Genes, Chromosomes and Cancer

Kan, Casina W. S.; Howell, Viive M.; Hahn, Michael A.; Marsh, Deborah J.

doi: 10.1002/gcc.22221pmid: 25280227

Ovarian cancer is the fifth most common cause of cancer death in women worldwide. Serous epithelial ovarian cancer (SEOC) is the most common and aggressive histological subtype. Widespread genomic alterations go hand‐in‐hand with aberrant DNA damage signaling and are a hallmark of high‐grade SEOC. MicroRNAs (miRNAs) are a class of small noncoding RNA molecules that are nonrandomly distributed in the genome. They are frequently located in chromosomal regions susceptible to copy number variation (CNV) associated with malignancy that can influence their expression. Widespread changes in miRNA expression have been reported in multiple cancer types including ovarian cancer. This review examines CNV and single nucleotide polymorphisms, two common types of genomic alterations that occur in ovarian cancer, in the context of their influence on the expression of miRNA and the ability of miRNA to bind to and regulate their target genes. This includes genes encoding proteins involved in DNA repair and the maintenance of genomic stability. Improved understanding of mechanisms of miRNA dysregulation and the role of miRNA in ovarian cancer will provide further insight into the pathogenesis and treatment of this disease. © 2014 Wiley Periodicals, Inc.

Kim, Myungshin; Lee, Shin Hyo; Kim, Jiyeon; Lee, Sung‐Eun; Kim, Yoo‐Jin; Min, Chang‐Ki

doi: 10.1002/gcc.22213pmid: 25145975

We performed single nucleotide polymorphism (SNP) array analysis of 35 newly diagnosed symptomatic multiple myeloma (MM) patients who received bortezomib‐melphalan‐prednisone (VMP) to identify collaborating genetic events that could predict the outcome of treatment. A total of 340 copy number variations (CNVs) were identified, with the most frequently identified CNVs being gains on 1q, 19p, 9q, 3q, 9p, 15q, 19q, 5q, 11q, 5p, and 7q and losses on 1p, X, 13q, 14q, and 6q. The number and proportion of detected abnormalities by SNP array were associated with presence of cytogenetic abnormalities and complex karyotype. Moreover, increasing genomic complexity as ascertained by SNP arrays correlated with outcome of the VMP treatment. The frequency of CNVs was significantly different according to achievement of very good partial response (VGPR) to VMP treatment (<VGPR vs. ≥VGPR, median 11.7 vs. 7.7, respectively, P = 0.032) or occurrence of progressive disease (PD) after VMP treatment (progression vs. nonprogression, median 11.6 and 6.5, respectively, P = 0.011). The proportion of CNV length was also significantly higher in patients who did not achieve VGPR compared with those with ≥VGPR (median 31.9 vs. 19.6%, respectively, P = 0.004) and also higher in patients with PD compared with those without it (median 31.9 vs. 15.8%, respectively, P = 0.005). The patients who did not achieve VGPR tended to have deletion of 1p (P = 0.011) and gain of 3q (P = 0.05). Occurrence of PD was associated with complex karyotype (P = 0.020) and gain of 3q (P = 0.022). Our data show that the occurrence of CNVs correlates with clinical outcomes to first‐line VMP treatment. © 2014 Wiley Periodicals, Inc.

Prieto‐Granada, Carlos; Zhang, Lei; Chen, Hsiao‐Wei; Sung, Yun‐Shao; Agaram, Narasimhan P; Jungbluth, Achim A; Antonescu, Cristina R

doi: 10.1002/gcc.22215pmid: 25231134

Sclerosing epithelioid fibrosarcoma (SEF) is a rare soft tissue tumor exhibiting considerable morphologic overlap with low‐grade fibromyxoid sarcoma (LGFMS). Moreover, both SEF and LGFMS show MUC4 expression by immunohistochemistry. While the majority of LGFMS cases are characterized by a FUS‐CREB3L1 fusion, both FUS‐CREB3L2 and EWSR1‐CREB3L1 fusions were recently demonstrated in a small number of LGFMS and SEF/LGFMS hybrid tumors. In contrast, recent studies pointed out that SEF harbor frequent EWSR1 rearrangements, with only a minority of cases showing FUS‐CREB3L2 fusions. In an effort to further characterize the molecular characteristics of pure SEF and hybrid SEF/LGFMS lesions, we undertook a clinicopathologic, immunohistochemical and genetic analysis of a series of 10 SEF and 8 hybrid SEF/LGFMS tumors. The mortality rate was similar between the two groups, 44% within the pure SEF group and 37% in the hybrid SEF/LGFMS with a mean overall follow‐up of 66 months. All but one pure SEF and all hybrid SEF/LGFMS‐tested cases showed MUC4 immunoreactivity. The majority (90%) of pure SEF cases showed EWSR1 gene rearrangements by fluorescence in situ hybridization with only one case exhibiting FUS rearrangement. Of the nine EWSR1 positive cases, six cases harbored CREB3L1 break‐apart, two had CREB3L2 rearrangement (a previously unreported finding) and one lacked evidence of CREB3L1/2 abnormalities. In contrast, all hybrid SEF/LGFMS tumors exhibited FUS and CREB3L2 rearrangements. These results further demarcate a relative cytogenetic dichotomy between pure SEF, often characterized by EWSR1 rearrangements, and hybrid SEF/LGFMS, harboring FUS‐CREB3L2 fusion; the latter group recapitulating the genotype of LGFMS. © 2014 Wiley Periodicals, Inc.

Ellberg, Carolina; Jernström, Helena; Broberg, Per; Borg, Åke; Olsson, Håkan

doi: 10.1002/gcc.22217pmid: 25251729

Three studies have reported that BRCA1/2 mutations of paternal origin confer an earlier age at breast cancer diagnosis compared with maternal origin. The primary aim of this study was to investigate the impact of parental origin of BRCA1/2 mutations on age at breast and ovarian cancer diagnosis. This study included 577 female BRCA1/2 mutation carriers. All BRCA1/2 mutation carriers belonged to families registered between 1993 and 2011 at the Oncogenetic Clinic at Skånes University Hospital, Lund, Sweden. Cox proportional hazard ratios were used to analyze time to breast or ovarian cancer diagnosis. A novel finding was that carriers of BRCA1 mutations of paternal origin were 4 years older at age of ovarian cancer (P = 0.009) compared with those carrying a BRCA1 mutation of maternal origin. BRCA1 carriers with mutations of paternal origin were 4 years younger at breast cancer diagnosis (P = 0.017) compared with those carrying a BRCA1 mutation of maternal origin, which is in agreement with three previous studies. Both findings were adjusted for of year of inclusion, birth date, and oral contraceptive pill use. No associations between parental origin of BRCA2 mutations and time to breast or ovarian cancer diagnosis were found. An attempt to handle a potential selection bias regarding use of oral contraceptives was made using multiple imputations by chained equations. The observed age difference may allow a greater understanding of mechanisms associated with the differences in cancer penetrance in BRCA1/2 mutation carriers, some of which may depend on paternal origin. © 2014 Wiley Periodicals, Inc.

Betti, Marta; Casalone, Elisabetta; Ferrante, Daniela; Romanelli, Antonio; Grosso, Federica; Guarrera, Simonetta; Righi, Luisella; Vatrano, Simona; Pelosi, Giuseppe; Libener, Roberta; Mirabelli, Dario; Boldorini, Renzo; Casadio, Caterina; Papotti, Mauro; Matullo, Giuseppe;