditary cases excluded* Hereditary cases included Chromosomal abnormalities Crude analysis Adjusted analysis† Chromosomal abnormalities Crude analysis Adjusted analysis† Offspring of survivors, No. (%) Offspring of siblings, No. (%) OR (95% CI) P‡ OR (95% CI) P‡ Offspring of survivors, No. (%) Offspring of siblings, No. (%) OR (95% CI) P‡ OR (95% CI) P‡ Total/overall risk 63 (100) 152 (100) 1.16 (0.86 to 1.56) .32 0.99 (0.67 to 1.44) .94 83 (100) 188 (100) 1.24 (0.95 to 1.60) .11 1.09 (0.80 to 1.50) .58 Numeric abnormalities 52 (82.5) 119 (78.3) 1.22 (0.88 to 1.70) .23 1.03 (0.67 to 1.57) .91 52 (62.7) 121 (64.4) 1.20 (0.87 to 1.67) .27 1.00 (0.66 to 1.53) .98  Autosomal abnormalities   Down syndrome§ 25 (39.6) 57 (37.5) 1.23 (0.77 to 1.97) .39 1.04 (0.62 to 1.78) .88 25 (30.2) 59 (31.4) 1.19 (0.74 to 1.89) .48 1.00 (0.60 to 1.67) .34   Patau syndrome‖ 3 (4.8) 5 (3.3) 1.68 (0.40 to 7.03) .48 1.56 (0.36 to 6.77) .55 3 (3.6) 5 (2.7) 1.68 (0.40 to 7.02) .48 1.58 (0.36 to 6.85) .55   Edward syndrome¶ 7 (11.1) 13 (8.6) 1.51 (0.60 to 3.78) .38 1.00 (0.35 to 2.84) 1.00 7 (8.4) 13 (6.9) 1.51 (0.60 to 3.78) .38 0.98 (0.35 to 2.77) .98   Trisomy 16 0 (0.0) 1 (0.7) — — — — 0 (0.0) 1 (0.5) — — — —   Trisomy 14# 0 (0.0) 1 (0.7) — — — — 0 (0.0) 1 (0.5) — — — —  Sex chromosome abnormalities   Klinefelter syndrome** 9 (14.3) 7 (4.6) 3.60 (1.34 to 9.66) .01 2.72 (0.99 to 7.47) .05 9 (10.9) 7 (3.7) 3.60 (1.34 to 9.66) .01 2.70 (0.98 to 7.41) .05   Turner syndrome†† 5 (7.9) 16 (10.5) 0.87 (0.32 to 2.39) .79 0.98 (0.35 to 2.78) .97 5 (6.0) 16 (8.5) 0.87 (0.32 to 2.39) .79 1.00 (0.40 to 2.83) 1.00   Triple X syndrome 1 (1.6) 2 (1.3) — — — — 1 (1.2) 2 (1.1) — — — —   Double Y syndrome 0 (0.0) 8 (5.2) — — — — 0 (0.0) 8 (4.3) — — — —   Male turner‡‡ 1 (1.6) 2 (1.3) — — — — 1 (1.2) 2 (1.1) — — — —   XX-male§§ 0 (0.0) 1 (0.7) — — — — 0 (0.0) 1 (0.5) — — — —   Triploidy 1 (1.6) 6 (3.9) — — — — 1 (1.2) 6 (3.2) — — — — Structural abnormalities 11 (17.5) 33 (21.7) 0.93 (0.47 to 1.85) .84 0.90 (0.45 to 1.81) .77 31 (37.3) 67 (35.6) 1.30 (0.85 to 1.98) .23 1.19 (0.77 to 1.84) .43  Reciprocal translocation 3 (4.8) 6 (3.9) — — — — 13 (15.7) 21 (11.2) — — — —  Robertsonian translocation 1 (1.6) 1 (0.7) — — — — 5 (6.0) 7 (3.7) — — — —  Deletion 3 (4.8) 13 (8.6) — — — — 4 (4.8) 13 (6.9) — — — —  Ring chromosome 1 (1.6) 3 (2.0) — — — — 1 (1.2) 3 (1.6) — — — —  Duplication 0 (0.0) 6 (3.9) — — — — 0 (0.0) 6 (3.2) — — — —  Inversion 2 (3.1) 2 (1.3) — — — — 7 (8.4) 12 (6.4) — — — —  Marker chromosome 0 (0.0) 1 (0.7) — — — — 0 (0.0) 4 (2.1) — — — —  Derivative chromosome 0 (0.0) 1 (0.7) — — — — 0 (0.0) 1 (0.5) — — — —  Isochromosome 1 (1.6) 0 (0.0) — — — — 1 (1.2) 0 (0.0) — — — — * Offspring are defined as fetuses and live-born children. A total of 83 offspring (including 31 fetuses) of survivors were identified with a chromosomal abnormality; of those, 20 hereditary cases (ie, same abnormal karyotype in parent and offspring, and thus not the result of a new mutation that might be related to preconception cancer treatment in the parent) were excluded. Among offspring of siblings, 188 cases (including 65 fetuses) were detected; of these, 36 hereditary cases were excluded. These hereditary cases were all structural abnormalities except two cases of Down syndrome (among offspring of siblings). In the survivor cohort, the number of terminated cases with Down syndrome was 12, one with Turner syndrome, seven with Edward syndrome, and one with Patau syndrome, resulting in an adjusted live-born rate of 12.4. The remaining 10 terminated cases counted for one live-born offspring each, as there is no strong evidence for an excess risk for these abnormalities (7). In the sibling cohort, the number of terminated cases with Down syndrome was 23, five with Turner, nine with Edward, and three with Patau syndrome, resulting in an adjusted live-born rate of 23.9. The remaining 25 terminated cases counted for one live-born offspring each. After exclusion of hereditary cases and inclusion of prenatal cases and after correction for expected viability, the adjusted proportion of live-born children with chromosomal abnormalities in the survivor cohort was 0.37% ((32 live born + 12.4 adjusted prenatal cases + 10 nonadjusted prenatal cases)/(14 580 live born + 12.4 adjusted terminated prenatal cases + 10 nonadjusted prenatal cases) × 100) vs an adjusted proportion of 0.33% in the sibling cohort ((84 + 23.9 + 25)/(40 794 + 23.9 + 25) × 100). Inclusion of the hereditary cases also resulted in similar proportions in the two cohorts, that is, 0.51% and 0.42% among survivors and siblings, respectively. Empty cells with em dash: No risk estimate calculated as there were very few outcomes. † Adjusted for maternal age and sex of the child. ‡ Two-sided P value calculated by Wald test. § Of the 84 cases with Down syndrome (47,XX/XY+21), two cases had Robertsonian translocations (not counted under “structural abnormalities”): 46,XY, der(14;21) (q10;q10),+21 and 46,XY, der(21;21) (q10;q10); and two cases had mosaic Down syndrome: 46,XX/47,XX,+21 and 47,XX,+21/48,XX,+8,+21. ‖ Of the eight cases with Patau syndrome (47,XX/XY+13), two cases had Robertsonian translocations (not counted under “structural abnormalities”): 46,XX,der(13;14) (q10;q10),+13 and 46,XY,der(13;14) (q10;q10)+13. ¶ Of the 20 cases with Edward syndrome (47,XX/XY+18), one case had mosaic Edward syndrome: 46,XX/47,XX,+18. # The case with Trisomy 14 was a mosaic Trisomy 14: 46,XX/47,XX,+14. ** Of the 16 cases with Klinefelter syndrome (47,XXY or 49,XXXXY), two cases had mosaic Klinefelter syndrome: 46,XY/47,XXY and 46,XY/47,XXY. †† Of the 21 cases with Turner syndrome (45,X), five cases had mosaic isochromosome Turner syndrome: three of 46,XX/46,X,i(X)(q10) and two 46,XX/46,X,i(X); and one case had mosaic marker Turner syndrome: 45,X/46,X,+mar. ‡‡ The cases with Male Turner syndrome had mosaic Male Turner syndrome: 45,X/46,XY. §§ The XX male had an unbalanced X,Y translocation: 46,X,der(X),t(X;Y)(p22.2;p11.2). Table 1. Crude and adjusted odds ratios of chromosomal abnormalities among offspring of 8945 survivors vs offspring of 19 536 siblings (with and without hereditary cases) Abnormal karyotypes Hereditary cases excluded* Hereditary cases included Chromosomal abnormalities Crude analysis Adjusted analysis† Chromosomal abnormalities Crude analysis Adjusted analysis† Offspring of survivors, No. (%) Offspring of siblings, No. (%) OR (95% CI) P‡ OR (95% CI) P‡ Offspring of survivors, No. (%) Offspring of siblings, No. (%) OR (95% CI) P‡ OR (95% CI) P‡ Total/overall risk 63 (100) 152 (100) 1.16 (0.86 to 1.56) .32 0.99 (0.67 to 1.44) .94 83 (100) 188 (100) 1.24 (0.95 to 1.60) .11 1.09 (0.80 to 1.50) .58 Numeric abnormalities 52 (82.5) 119 (78.3) 1.22 (0.88 to 1.70) .23 1.03 (0.67 to 1.57) .91 52 (62.7) 121 (64.4) 1.20 (0.87 to 1.67) .27 1.00 (0.66 to 1.53) .98  Autosomal abnormalities   Down syndrome§ 25 (39.6) 57 (37.5) 1.23 (0.77 to 1.97) .39 1.04 (0.62 to 1.78) .88 25 (30.2) 59 (31.4) 1.19 (0.74 to 1.89) .48 1.00 (0.60 to 1.67) .34   Patau syndrome‖ 3 (4.8) 5 (3.3) 1.68 (0.40 to 7.03) .48 1.56 (0.36 to 6.77) .55 3 (3.6) 5 (2.7) 1.68 (0.40 to 7.02) .48 1.58 (0.36 to 6.85) .55   Edward syndrome¶ 7 (11.1) 13 (8.6) 1.51 (0.60 to 3.78) .38 1.00 (0.35 to 2.84) 1.00 7 (8.4) 13 (6.9) 1.51 (0.60 to 3.78) .38 0.98 (0.35 to 2.77) .98   Trisomy 16 0 (0.0) 1 (0.7) — — — — 0 (0.0) 1 (0.5) — — — —   Trisomy 14# 0 (0.0) 1 (0.7) — — — — 0 (0.0) 1 (0.5) — — — —  Sex chromosome abnormalities   Klinefelter syndrome** 9 (14.3) 7 (4.6) 3.60 (1.34 to 9.66) .01 2.72 (0.99 to 7.47) .05 9 (10.9) 7 (3.7) 3.60 (1.34 to 9.66) .01 2.70 (0.98 to 7.41) .05   Turner syndrome†† 5 (7.9) 16 (10.5) 0.87 (0.32 to 2.39) .79 0.98 (0.35 to 2.78) .97 5 (6.0) 16 (8.5) 0.87 (0.32 to 2.39) .79 1.00 (0.40 to 2.83) 1.00   Triple X syndrome 1 (1.6) 2 (1.3) — — — — 1 (1.2) 2 (1.1) — — — —   Double Y syndrome 0 (0.0) 8 (5.2) — — — — 0 (0.0) 8 (4.3) — — — —   Male turner‡‡ 1 (1.6) 2 (1.3) — — — — 1 (1.2) 2 (1.1) — — — —   XX-male§§ 0 (0.0) 1 (0.7) — — — — 0 (0.0) 1 (0.5) — — — —   Triploidy 1 (1.6) 6 (3.9) — — — — 1 (1.2) 6 (3.2) — — — — Structural abnormalities 11 (17.5) 33 (21.7) 0.93 (0.47 to 1.85) .84 0.90 (0.45 to 1.81) .77 31 (37.3) 67 (35.6) 1.30 (0.85 to 1.98) .23 1.19 (0.77 to 1.84) .43  Reciprocal translocation 3 (4.8) 6 (3.9) — — — — 13 (15.7) 21 (11.2) — — — —  Robertsonian translocation 1 (1.6) 1 (0.7) — — — — 5 (6.0) 7 (3.7) — — — —  Deletion 3 (4.8) 13 (8.6) — — — — 4 (4.8) 13 (6.9) — — — —  Ring chromosome 1 (1.6) 3 (2.0) — — — — 1 (1.2) 3 (1.6) — — — —  Duplication 0 (0.0) 6 (3.9) — — — — 0 (0.0) 6 (3.2) — — — —  Inversion 2 (3.1) 2 (1.3) — — — — 7 (8.4) 12 (6.4) — — — —  Marker chromosome 0 (0.0) 1 (0.7) — — — — 0 (0.0) 4 (2.1) — — — —  Derivative chromosome 0 (0.0) 1 (0.7) — — — — 0 (0.0) 1 (0.5) — — — —  Isochromosome 1 (1.6) 0 (0.0) — — — — 1 (1.2) 0 (0.0) — — — — Abnormal karyotypes Hereditary cases excluded* Hereditary cases included Chromosomal abnormalities Crude analysis Adjusted analysis† Chromosomal abnormalities Crude analysis Adjusted analysis† Offspring of survivors, No. (%) Offspring of siblings, No. (%) OR (95% CI) P‡ OR (95% CI) P‡ Offspring of survivors, No. (%) Offspring of siblings, No. (%) OR (95% CI) P‡ OR (95% CI) P‡ Total/overall risk 63 (100) 152 (100) 1.16 (0.86 to 1.56) .32 0.99 (0.67 to 1.44) .94 83 (100) 188 (100) 1.24 (0.95 to 1.60) .11 1.09 (0.80 to 1.50) .58 Numeric abnormalities 52 (82.5) 119 (78.3) 1.22 (0.88 to 1.70) .23 1.03 (0.67 to 1.57) .91 52 (62.7) 121 (64.4) 1.20 (0.87 to 1.67) .27 1.00 (0.66 to 1.53) .98  Autosomal abnormalities   Down syndrome§ 25 (39.6) 57 (37.5) 1.23 (0.77 to 1.97) .39 1.04 (0.62 to 1.78) .88 25 (30.2) 59 (31.4) 1.19 (0.74 to 1.89) .48 1.00 (0.60 to 1.67) .34   Patau syndrome‖ 3 (4.8) 5 (3.3) 1.68 (0.40 to 7.03) .48 1.56 (0.36 to 6.77) .55 3 (3.6) 5 (2.7) 1.68 (0.40 to 7.02) .48 1.58 (0.36 to 6.85) .55   Edward syndrome¶ 7 (11.1) 13 (8.6) 1.51 (0.60 to 3.78) .38 1.00 (0.35 to 2.84) 1.00 7 (8.4) 13 (6.9) 1.51 (0.60 to 3.78) .38 0.98 (0.35 to 2.77) .98   Trisomy 16 0 (0.0) 1 (0.7) — — — — 0 (0.0) 1 (0.5) — — — —   Trisomy 14# 0 (0.0) 1 (0.7) — — — — 0 (0.0) 1 (0.5) — — — —  Sex chromosome abnormalities   Klinefelter syndrome** 9 (14.3) 7 (4.6) 3.60 (1.34 to 9.66) .01 2.72 (0.99 to 7.47) .05 9 (10.9) 7 (3.7) 3.60 (1.34 to 9.66) .01 2.70 (0.98 to 7.41) .05   Turner syndrome†† 5 (7.9) 16 (10.5) 0.87 (0.32 to 2.39) .79 0.98 (0.35 to 2.78) .97 5 (6.0) 16 (8.5) 0.87 (0.32 to 2.39) .79 1.00 (0.40 to 2.83) 1.00   Triple X syndrome 1 (1.6) 2 (1.3) — — — — 1 (1.2) 2 (1.1) — — — —   Double Y syndrome 0 (0.0) 8 (5.2) — — — — 0 (0.0) 8 (4.3) — — — —   Male turner‡‡ 1 (1.6) 2 (1.3) — — — — 1 (1.2) 2 (1.1) — — — —   XX-male§§ 0 (0.0) 1 (0.7) — — — — 0 (0.0) 1 (0.5) — — — —   Triploidy 1 (1.6) 6 (3.9) — — — — 1 (1.2) 6 (3.2) — — — — Structural abnormalities 11 (17.5) 33 (21.7) 0.93 (0.47 to 1.85) .84 0.90 (0.45 to 1.81) .77 31 (37.3) 67 (35.6) 1.30 (0.85 to 1.98) .23 1.19 (0.77 to 1.84) .43  Reciprocal translocation 3 (4.8) 6 (3.9) — — — — 13 (15.7) 21 (11.2) — — — —  Robertsonian translocation 1 (1.6) 1 (0.7) — — — — 5 (6.0) 7 (3.7) — — — —  Deletion 3 (4.8) 13 (8.6) — — — — 4 (4.8) 13 (6.9) — — — —  Ring chromosome 1 (1.6) 3 (2.0) — — — — 1 (1.2) 3 (1.6) — — — —  Duplication 0 (0.0) 6 (3.9) — — — — 0 (0.0) 6 (3.2) — — — —  Inversion 2 (3.1) 2 (1.3) — — — — 7 (8.4) 12 (6.4) — — — —  Marker chromosome 0 (0.0) 1 (0.7) — — — — 0 (0.0) 4 (2.1) — — — —  Derivative chromosome 0 (0.0) 1 (0.7) — — — — 0 (0.0) 1 (0.5) — — — —  Isochromosome 1 (1.6) 0 (0.0) — — — — 1 (1.2) 0 (0.0) — — — — * Offspring are defined as fetuses and live-born children. A total of 83 offspring (including 31 fetuses) of survivors were identified with a chromosomal abnormality; of those, 20 hereditary cases (ie, same abnormal karyotype in parent and offspring, and thus not the result of a new mutation that might be related to preconception cancer treatment in the parent) were excluded. Among offspring of siblings, 188 cases (including 65 fetuses) were detected; of these, 36 hereditary cases were excluded. These hereditary cases were all structural abnormalities except two cases of Down syndrome (among offspring of siblings). In the survivor cohort, the number of terminated cases with Down syndrome was 12, one with Turner syndrome, seven with Edward syndrome, and one with Patau syndrome, resulting in an adjusted live-born rate of 12.4. The remaining 10 terminated cases counted for one live-born offspring each, as there is no strong evidence for an excess risk for these abnormalities (7). In the sibling cohort, the number of terminated cases with Down syndrome was 23, five with Turner, nine with Edward, and three with Patau syndrome, resulting in an adjusted live-born rate of 23.9. The remaining 25 terminated cases counted for one live-born offspring each. After exclusion of hereditary cases and inclusion of prenatal cases and after correction for expected viability, the adjusted proportion of live-born children with chromosomal abnormalities in the survivor cohort was 0.37% ((32 live born + 12.4 adjusted prenatal cases + 10 nonadjusted prenatal cases)/(14 580 live born + 12.4 adjusted terminated prenatal cases + 10 nonadjusted prenatal cases) × 100) vs an adjusted proportion of 0.33% in the sibling cohort ((84 + 23.9 + 25)/(40 794 + 23.9 + 25) × 100). Inclusion of the hereditary cases also resulted in similar proportions in the two cohorts, that is, 0.51% and 0.42% among survivors and siblings, respectively. Empty cells with em dash: No risk estimate calculated as there were very few outcomes. † Adjusted for maternal age and sex of the child. ‡ Two-sided P value calculated by Wald test. § Of the 84 cases with Down syndrome (47,XX/XY+21), two cases had Robertsonian translocations (not counted under “structural abnormalities”): 46,XY, der(14;21) (q10;q10),+21 and 46,XY, der(21;21) (q10;q10); and two cases had mosaic Down syndrome: 46,XX/47,XX,+21 and 47,XX,+21/48,XX,+8,+21. ‖ Of the eight cases with Patau syndrome (47,XX/XY+13), two cases had Robertsonian translocations (not counted under “structural abnormalities”): 46,XX,der(13;14) (q10;q10),+13 and 46,XY,der(13;14) (q10;q10)+13. ¶ Of the 20 cases with Edward syndrome (47,XX/XY+18), one case had mosaic Edward syndrome: 46,XX/47,XX,+18. # The case with Trisomy 14 was a mosaic Trisomy 14: 46,XX/47,XX,+14. ** Of the 16 cases with Klinefelter syndrome (47,XXY or 49,XXXXY), two cases had mosaic Klinefelter syndrome: 46,XY/47,XXY and 46,XY/47,XXY. †† Of the 21 cases with Turner syndrome (45,X), five cases had mosaic isochromosome Turner syndrome: three of 46,XX/46,X,i(X)(q10) and two 46,XX/46,X,i(X); and one case had mosaic marker Turner syndrome: 45,X/46,X,+mar. ‡‡ The cases with Male Turner syndrome had mosaic Male Turner syndrome: 45,X/46,XY. §§ The XX male had an unbalanced X,Y translocation: 46,X,der(X),t(X;Y)(p22.2;p11.2). Table 2. Risk of nonhereditary chromosomal abnormalities among 14 591 offspring of 8945 cancer survivors by parental treatment with radiation and by radiation dose to ovary and testis received by parent in a subcohort of 860 survivors with estimated gonadal dose Parental treatment with radiation No. of survivors No. of survivors’ offspring* Offspring with chromosomal abnormalities* OR (95% CI)† P‡ Radiation treatment (from Danish Cancer Registry) 8945 14 591 63 – –  No 6604 10 690 50 1.00 (reference) –  Yes 2215 3710 13 0.75 (0.41 to 1.35) .35  Unknown 126 191 – – – Parental gonadal dose, Gy 860 1745 12 – –  Male survivors 496 991 8 – –   Testicular dose (mean = 0.95, range = 0.001–43.2 for those irradiated)    0 (nonirradiated) 127 297 1 1.00 (reference) –    >0 to < 0.50 213 410 3 2.18 (0.23 to 21.08) .50    ≥0.50 129 224 4 5.38 (0.60 to 48.49) .13    Unknown§ 27 60 – – –    Continuous dose per Gy‖ 342 634 – 0.97 (0.67 to 1.41) .89  Female survivors 364 754 4 – –   Ovarian minimum dose (mean = 0.91, range = 0.001–50 for those irradiated)    0 (nonirradiated) 143 321 2 1.00 (reference) –    >0 to < 0.50 149 281 2 1.14 (0.16 to 8.17) .89    ≥0.50 50 92 0 – –    Unknown§ 22 60 – – –    Continuous dose per 0.01 Gy‖ 199 373 – 0.37 (0.08 to 1.76) .21 Parental treatment with radiation No. of survivors No. of survivors’ offspring* Offspring with chromosomal abnormalities* OR (95% CI)† P‡ Radiation treatment (from Danish Cancer Registry) 8945 14 591 63 – –  No 6604 10 690 50 1.00 (reference) –  Yes 2215 3710 13 0.75 (0.41 to 1.35) .35  Unknown 126 191 – – – Parental gonadal dose, Gy 860 1745 12 – –  Male survivors 496 991 8 – –   Testicular dose (mean = 0.95, range = 0.001–43.2 for those irradiated)    0 (nonirradiated) 127 297 1 1.00 (reference) –    >0 to < 0.50 213 410 3 2.18 (0.23 to 21.08) .50    ≥0.50 129 224 4 5.38 (0.60 to 48.49) .13    Unknown§ 27 60 – – –    Continuous dose per Gy‖ 342 634 – 0.97 (0.67 to 1.41) .89  Female survivors 364 754 4 – –   Ovarian minimum dose (mean = 0.91, range = 0.001–50 for those irradiated)    0 (nonirradiated) 143 321 2 1.00 (reference) –    >0 to < 0.50 149 281 2 1.14 (0.16 to 8.17) .89    ≥0.50 50 92 0 – –    Unknown§ 22 60 – – –    Continuous dose per 0.01 Gy‖ 199 373 – 0.37 (0.08 to 1.76) .21 * Including fetal abnormalities and excluding hereditary cases resulted in 14 591 offspring (14 580 live-born and 11 fetuses). † The risk estimate calculated for radiation (yes/no) was adjusted for maternal age and sex of the child. Because of the low numbers of affected offspring in the separate categories of parental doses to the gonads, no adjustment was made for these risk estimates. ‡ Two-sided P value calculated by Wald test. § Doses could not be estimated because of incomplete information in the medical records. ‖ Radiation dose to the gonads treated as a continuous variable per unit Gy; Continuous dose per Gy for testicular dose and per 0.01 Gy for ovarian minimum dose. Table 2. Risk of nonhereditary chromosomal abnormalities among 14 591 offspring of 8945 cancer survivors by parental treatment with radiation and by radiation dose to ovary and testis received by parent in a subcohort of 860 survivors with estimated gonadal dose Parental treatment with radiation No. of survivors No. of survivors’ offspring* Offspring with chromosomal abnormalities* OR (95% CI)† P‡ Radiation treatment (from Danish Cancer Registry) 8945 14 591 63 – –  No 6604 10 690 50 1.00 (reference) –  Yes 2215 3710 13 0.75 (0.41 to 1.35) .35  Unknown 126 191 – – – Parental gonadal dose, Gy 860 1745 12 – –  Male survivors 496 991 8 – –   Testicular dose (mean = 0.95, range = 0.001–43.2 for those irradiated)    0 (nonirradiated) 127 297 1 1.00 (reference) –    >0 to < 0.50 213 410 3 2.18 (0.23 to 21.08) .50    ≥0.50 129 224 4 5.38 (0.60 to 48.49) .13    Unknown§ 27 60 – – –    Continuous dose per Gy‖ 342 634 – 0.97 (0.67 to 1.41) .89  Female survivors 364 754 4 – –   Ovarian minimum dose (mean = 0.91, range = 0.001–50 for those irradiated)    0 (nonirradiated) 143 321 2 1.00 (reference) –    >0 to < 0.50 149 281 2 1.14 (0.16 to 8.17) .89    ≥0.50 50 92 0 – –    Unknown§ 22 60 – – –    Continuous dose per 0.01 Gy‖ 199 373 – 0.37 (0.08 to 1.76) .21 Parental treatment with radiation No. of survivors No. of survivors’ offspring* Offspring with chromosomal abnormalities* OR (95% CI)† P‡ Radiation treatment (from Danish Cancer Registry) 8945 14 591 63 – –  No 6604 10 690 50 1.00 (reference) –  Yes 2215 3710 13 0.75 (0.41 to 1.35) .35  Unknown 126 191 – – – Parental gonadal dose, Gy 860 1745 12 – –  Male survivors 496 991 8 – –   Testicular dose (mean = 0.95, range = 0.001–43.2 for those irradiated)    0 (nonirradiated) 127 297 1 1.00 (reference) –    >0 to < 0.50 213 410 3 2.18 (0.23 to 21.08) .50    ≥0.50 129 224 4 5.38 (0.60 to 48.49) .13    Unknown§ 27 60 – – –    Continuous dose per Gy‖ 342 634 – 0.97 (0.67 to 1.41) .89  Female survivors 364 754 4 – –   Ovarian minimum dose (mean = 0.91, range = 0.001–50 for those irradiated)    0 (nonirradiated) 143 321 2 1.00 (reference) –    >0 to < 0.50 149 281 2 1.14 (0.16 to 8.17) .89    ≥0.50 50 92 0 – –    Unknown§ 22 60 – – –    Continuous dose per 0.01 Gy‖ 199 373 – 0.37 (0.08 to 1.76) .21 * Including fetal abnormalities and excluding hereditary cases resulted in 14 591 offspring (14 580 live-born and 11 fetuses). † The risk estimate calculated for radiation (yes/no) was adjusted for maternal age and sex of the child. Because of the low numbers of affected offspring in the separate categories of parental doses to the gonads, no adjustment was made for these risk estimates. ‡ Two-sided P value calculated by Wald test. § Doses could not be estimated because of incomplete information in the medical records. ‖ Radiation dose to the gonads treated as a continuous variable per unit Gy; Continuous dose per Gy for testicular dose and per 0.01 Gy for ovarian minimum dose. Our previous study (8) identified only eight cancer survivors with at least one live-born or fetus with an abnormality. Expanding the study period from 1996 to 2002 and including young adult cancer survivors nearly doubled the number of cancer survivors and increased the number of chromosomal abnormalities among their children by eight-fold. The results are more statistically powerful, and reaching the same conclusion is reassuring. Previous studies examining other health indicators of a possible mutagenic effect of cancer therapy passed on to offspring, such as single-gene disorders (purely genetic diseases) (9) and congenital malformations (less genetic), report the same reassuring findings (10–12), as did the study of children of the Japanese atomic bomb survivors (13). Our study has several potential limitations. Germ-cell mutations, especially chromosomal, might lead to spontaneous abortion in early gestation, when women are not aware of a pregnancy and therefore not registered with a miscarriage. Some fatal chromosomal abnormalities might have been missed in any early aborted fetuses. Lack of information on abnormal karyotypes in stillbirths (observed in about 13% of all stillbirths [14] but not systematically reported to the Danish Cytogenetic Registry) might have resulted in an underestimate of chromosomal abnormalities. Only 25% of adult males with Klinefelter syndrome are diagnosed, and fewer than 10% are diagnosed before puberty (15,16). The number of survivors’ offspring with Klinefelter syndrome was similar to that expected in the general population, whereas the number in siblings was considerably lower than expected. The borderline increased risk of Klinefelter syndrome in survivors’ offspring might be due to small numbers, sampling variation, or chance due to multiple comparisons. Also, Turner syndrome might not be recognized in childhood (17). Strengths include identification of all cancer survivors from the Danish Cancer Registry including adolescents and young adults and unbiased identification of siblings and children through linkage to the CPR and of affected offspring in the Danish Cytogenetic Registry. These reassuring findings for cancer survivors who are able to have children indicate that nonhereditary cancer and cancer treatments do not result in transmissible cytogenetic abnormalities in human germ cells. Note We thank programmer Jan Hansen of the Danish Cytogenetic Registry for data extraction. References 1 Madanat-Harjuoja LM , Pokhrel A , Kivivuori SM et al. , Childhood cancer survival in Finland (1953-2010): A nation-wide population-based study . Int J Cancer. 2014 ; 135 ( 9 ): 2129 – 2134 . Google Scholar CrossRef Search ADS PubMed 2 Gatta G , Zigon G , Capocaccia R et al. , Survival of European children and young adults with cancer diagnosed 1995-2002 . Eur J Cancer. 2009 ; 45 ( 6 ): 992 – 1005 . http://dx.doi.org/10.1016/j.ejca.2008.11.042 Google Scholar CrossRef Search ADS PubMed 3 Schmidt R , Richter D , Sender A et al. , Motivations for having children after cancer - a systematic review of the literature . Eur J Cancer Care (Engl). 2016 ; 25 ( 1 ): 6 – 17 . http://dx.doi.org/10.1111/ecc.12276 Google Scholar CrossRef Search ADS PubMed 4 Mughal SK , Myazin AE , Zhavoronkov LP et al. , The dose and dose-rate effects of paternal irradiation on transgenerational instability in mice: A radiotherapy connection . PLoS One. 2012 ; 7 ( 7 ): e41300 . Google Scholar CrossRef Search ADS PubMed 5 Glen CD , Dubrova YE. Exposure to anticancer drugs can result in transgenerational genomic instability in mice . Proc Natl Acad Sci U S A. 2012 ; 109 ( 8 ): 2984 – 2988 . http://dx.doi.org/10.1073/pnas.1119396109 Google Scholar CrossRef Search ADS PubMed 6 Stovall M , Donaldson SS , Weathers RE et al. , Genetic effects of radiotherapy for childhood cancer: Gonadal dose reconstruction . Int J Radiat Oncol Biol Phys. 2004 ; 60 ( 2 ): 542 – 552 . http://dx.doi.org/10.1016/j.ijrobp.2004.03.017 Google Scholar CrossRef Search ADS PubMed 7 Hook EB , Topol BB , Cross PK. The natural history of cytogenetically abnormal fetuses detected at midtrimester amniocentesis which are not terminated electively: New data and estimates of the excess and relative risk of late fetal death associated with 47,+21 and some other abnormal karyotypes . Am J Hum Genet. 1989 ; 45 ( 6 ): 855 – 861 . Google Scholar PubMed 8 Winther JF , Boice JD Jr , Mulvihill JJ et al. , Chromosomal abnormalities among offspring of childhood-cancer survivors in Denmark: A population-based study . Am J Hum Genet. 2004 ; 74 ( 6 ): 1282 – 1285 . http://dx.doi.org/10.1086/421473 Google Scholar CrossRef Search ADS PubMed 9 Mulvihill JJ , Byrne J. Genetic counseling for the cancer survivor: Possible germ cell effects of cancer therapy. In: Green DM , D’Angio GJ , eds. Late Effects of Treatment for Childhood Cancer. New York : Wiley-Liss ; 1992 : 113 – 120 . 10 Byrne J , Rasmussen SA , Steinhorn SC et al. , Genetic disease in offspring of long-term survivors of childhood and adolescent cancer . Am J Hum Genet. 1998 ; 62 ( 1 ): 45 – 52 . http://dx.doi.org/10.1086/301677 Google Scholar CrossRef Search ADS PubMed 11 Winther JF , Olsen JH , Wu H et al. , Genetic disease in the children of Danish survivors of childhood and adolescent cancer . J Clin Oncol. 2012 ; 30 ( 1 ): 27 – 33 . http://dx.doi.org/10.1200/JCO.2011.35.0504 Google Scholar CrossRef Search ADS PubMed 12 Signorello LB , Mulvihill JJ , Green DM et al. , Congenital anomalies in the children of cancer survivors: A report from the childhood cancer survivor study . J Clin Oncol. 2012 ; 30 ( 3 ): 239 – 245 . http://dx.doi.org/10.1200/JCO.2011.37.2938 Google Scholar CrossRef Search ADS PubMed 13 Schull WJ. The children of atomic bomb survivors: A synopsis . J Radiol Prot. 2003 ; 23 ( 4 ): 369 – 384 . http://dx.doi.org/10.1088/0952-4746/23/4/R302 Google Scholar CrossRef Search ADS PubMed 14 Korteweg FJ , Bouman K , Erwich JJ et al. , Cytogenetic analysis after evaluation of 750 fetal deaths: Proposal for diagnostic workup . Obstet Gynecol. 2008 ; 111 ( 4 ): 865 – 874 . http://dx.doi.org/10.1097/AOG.0b013e31816a4ee3 Google Scholar CrossRef Search ADS PubMed 15 Bojesen A , Juul S , Gravholt CH. Prenatal and postnatal prevalence of Klinefelter syndrome: A national registry study . J Clin Endocrinol Metab. 2003 ; 88 ( 2 ): 622 – 626 . http://dx.doi.org/10.1210/jc.2002-021491 Google Scholar CrossRef Search ADS PubMed 16 Abramsky L , Chapple J. 47,XXY (Klinefelter syndrome) and 47,XYY: Estimated rates of and indication for postnatal diagnosis with implications for prenatal counselling . Prenat Diagn. 1997 ; 17 ( 4 ): 363 – 368 . http://dx.doi.org/10.1002/(SICI)1097-0223(199704)17:4<363::AID-PD79>3.0.CO;2-O Google Scholar CrossRef Search ADS PubMed 17 Sybert VP , McCauley E. Turner's syndrome . N Engl J Med. 2004 ; 351 ( 12 ): 1227 – 1238 . http://dx.doi.org/10.1056/NEJMra030360 Google Scholar CrossRef Search ADS PubMed © The Author 2017. Published by Oxford University Press. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com. This article is published and distributed under the terms of the Oxford University Press, Standard Journals Publication Model (https://academic.oup.com/journals/pages/about_us/legal/notices) http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png JNCI: Journal of the National Cancer Institute Oxford University Press

Chromosomal Abnormalities in Offspring of Young Cancer Survivors: A Population-Based Cohort Study in Denmark

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Oxford University Press
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© The Author 2017. Published by Oxford University Press. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.
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0027-8874
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1460-2105
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10.1093/jnci/djx248
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Abstract

Abstract To examine whether cancer survivors diagnosed before age 35 years are more likely to have offspring with chromosomal abnormalities than their siblings, chromosomal abnormalities were determined in a population-based cohort of 14 611 offspring (14 580 live-born children and 31 fetuses) of 8945 Danish cancer survivors and 40 859 offspring (40 794 live-born children and 65 fetuses) of 19 536 siblings. Chromosomal abnormalities include numeric and structural abnormalities. Odds ratios were estimated by multiple logistic regression models comparing the risk of chromosomal abnormalities among survivors’ offspring with that in siblings’ offspring. In a subgroup of survivors with gonadal radiation doses (mean = 0.95 Gy for males and 0.91 Gy for females), no indication of a dose response was found. Overall, no increased risk of chromosomal abnormalities among survivors’ offspring was observed compared with their siblings’ offspring (odds ratio = 0.99, 95% confidence interval = 0.67 to 1.44, two-sided P = .94), with similar risk between male and female survivors. Cancer survivors were not more likely than their siblings to have children with a chromosomal abnormality. The overall five-year survival rate among cancer survivors diagnosed before age 35 years has increased as a consequence of improved cancer treatment and now approaches 80% (1,2). The growing cohort of cancer survivors worry about whether their children will be healthy or be born with a congenital malformation or a genetic condition related to their cancer or treatment (3). These concerns are plausible as radiation and certain chemotherapeutics are potent germ cell mutagens, which in mice lead to genetic disease in the next generation (4,5). In a nationwide population-based cohort study, we evaluated whether preconception cancer treatments in childhood, adolescence, and young adulthood cause transgenerational germ cell mutations seen as chromosomal abnormalities in offspring (defined as a fetus or a live-born child) conceived after treatment. In the nationwide and population-based Danish Cancer Registry, we identified 8945 cancer survivors (56.2% males) diagnosed before age 35 years in 1943–2002 (80.3% were older than age 20 years) who were alive on or born after April 1, 1968, when the national Central Population Register (CPR) was established, and who had a child in Denmark conceived at least nine months after diagnosis. A total of 14 580 live-born children (7468 boys, 7112 girls) were identified from the CPR. Similar linkages identified 19 536 siblings of survivors (48.6% males) and their 40 794 live-born children (20 850 boys, 19 944 girls), providing the comparison cohort. A search for chromosomal abnormalities in the Danish Cytogenetic Registry from 1960 through 2007, including data on all abnormal karyotypes for fetuses or live-born children and their parents, if tested, resulted in 52 live-born children and 31 fetuses of 8945 survivors and 123 children and 65 fetuses of 19 536 siblings identified with a chromosomal abnormality. Adding the number of fetuses to the live-born children in each of the two cohorts resulted in 14 611 offspring of cancer survivors and 40 859 offspring of siblings. Information on radiotherapy (yes/no) was extracted from the Danish Cancer Registry on the entire survivor cohort. In a subgroup of 860 cancer survivors, it was possible to estimate gonadal radiation doses at the MD Anderson Cancer Center (Houston, TX) based on information from medical records including radiation beam energies and position and documented procedures to reduce gonadal dose. Radiation dose outside the treatment beam was measured using a three-dimensional water phantom simulating the size of a person at the age of radiotherapy (6). If the same karyotype was known to be present in one or both parents, the case was classified as hereditary. To include the prenatally diagnosed and terminated cases (ie, fetuses) when estimating the proportion of live-born children, these cases were adjusted for viability using the following survival probabilities: 0.74 for Down syndrome, 0.35 for Turner syndrome, 0.36 for Edward syndrome, 0.63 for Patau syndrome (7). These estimates were calculated to compare the adjusted proportion of live-born children affected in survivor families with sibling families. A logistic regression model estimating odds ratios (ORs) with 95% confidence intervals (CIs) was used to compare the risk of chromosomal abnormalities among survivors’ offspring with that in siblings’ offspring adjusting for maternal age and sex of the child. Statistical significance was defined as a two-sided P value of less than .05. In 860 survivors with gonadal radiation doses estimated, a dose-response analysis was conducted to evaluate the association between gonadal radiation dose and the risk of chromosomal abnormalities. We computed a Ptrend by treating radiation dose to the gonads as a continuous variable. After excluding 56 hereditary cytogenetic cases, 63 survivors’ offspring and 152 siblings’ offspring were identified with a chromosomal abnormality (Table 1). The viability-adjusted live-born proportions of offspring with abnormalities were similar between survivors (0.37%) and siblings (0.33%). The adjusted OR did not indicate an increased risk of abnormalities among survivors’ offspring compared with that in siblings’ offspring (OR = 0.99, 95% CI = 0.67 to 1.44, P = .94). The risk of Klinefelter syndrome was increased among cancer survivors’ offspring (ORadj = 2.72, 95% CI = 0.99 to 7.47, P = .05). No indication of a dose response was found between gonadal radiation dose (mean = 0.95 Gy for males and 0.91 Gy for females) and risk of chromosomal abnormalities in the offspring (Table 2). The risk of having an offspring affected was similar between male and female survivors (OR = 1.25, 95% CI = 0.80 to 1.95, P = .33; not shown). Table 1. Crude and adjusted odds ratios of chromosomal abnormalities among offspring of 8945 survivors vs offspring of 19 536 siblings (with and without hereditary cases) Abnormal karyotypes Hereditary cases excluded* Hereditary cases included Chromosomal abnormalities Crude analysis Adjusted analysis† Chromosomal abnormalities Crude analysis Adjusted analysis† Offspring of survivors, No. (%) Offspring of siblings, No. (%) OR (95% CI) P‡ OR (95% CI) P‡ Offspring of survivors, No. (%) Offspring of siblings, No. (%) OR (95% CI) P‡ OR (95% CI) P‡ Total/overall risk 63 (100) 152 (100) 1.16 (0.86 to 1.56) .32 0.99 (0.67 to 1.44) .94 83 (100) 188 (100) 1.24 (0.95 to 1.60) .11 1.09 (0.80 to 1.50) .58 Numeric abnormalities 52 (82.5) 119 (78.3) 1.22 (0.88 to 1.70) .23 1.03 (0.67 to 1.57) .91 52 (62.7) 121 (64.4) 1.20 (0.87 to 1.67) .27 1.00 (0.66 to 1.53) .98  Autosomal abnormalities   Down syndrome§ 25 (39.6) 57 (37.5) 1.23 (0.77 to 1.97) .39 1.04 (0.62 to 1.78) .88 25 (30.2) 59 (31.4) 1.19 (0.74 to 1.89) .48 1.00 (0.60 to 1.67) .34   Patau syndrome‖ 3 (4.8) 5 (3.3) 1.68 (0.40 to 7.03) .48 1.56 (0.36 to 6.77) .55 3 (3.6) 5 (2.7) 1.68 (0.40 to 7.02) .48 1.58 (0.36 to 6.85) .55   Edward syndrome¶ 7 (11.1) 13 (8.6) 1.51 (0.60 to 3.78) .38 1.00 (0.35 to 2.84) 1.00 7 (8.4) 13 (6.9) 1.51 (0.60 to 3.78) .38 0.98 (0.35 to 2.77) .98   Trisomy 16 0 (0.0) 1 (0.7) — — — — 0 (0.0) 1 (0.5) — — — —   Trisomy 14# 0 (0.0) 1 (0.7) — — — — 0 (0.0) 1 (0.5) — — — —  Sex chromosome abnormalities   Klinefelter syndrome** 9 (14.3) 7 (4.6) 3.60 (1.34 to 9.66) .01 2.72 (0.99 to 7.47) .05 9 (10.9) 7 (3.7) 3.60 (1.34 to 9.66) .01 2.70 (0.98 to 7.41) .05   Turner syndrome†† 5 (7.9) 16 (10.5) 0.87 (0.32 to 2.39) .79 0.98 (0.35 to 2.78) .97 5 (6.0) 16 (8.5) 0.87 (0.32 to 2.39) .79 1.00 (0.40 to 2.83) 1.00   Triple X syndrome 1 (1.6) 2 (1.3) — — — — 1 (1.2) 2 (1.1) — — — —   Double Y syndrome 0 (0.0) 8 (5.2) — — — — 0 (0.0) 8 (4.3) — — — —   Male turner‡‡ 1 (1.6) 2 (1.3) — — — — 1 (1.2) 2 (1.1) — — — —   XX-male§§ 0 (0.0) 1 (0.7) — — — — 0 (0.0) 1 (0.5) — — — —   Triploidy 1 (1.6) 6 (3.9) — — — — 1 (1.2) 6 (3.2) — — — — Structural abnormalities 11 (17.5) 33 (21.7) 0.93 (0.47 to 1.85) .84 0.90 (0.45 to 1.81) .77 31 (37.3) 67 (35.6) 1.30 (0.85 to 1.98) .23 1.19 (0.77 to 1.84) .43  Reciprocal translocation 3 (4.8) 6 (3.9) — — — — 13 (15.7) 21 (11.2) — — — —  Robertsonian translocation 1 (1.6) 1 (0.7) — — — — 5 (6.0) 7 (3.7) — — — —  Deletion 3 (4.8) 13 (8.6) — — — — 4 (4.8) 13 (6.9) — — — —  Ring chromosome 1 (1.6) 3 (2.0) — — — — 1 (1.2) 3 (1.6) — — — —  Duplication 0 (0.0) 6 (3.9) — — — — 0 (0.0) 6 (3.2) — — — —  Inversion 2 (3.1) 2 (1.3) — — — — 7 (8.4) 12 (6.4) — — — —  Marker chromosome 0 (0.0) 1 (0.7) — — — — 0 (0.0) 4 (2.1) — — — —  Derivative chromosome 0 (0.0) 1 (0.7) — — — — 0 (0.0) 1 (0.5) — — — —  Isochromosome 1 (1.6) 0 (0.0) — — — — 1 (1.2) 0 (0.0) — — — — Abnormal karyotypes Hereditary cases excluded* Hereditary cases included Chromosomal abnormalities Crude analysis Adjusted analysis† Chromosomal abnormalities Crude analysis Adjusted analysis† Offspring of survivors, No. (%) Offspring of siblings, No. (%) OR (95% CI) P‡ OR (95% CI) P‡ Offspring of survivors, No. (%) Offspring of siblings, No. (%) OR (95% CI) P‡ OR (95% CI) P‡ Total/overall risk 63 (100) 152 (100) 1.16 (0.86 to 1.56) .32 0.99 (0.67 to 1.44) .94 83 (100) 188 (100) 1.24 (0.95 to 1.60) .11 1.09 (0.80 to 1.50) .58 Numeric abnormalities 52 (82.5) 119 (78.3) 1.22 (0.88 to 1.70) .23 1.03 (0.67 to 1.57) .91 52 (62.7) 121 (64.4) 1.20 (0.87 to 1.67) .27 1.00 (0.66 to 1.53) .98  Autosomal abnormalities   Down syndrome§ 25 (39.6) 57 (37.5) 1.23 (0.77 to 1.97) .39 1.04 (0.62 to 1.78) .88 25 (30.2) 59 (31.4) 1.19 (0.74 to 1.89) .48 1.00 (0.60 to 1.67) .34   Patau syndrome‖ 3 (4.8) 5 (3.3) 1.68 (0.40 to 7.03) .48 1.56 (0.36 to 6.77) .55 3 (3.6) 5 (2.7) 1.68 (0.40 to 7.02) .48 1.58 (0.36 to 6.85) .55   Edward syndrome¶ 7 (11.1) 13 (8.6) 1.51 (0.60 to 3.78) .38 1.00 (0.35 to 2.84) 1.00 7 (8.4) 13 (6.9) 1.51 (0.60 to 3.78) .38 0.98 (0.35 to 2.77) .98   Trisomy 16 0 (0.0) 1 (0.7) — — — — 0 (0.0) 1 (0.5) — — — —   Trisomy 14# 0 (0.0) 1 (0.7) — — — — 0 (0.0) 1 (0.5) — — — —  Sex chromosome abnormalities   Klinefelter syndrome** 9 (14.3) 7 (4.6) 3.60 (1.34 to 9.66) .01 2.72 (0.99 to 7.47) .05 9 (10.9) 7 (3.7) 3.60 (1.34 to 9.66) .01 2.70 (0.98 to 7.41) .05   Turner syndrome†† 5 (7.9) 16 (10.5) 0.87 (0.32 to 2.39) .79 0.98 (0.35 to 2.78) .97 5 (6.0) 16 (8.5) 0.87 (0.32 to 2.39) .79 1.00 (0.40 to 2.83) 1.00   Triple X syndrome 1 (1.6) 2 (1.3) — — — — 1 (1.2) 2 (1.1) — — — —   Double Y syndrome 0 (0.0) 8 (5.2) — — — — 0 (0.0) 8 (4.3) — — — —   Male turner‡‡ 1 (1.6) 2 (1.3) — — — — 1 (1.2) 2 (1.1) — — — —   XX-male§§ 0 (0.0) 1 (0.7) — — — — 0 (0.0) 1 (0.5) — — — —   Triploidy 1 (1.6) 6 (3.9) — — — — 1 (1.2) 6 (3.2) — — — — Structural abnormalities 11 (17.5) 33 (21.7) 0.93 (0.47 to 1.85) .84 0.90 (0.45 to 1.81) .77 31 (37.3) 67 (35.6) 1.30 (0.85 to 1.98) .23 1.19 (0.77 to 1.84) .43  Reciprocal translocation 3 (4.8) 6 (3.9) — — — — 13 (15.7) 21 (11.2) — — — —  Robertsonian translocation 1 (1.6) 1 (0.7) — — — — 5 (6.0) 7 (3.7) — — — —  Deletion 3 (4.8) 13 (8.6) — — — — 4 (4.8) 13 (6.9) — — — —  Ring chromosome 1 (1.6) 3 (2.0) — — — — 1 (1.2) 3 (1.6) — — — —  Duplication 0 (0.0) 6 (3.9) — — — — 0 (0.0) 6 (3.2) — — — —  Inversion 2 (3.1) 2 (1.3) — — — — 7 (8.4) 12 (6.4) — — — —  Marker chromosome 0 (0.0) 1 (0.7) — — — — 0 (0.0) 4 (2.1) — — — —  Derivative chromosome 0 (0.0) 1 (0.7) — — — — 0 (0.0) 1 (0.5) — — — —  Isochromosome 1 (1.6) 0 (0.0) — — — — 1 (1.2) 0 (0.0) — — — — * Offspring are defined as fetuses and live-born children. A total of 83 offspring (including 31 fetuses) of survivors were identified with a chromosomal abnormality; of those, 20 hereditary cases (ie, same abnormal karyotype in parent and offspring, and thus not the result of a new mutation that might be related to preconception cancer treatment in the parent) were excluded. Among offspring of siblings, 188 cases (including 65 fetuses) were detected; of these, 36 hereditary cases were excluded. These hereditary cases were all structural abnormalities except two cases of Down syndrome (among offspring of siblings). In the survivor cohort, the number of terminated cases with Down syndrome was 12, one with Turner syndrome, seven with Edward syndrome, and one with Patau syndrome, resulting in an adjusted live-born rate of 12.4. The remaining 10 terminated cases counted for one live-born offspring each, as there is no strong evidence for an excess risk for these abnormalities (7). In the sibling cohort, the number of terminated cases with Down syndrome was 23, five with Turner, nine with Edward, and three with Patau syndrome, resulting in an adjusted live-born rate of 23.9. The remaining 25 terminated cases counted for one live-born offspring each. After exclusion of hereditary cases and inclusion of prenatal cases and after correction for expected viability, the adjusted proportion of live-born children with chromosomal abnormalities in the survivor cohort was 0.37% ((32 live born + 12.4 adjusted prenatal cases + 10 nonadjusted prenatal cases)/(14 580 live born + 12.4 adjusted terminated prenatal cases + 10 nonadjusted prenatal cases) × 100) vs an adjusted proportion of 0.33% in the sibling cohort ((84 + 23.9 + 25)/(40 794 + 23.9 + 25) × 100). Inclusion of the hereditary cases also resulted in similar proportions in the two cohorts, that is, 0.51% and 0.42% among survivors and siblings, respectively. Empty cells with em dash: No risk estimate calculated as there were very few outcomes. † Adjusted for maternal age and sex of the child. ‡ Two-sided P value calculated by Wald test. § Of the 84 cases with Down syndrome (47,XX/XY+21), two cases had Robertsonian translocations (not counted under “structural abnormalities”): 46,XY, der(14;21) (q10;q10),+21 and 46,XY, der(21;21) (q10;q10); and two cases had mosaic Down syndrome: 46,XX/47,XX,+21 and 47,XX,+21/48,XX,+8,+21. ‖ Of the eight cases with Patau syndrome (47,XX/XY+13), two cases had Robertsonian translocations (not counted under “structural abnormalities”): 46,XX,der(13;14) (q10;q10),+13 and 46,XY,der(13;14) (q10;q10)+13. ¶ Of the 20 cases with Edward syndrome (47,XX/XY+18), one case had mosaic Edward syndrome: 46,XX/47,XX,+18. # The case with Trisomy 14 was a mosaic Trisomy 14: 46,XX/47,XX,+14. ** Of the 16 cases with Klinefelter syndrome (47,XXY or 49,XXXXY), two cases had mosaic Klinefelter syndrome: 46,XY/47,XXY and 46,XY/47,XXY. †† Of the 21 cases with Turner syndrome (45,X), five cases had mosaic isochromosome Turner syndrome: three of 46,XX/46,X,i(X)(q10) and two 46,XX/46,X,i(X); and one case had mosaic marker Turner syndrome: 45,X/46,X,+mar. ‡‡ The cases with Male Turner syndrome had mosaic Male Turner syndrome: 45,X/46,XY. §§ The XX male had an unbalanced X,Y translocation: 46,X,der(X),t(X;Y)(p22.2;p11.2). Table 1. Crude and adjusted odds ratios of chromosomal abnormalities among offspring of 8945 survivors vs offspring of 19 536 siblings (with and without hereditary cases) Abnormal karyotypes Hereditary cases excluded* Hereditary cases included Chromosomal abnormalities Crude analysis Adjusted analysis† Chromosomal abnormalities Crude analysis Adjusted analysis† Offspring of survivors, No. (%) Offspring of siblings, No. (%) OR (95% CI) P‡ OR (95% CI) P‡ Offspring of survivors, No. (%) Offspring of siblings, No. (%) OR (95% CI) P‡ OR (95% CI) P‡ Total/overall risk 63 (100) 152 (100) 1.16 (0.86 to 1.56) .32 0.99 (0.67 to 1.44) .94 83 (100) 188 (100) 1.24 (0.95 to 1.60) .11 1.09 (0.80 to 1.50) .58 Numeric abnormalities 52 (82.5) 119 (78.3) 1.22 (0.88 to 1.70) .23 1.03 (0.67 to 1.57) .91 52 (62.7) 121 (64.4) 1.20 (0.87 to 1.67) .27 1.00 (0.66 to 1.53) .98  Autosomal abnormalities   Down syndrome§ 25 (39.6) 57 (37.5) 1.23 (0.77 to 1.97) .39 1.04 (0.62 to 1.78) .88 25 (30.2) 59 (31.4) 1.19 (0.74 to 1.89) .48 1.00 (0.60 to 1.67) .34   Patau syndrome‖ 3 (4.8) 5 (3.3) 1.68 (0.40 to 7.03) .48 1.56 (0.36 to 6.77) .55 3 (3.6) 5 (2.7) 1.68 (0.40 to 7.02) .48 1.58 (0.36 to 6.85) .55   Edward syndrome¶ 7 (11.1) 13 (8.6) 1.51 (0.60 to 3.78) .38 1.00 (0.35 to 2.84) 1.00 7 (8.4) 13 (6.9) 1.51 (0.60 to 3.78) .38 0.98 (0.35 to 2.77) .98   Trisomy 16 0 (0.0) 1 (0.7) — — — — 0 (0.0) 1 (0.5) — — — —   Trisomy 14# 0 (0.0) 1 (0.7) — — — — 0 (0.0) 1 (0.5) — — — —  Sex chromosome abnormalities   Klinefelter syndrome** 9 (14.3) 7 (4.6) 3.60 (1.34 to 9.66) .01 2.72 (0.99 to 7.47) .05 9 (10.9) 7 (3.7) 3.60 (1.34 to 9.66) .01 2.70 (0.98 to 7.41) .05   Turner syndrome†† 5 (7.9) 16 (10.5) 0.87 (0.32 to 2.39) .79 0.98 (0.35 to 2.78) .97 5 (6.0) 16 (8.5) 0.87 (0.32 to 2.39) .79 1.00 (0.40 to 2.83) 1.00   Triple X syndrome 1 (1.6) 2 (1.3) — — — — 1 (1.2) 2 (1.1) — — — —   Double Y syndrome 0 (0.0) 8 (5.2) — — — — 0 (0.0) 8 (4.3) — — — —   Male turner‡‡ 1 (1.6) 2 (1.3) — — — — 1 (1.2) 2 (1.1) — — — —   XX-male§§ 0 (0.0) 1 (0.7) — — — — 0 (0.0) 1 (0.5) — — — —   Triploidy 1 (1.6) 6 (3.9) — — — — 1 (1.2) 6 (3.2) — — — — Structural abnormalities 11 (17.5) 33 (21.7) 0.93 (0.47 to 1.85) .84 0.90 (0.45 to 1.81) .77 31 (37.3) 67 (35.6) 1.30 (0.85 to 1.98) .23 1.19 (0.77 to 1.84) .43  Reciprocal translocation 3 (4.8) 6 (3.9) — — — — 13 (15.7) 21 (11.2) — — — —  Robertsonian translocation 1 (1.6) 1 (0.7) — — — — 5 (6.0) 7 (3.7) — — — —  Deletion 3 (4.8) 13 (8.6) — — — — 4 (4.8) 13 (6.9) — — — —  Ring chromosome 1 (1.6) 3 (2.0) — — — — 1 (1.2) 3 (1.6) — — — —  Duplication 0 (0.0) 6 (3.9) — — — — 0 (0.0) 6 (3.2) — — — —  Inversion 2 (3.1) 2 (1.3) — — — — 7 (8.4) 12 (6.4) — — — —  Marker chromosome 0 (0.0) 1 (0.7) — — — — 0 (0.0) 4 (2.1) — — — —  Derivative chromosome 0 (0.0) 1 (0.7) — — — — 0 (0.0) 1 (0.5) — — — —  Isochromosome 1 (1.6) 0 (0.0) — — — — 1 (1.2) 0 (0.0) — — — — Abnormal karyotypes Hereditary cases excluded* Hereditary cases included Chromosomal abnormalities Crude analysis Adjusted analysis† Chromosomal abnormalities Crude analysis Adjusted analysis† Offspring of survivors, No. (%) Offspring of siblings, No. (%) OR (95% CI) P‡ OR (95% CI) P‡ Offspring of survivors, No. (%) Offspring of siblings, No. (%) OR (95% CI) P‡ OR (95% CI) P‡ Total/overall risk 63 (100) 152 (100) 1.16 (0.86 to 1.56) .32 0.99 (0.67 to 1.44) .94 83 (100) 188 (100) 1.24 (0.95 to 1.60) .11 1.09 (0.80 to 1.50) .58 Numeric abnormalities 52 (82.5) 119 (78.3) 1.22 (0.88 to 1.70) .23 1.03 (0.67 to 1.57) .91 52 (62.7) 121 (64.4) 1.20 (0.87 to 1.67) .27 1.00 (0.66 to 1.53) .98  Autosomal abnormalities   Down syndrome§ 25 (39.6) 57 (37.5) 1.23 (0.77 to 1.97) .39 1.04 (0.62 to 1.78) .88 25 (30.2) 59 (31.4) 1.19 (0.74 to 1.89) .48 1.00 (0.60 to 1.67) .34   Patau syndrome‖ 3 (4.8) 5 (3.3) 1.68 (0.40 to 7.03) .48 1.56 (0.36 to 6.77) .55 3 (3.6) 5 (2.7) 1.68 (0.40 to 7.02) .48 1.58 (0.36 to 6.85) .55   Edward syndrome¶ 7 (11.1) 13 (8.6) 1.51 (0.60 to 3.78) .38 1.00 (0.35 to 2.84) 1.00 7 (8.4) 13 (6.9) 1.51 (0.60 to 3.78) .38 0.98 (0.35 to 2.77) .98   Trisomy 16 0 (0.0) 1 (0.7) — — — — 0 (0.0) 1 (0.5) — — — —   Trisomy 14# 0 (0.0) 1 (0.7) — — — — 0 (0.0) 1 (0.5) — — — —  Sex chromosome abnormalities   Klinefelter syndrome** 9 (14.3) 7 (4.6) 3.60 (1.34 to 9.66) .01 2.72 (0.99 to 7.47) .05 9 (10.9) 7 (3.7) 3.60 (1.34 to 9.66) .01 2.70 (0.98 to 7.41) .05   Turner syndrome†† 5 (7.9) 16 (10.5) 0.87 (0.32 to 2.39) .79 0.98 (0.35 to 2.78) .97 5 (6.0) 16 (8.5) 0.87 (0.32 to 2.39) .79 1.00 (0.40 to 2.83) 1.00   Triple X syndrome 1 (1.6) 2 (1.3) — — — — 1 (1.2) 2 (1.1) — — — —   Double Y syndrome 0 (0.0) 8 (5.2) — — — — 0 (0.0) 8 (4.3) — — — —   Male turner‡‡ 1 (1.6) 2 (1.3) — — — — 1 (1.2) 2 (1.1) — — — —   XX-male§§ 0 (0.0) 1 (0.7) — — — — 0 (0.0) 1 (0.5) — — — —   Triploidy 1 (1.6) 6 (3.9) — — — — 1 (1.2) 6 (3.2) — — — — Structural abnormalities 11 (17.5) 33 (21.7) 0.93 (0.47 to 1.85) .84 0.90 (0.45 to 1.81) .77 31 (37.3) 67 (35.6) 1.30 (0.85 to 1.98) .23 1.19 (0.77 to 1.84) .43  Reciprocal translocation 3 (4.8) 6 (3.9) — — — — 13 (15.7) 21 (11.2) — — — —  Robertsonian translocation 1 (1.6) 1 (0.7) — — — — 5 (6.0) 7 (3.7) — — — —  Deletion 3 (4.8) 13 (8.6) — — — — 4 (4.8) 13 (6.9) — — — —  Ring chromosome 1 (1.6) 3 (2.0) — — — — 1 (1.2) 3 (1.6) — — — —  Duplication 0 (0.0) 6 (3.9) — — — — 0 (0.0) 6 (3.2) — — — —  Inversion 2 (3.1) 2 (1.3) — — — — 7 (8.4) 12 (6.4) — — — —  Marker chromosome 0 (0.0) 1 (0.7) — — — — 0 (0.0) 4 (2.1) — — — —  Derivative chromosome 0 (0.0) 1 (0.7) — — — — 0 (0.0) 1 (0.5) — — — —  Isochromosome 1 (1.6) 0 (0.0) — — — — 1 (1.2) 0 (0.0) — — — — * Offspring are defined as fetuses and live-born children. A total of 83 offspring (including 31 fetuses) of survivors were identified with a chromosomal abnormality; of those, 20 hereditary cases (ie, same abnormal karyotype in parent and offspring, and thus not the result of a new mutation that might be related to preconception cancer treatment in the parent) were excluded. Among offspring of siblings, 188 cases (including 65 fetuses) were detected; of these, 36 hereditary cases were excluded. These hereditary cases were all structural abnormalities except two cases of Down syndrome (among offspring of siblings). In the survivor cohort, the number of terminated cases with Down syndrome was 12, one with Turner syndrome, seven with Edward syndrome, and one with Patau syndrome, resulting in an adjusted live-born rate of 12.4. The remaining 10 terminated cases counted for one live-born offspring each, as there is no strong evidence for an excess risk for these abnormalities (7). In the sibling cohort, the number of terminated cases with Down syndrome was 23, five with Turner, nine with Edward, and three with Patau syndrome, resulting in an adjusted live-born rate of 23.9. The remaining 25 terminated cases counted for one live-born offspring each. After exclusion of hereditary cases and inclusion of prenatal cases and after correction for expected viability, the adjusted proportion of live-born children with chromosomal abnormalities in the survivor cohort was 0.37% ((32 live born + 12.4 adjusted prenatal cases + 10 nonadjusted prenatal cases)/(14 580 live born + 12.4 adjusted terminated prenatal cases + 10 nonadjusted prenatal cases) × 100) vs an adjusted proportion of 0.33% in the sibling cohort ((84 + 23.9 + 25)/(40 794 + 23.9 + 25) × 100). Inclusion of the hereditary cases also resulted in similar proportions in the two cohorts, that is, 0.51% and 0.42% among survivors and siblings, respectively. Empty cells with em dash: No risk estimate calculated as there were very few outcomes. † Adjusted for maternal age and sex of the child. ‡ Two-sided P value calculated by Wald test. § Of the 84 cases with Down syndrome (47,XX/XY+21), two cases had Robertsonian translocations (not counted under “structural abnormalities”): 46,XY, der(14;21) (q10;q10),+21 and 46,XY, der(21;21) (q10;q10); and two cases had mosaic Down syndrome: 46,XX/47,XX,+21 and 47,XX,+21/48,XX,+8,+21. ‖ Of the eight cases with Patau syndrome (47,XX/XY+13), two cases had Robertsonian translocations (not counted under “structural abnormalities”): 46,XX,der(13;14) (q10;q10),+13 and 46,XY,der(13;14) (q10;q10)+13. ¶ Of the 20 cases with Edward syndrome (47,XX/XY+18), one case had mosaic Edward syndrome: 46,XX/47,XX,+18. # The case with Trisomy 14 was a mosaic Trisomy 14: 46,XX/47,XX,+14. ** Of the 16 cases with Klinefelter syndrome (47,XXY or 49,XXXXY), two cases had mosaic Klinefelter syndrome: 46,XY/47,XXY and 46,XY/47,XXY. †† Of the 21 cases with Turner syndrome (45,X), five cases had mosaic isochromosome Turner syndrome: three of 46,XX/46,X,i(X)(q10) and two 46,XX/46,X,i(X); and one case had mosaic marker Turner syndrome: 45,X/46,X,+mar. ‡‡ The cases with Male Turner syndrome had mosaic Male Turner syndrome: 45,X/46,XY. §§ The XX male had an unbalanced X,Y translocation: 46,X,der(X),t(X;Y)(p22.2;p11.2). Table 2. Risk of nonhereditary chromosomal abnormalities among 14 591 offspring of 8945 cancer survivors by parental treatment with radiation and by radiation dose to ovary and testis received by parent in a subcohort of 860 survivors with estimated gonadal dose Parental treatment with radiation No. of survivors No. of survivors’ offspring* Offspring with chromosomal abnormalities* OR (95% CI)† P‡ Radiation treatment (from Danish Cancer Registry) 8945 14 591 63 – –  No 6604 10 690 50 1.00 (reference) –  Yes 2215 3710 13 0.75 (0.41 to 1.35) .35  Unknown 126 191 – – – Parental gonadal dose, Gy 860 1745 12 – –  Male survivors 496 991 8 – –   Testicular dose (mean = 0.95, range = 0.001–43.2 for those irradiated)    0 (nonirradiated) 127 297 1 1.00 (reference) –    >0 to < 0.50 213 410 3 2.18 (0.23 to 21.08) .50    ≥0.50 129 224 4 5.38 (0.60 to 48.49) .13    Unknown§ 27 60 – – –    Continuous dose per Gy‖ 342 634 – 0.97 (0.67 to 1.41) .89  Female survivors 364 754 4 – –   Ovarian minimum dose (mean = 0.91, range = 0.001–50 for those irradiated)    0 (nonirradiated) 143 321 2 1.00 (reference) –    >0 to < 0.50 149 281 2 1.14 (0.16 to 8.17) .89    ≥0.50 50 92 0 – –    Unknown§ 22 60 – – –    Continuous dose per 0.01 Gy‖ 199 373 – 0.37 (0.08 to 1.76) .21 Parental treatment with radiation No. of survivors No. of survivors’ offspring* Offspring with chromosomal abnormalities* OR (95% CI)† P‡ Radiation treatment (from Danish Cancer Registry) 8945 14 591 63 – –  No 6604 10 690 50 1.00 (reference) –  Yes 2215 3710 13 0.75 (0.41 to 1.35) .35  Unknown 126 191 – – – Parental gonadal dose, Gy 860 1745 12 – –  Male survivors 496 991 8 – –   Testicular dose (mean = 0.95, range = 0.001–43.2 for those irradiated)    0 (nonirradiated) 127 297 1 1.00 (reference) –    >0 to < 0.50 213 410 3 2.18 (0.23 to 21.08) .50    ≥0.50 129 224 4 5.38 (0.60 to 48.49) .13    Unknown§ 27 60 – – –    Continuous dose per Gy‖ 342 634 – 0.97 (0.67 to 1.41) .89  Female survivors 364 754 4 – –   Ovarian minimum dose (mean = 0.91, range = 0.001–50 for those irradiated)    0 (nonirradiated) 143 321 2 1.00 (reference) –    >0 to < 0.50 149 281 2 1.14 (0.16 to 8.17) .89    ≥0.50 50 92 0 – –    Unknown§ 22 60 – – –    Continuous dose per 0.01 Gy‖ 199 373 – 0.37 (0.08 to 1.76) .21 * Including fetal abnormalities and excluding hereditary cases resulted in 14 591 offspring (14 580 live-born and 11 fetuses). † The risk estimate calculated for radiation (yes/no) was adjusted for maternal age and sex of the child. Because of the low numbers of affected offspring in the separate categories of parental doses to the gonads, no adjustment was made for these risk estimates. ‡ Two-sided P value calculated by Wald test. § Doses could not be estimated because of incomplete information in the medical records. ‖ Radiation dose to the gonads treated as a continuous variable per unit Gy; Continuous dose per Gy for testicular dose and per 0.01 Gy for ovarian minimum dose. Table 2. Risk of nonhereditary chromosomal abnormalities among 14 591 offspring of 8945 cancer survivors by parental treatment with radiation and by radiation dose to ovary and testis received by parent in a subcohort of 860 survivors with estimated gonadal dose Parental treatment with radiation No. of survivors No. of survivors’ offspring* Offspring with chromosomal abnormalities* OR (95% CI)† P‡ Radiation treatment (from Danish Cancer Registry) 8945 14 591 63 – –  No 6604 10 690 50 1.00 (reference) –  Yes 2215 3710 13 0.75 (0.41 to 1.35) .35  Unknown 126 191 – – – Parental gonadal dose, Gy 860 1745 12 – –  Male survivors 496 991 8 – –   Testicular dose (mean = 0.95, range = 0.001–43.2 for those irradiated)    0 (nonirradiated) 127 297 1 1.00 (reference) –    >0 to < 0.50 213 410 3 2.18 (0.23 to 21.08) .50    ≥0.50 129 224 4 5.38 (0.60 to 48.49) .13    Unknown§ 27 60 – – –    Continuous dose per Gy‖ 342 634 – 0.97 (0.67 to 1.41) .89  Female survivors 364 754 4 – –   Ovarian minimum dose (mean = 0.91, range = 0.001–50 for those irradiated)    0 (nonirradiated) 143 321 2 1.00 (reference) –    >0 to < 0.50 149 281 2 1.14 (0.16 to 8.17) .89    ≥0.50 50 92 0 – –    Unknown§ 22 60 – – –    Continuous dose per 0.01 Gy‖ 199 373 – 0.37 (0.08 to 1.76) .21 Parental treatment with radiation No. of survivors No. of survivors’ offspring* Offspring with chromosomal abnormalities* OR (95% CI)† P‡ Radiation treatment (from Danish Cancer Registry) 8945 14 591 63 – –  No 6604 10 690 50 1.00 (reference) –  Yes 2215 3710 13 0.75 (0.41 to 1.35) .35  Unknown 126 191 – – – Parental gonadal dose, Gy 860 1745 12 – –  Male survivors 496 991 8 – –   Testicular dose (mean = 0.95, range = 0.001–43.2 for those irradiated)    0 (nonirradiated) 127 297 1 1.00 (reference) –    >0 to < 0.50 213 410 3 2.18 (0.23 to 21.08) .50    ≥0.50 129 224 4 5.38 (0.60 to 48.49) .13    Unknown§ 27 60 – – –    Continuous dose per Gy‖ 342 634 – 0.97 (0.67 to 1.41) .89  Female survivors 364 754 4 – –   Ovarian minimum dose (mean = 0.91, range = 0.001–50 for those irradiated)    0 (nonirradiated) 143 321 2 1.00 (reference) –    >0 to < 0.50 149 281 2 1.14 (0.16 to 8.17) .89    ≥0.50 50 92 0 – –    Unknown§ 22 60 – – –    Continuous dose per 0.01 Gy‖ 199 373 – 0.37 (0.08 to 1.76) .21 * Including fetal abnormalities and excluding hereditary cases resulted in 14 591 offspring (14 580 live-born and 11 fetuses). † The risk estimate calculated for radiation (yes/no) was adjusted for maternal age and sex of the child. Because of the low numbers of affected offspring in the separate categories of parental doses to the gonads, no adjustment was made for these risk estimates. ‡ Two-sided P value calculated by Wald test. § Doses could not be estimated because of incomplete information in the medical records. ‖ Radiation dose to the gonads treated as a continuous variable per unit Gy; Continuous dose per Gy for testicular dose and per 0.01 Gy for ovarian minimum dose. Our previous study (8) identified only eight cancer survivors with at least one live-born or fetus with an abnormality. Expanding the study period from 1996 to 2002 and including young adult cancer survivors nearly doubled the number of cancer survivors and increased the number of chromosomal abnormalities among their children by eight-fold. The results are more statistically powerful, and reaching the same conclusion is reassuring. Previous studies examining other health indicators of a possible mutagenic effect of cancer therapy passed on to offspring, such as single-gene disorders (purely genetic diseases) (9) and congenital malformations (less genetic), report the same reassuring findings (10–12), as did the study of children of the Japanese atomic bomb survivors (13). Our study has several potential limitations. Germ-cell mutations, especially chromosomal, might lead to spontaneous abortion in early gestation, when women are not aware of a pregnancy and therefore not registered with a miscarriage. Some fatal chromosomal abnormalities might have been missed in any early aborted fetuses. Lack of information on abnormal karyotypes in stillbirths (observed in about 13% of all stillbirths [14] but not systematically reported to the Danish Cytogenetic Registry) might have resulted in an underestimate of chromosomal abnormalities. Only 25% of adult males with Klinefelter syndrome are diagnosed, and fewer than 10% are diagnosed before puberty (15,16). The number of survivors’ offspring with Klinefelter syndrome was similar to that expected in the general population, whereas the number in siblings was considerably lower than expected. The borderline increased risk of Klinefelter syndrome in survivors’ offspring might be due to small numbers, sampling variation, or chance due to multiple comparisons. Also, Turner syndrome might not be recognized in childhood (17). Strengths include identification of all cancer survivors from the Danish Cancer Registry including adolescents and young adults and unbiased identification of siblings and children through linkage to the CPR and of affected offspring in the Danish Cytogenetic Registry. These reassuring findings for cancer survivors who are able to have children indicate that nonhereditary cancer and cancer treatments do not result in transmissible cytogenetic abnormalities in human germ cells. Note We thank programmer Jan Hansen of the Danish Cytogenetic Registry for data extraction. References 1 Madanat-Harjuoja LM , Pokhrel A , Kivivuori SM et al. , Childhood cancer survival in Finland (1953-2010): A nation-wide population-based study . Int J Cancer. 2014 ; 135 ( 9 ): 2129 – 2134 . Google Scholar CrossRef Search ADS PubMed 2 Gatta G , Zigon G , Capocaccia R et al. , Survival of European children and young adults with cancer diagnosed 1995-2002 . Eur J Cancer. 2009 ; 45 ( 6 ): 992 – 1005 . http://dx.doi.org/10.1016/j.ejca.2008.11.042 Google Scholar CrossRef Search ADS PubMed 3 Schmidt R , Richter D , Sender A et al. , Motivations for having children after cancer - a systematic review of the literature . 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The natural history of cytogenetically abnormal fetuses detected at midtrimester amniocentesis which are not terminated electively: New data and estimates of the excess and relative risk of late fetal death associated with 47,+21 and some other abnormal karyotypes . Am J Hum Genet. 1989 ; 45 ( 6 ): 855 – 861 . Google Scholar PubMed 8 Winther JF , Boice JD Jr , Mulvihill JJ et al. , Chromosomal abnormalities among offspring of childhood-cancer survivors in Denmark: A population-based study . Am J Hum Genet. 2004 ; 74 ( 6 ): 1282 – 1285 . http://dx.doi.org/10.1086/421473 Google Scholar CrossRef Search ADS PubMed 9 Mulvihill JJ , Byrne J. Genetic counseling for the cancer survivor: Possible germ cell effects of cancer therapy. In: Green DM , D’Angio GJ , eds. Late Effects of Treatment for Childhood Cancer. New York : Wiley-Liss ; 1992 : 113 – 120 . 10 Byrne J , Rasmussen SA , Steinhorn SC et al. , Genetic disease in offspring of long-term survivors of childhood and adolescent cancer . Am J Hum Genet. 1998 ; 62 ( 1 ): 45 – 52 . http://dx.doi.org/10.1086/301677 Google Scholar CrossRef Search ADS PubMed 11 Winther JF , Olsen JH , Wu H et al. , Genetic disease in the children of Danish survivors of childhood and adolescent cancer . J Clin Oncol. 2012 ; 30 ( 1 ): 27 – 33 . http://dx.doi.org/10.1200/JCO.2011.35.0504 Google Scholar CrossRef Search ADS PubMed 12 Signorello LB , Mulvihill JJ , Green DM et al. , Congenital anomalies in the children of cancer survivors: A report from the childhood cancer survivor study . J Clin Oncol. 2012 ; 30 ( 3 ): 239 – 245 . http://dx.doi.org/10.1200/JCO.2011.37.2938 Google Scholar CrossRef Search ADS PubMed 13 Schull WJ. The children of atomic bomb survivors: A synopsis . J Radiol Prot. 2003 ; 23 ( 4 ): 369 – 384 . http://dx.doi.org/10.1088/0952-4746/23/4/R302 Google Scholar CrossRef Search ADS PubMed 14 Korteweg FJ , Bouman K , Erwich JJ et al. , Cytogenetic analysis after evaluation of 750 fetal deaths: Proposal for diagnostic workup . Obstet Gynecol. 2008 ; 111 ( 4 ): 865 – 874 . http://dx.doi.org/10.1097/AOG.0b013e31816a4ee3 Google Scholar CrossRef Search ADS PubMed 15 Bojesen A , Juul S , Gravholt CH. Prenatal and postnatal prevalence of Klinefelter syndrome: A national registry study . J Clin Endocrinol Metab. 2003 ; 88 ( 2 ): 622 – 626 . http://dx.doi.org/10.1210/jc.2002-021491 Google Scholar CrossRef Search ADS PubMed 16 Abramsky L , Chapple J. 47,XXY (Klinefelter syndrome) and 47,XYY: Estimated rates of and indication for postnatal diagnosis with implications for prenatal counselling . Prenat Diagn. 1997 ; 17 ( 4 ): 363 – 368 . http://dx.doi.org/10.1002/(SICI)1097-0223(199704)17:4<363::AID-PD79>3.0.CO;2-O Google Scholar CrossRef Search ADS PubMed 17 Sybert VP , McCauley E. Turner's syndrome . N Engl J Med. 2004 ; 351 ( 12 ): 1227 – 1238 . http://dx.doi.org/10.1056/NEJMra030360 Google Scholar CrossRef Search ADS PubMed © The Author 2017. Published by Oxford University Press. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com. This article is published and distributed under the terms of the Oxford University Press, Standard Journals Publication Model (https://academic.oup.com/journals/pages/about_us/legal/notices)

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JNCI: Journal of the National Cancer InstituteOxford University Press

Published: Dec 7, 2017

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