Breast Cancer Research and Treatment (2018) 168:277–281
Are VNTRs co‑localizing with breast cancer‑associated SNPs?
· Susan L. Neuhausen
· Hagit Schayek
· Yael Laitman
· Antoniou C. Antonis
· Eitan Friedman
Received: 13 November 2017 / Accepted: 18 November 2017 / Published online: 22 November 2017
© Springer Science+Business Media, LLC, part of Springer Nature 2017
Purpose Several common genetic variants (single-nucleotide polymorphisms, SNPs) have been shown to be associated
with breast cancer (BC) risk in the general population, and to modify BC risk for BRCA1 and BRCA2 mutation carriers. Co-
localization of variable number of tandem repeats (VNTRs) with these BC-associated SNPS has not been comprehensively
Methods Cross referencing of genome-wide VNTRs with the known BC genome-wide association studies (GWAS) SNPs
signiﬁcantly associated with increased risk for developing breast cancer was carried out. Analysis was based on the overlap
between the VNTRs and 10-kb windows around these BC-susceptibility SNPs.
Results Cross referencing of the 1.2 million TR with the 161 known BC-associated SNPs in the general population led to
690 matches. Of those, in 17 VNTRs, the SNP was within the VNTR. Analysis restricted to loci known to modify BC pen-
etrance in BRCA1 (n = 31) and BRCA2 (n = 33) mutation carriers led to 139 and 170 co-localization matches, respectively.
For these, none of the SNPs were within the VNTR. The distances between the SNPs and the VNTRs were not signiﬁcantly
diﬀerent from what was expected to occur by chance alone (p = 0.61; p = 0.44; p = 0.25, respectively).
Conclusion There is no evidence that VNTRs co-localize with currently reported SNP tagged BC GWAS loci.
Keywords Tandem repeats · Breast cancer susceptibility · GWAS-based SNPs · Penetrance · BRCA1 and BRCA2
Several genetic variants that contribute to breast cancer (BC)
susceptibility have been identiﬁed, with BRCA1 and BRCA2
being the predominant, clinically relevant genes . In some
families exhibiting familial aggregation of BC, BC is diag-
nosed at earlier age with each successive generation . This
phenomenon has largely been attributed to a birth cohort
eﬀect . However, it is plausible that these observed suc-
cessive generational younger ages at diagnosis may reﬂect
a genetic-based phenomenon called anticipation. Anticipa-
tion, predominantly noted in neurodegenerative disorders,
implies that there are dynamic mutations particularly aﬀect-
ing trinucleotide repeat expansion that impact the phenotype
and age at diagnosis . Previous studies reported that in
some cases, anticipation can clinically be deﬁned in sub-
set of familial BC cases , yet not all studies concur .
Furthermore, a similar, anticipation-compatible phenom-
enon has been reported in some families carrying mutant
BRCA1/2 alleles [2, 6]. While BRCA1/2 germline mutation
carriers are at signiﬁcantly increased risk for developing
breast and/or ovarian cancer, penetrance is incomplete .
Combined with the variable age at diagnosis of identical
mutation carriers, incomplete penetrance is suggestive of
the existence of modiﬁer factors—genetic and environmental
. Several single-nucleotide polymorphisms (SNPs) have
been shown to be associated with breast or ovarian cancer
risks in BRCA1 and BRCA2 mutation carriers (http://apps.
ccge.medschl.cam.ac.uk/consortia/cimba//). Although the
Electronic supplementary material The online version of this
article (https://doi.org/10.1007/s10549-017-4588-7) contains
supplementary material, which is available to authorized users.
* Eitan Friedman
Department of Public Health and Primary Care, Centre
for Cancer Genetic Epidemiology, University of Cambridge,
Department of Population Sciences, Beckman Research
Institute, City of Hope, Duarte, CA, USA
Oncogenetics Unit, Institute of Human Genetics, Sheba
Medical Center, 52621 Tel-Hashomer, Israel
Sackler School of Medicine, Tel-Aviv University, Tel-Aviv,