Abstract 74: Value of bilateral breast cancer for identification of rare recessive at-risk alleles: evidence for the role of homozygous GEN1 c.2515_2519delAAGTT mutation.
Authors: Kuligina Ekaterina S. , Sokolenko Anna P. , Mitiushkina Nathalia V. , Abysheva Svetlana N. , Preobrazhenskaya Elena V. , Gorodnova Tatiana V. , Yanus Grigoriy A. , Togo Alexandr V. , Cherdyntseva Nadezhda V. , Larionov Alexey A. , Kuznetsov Sergey G. , Imyanitov Evgeny N. 
Published: August 2013

Abstract
Current approaches to identification of cancer-predisposing alleles are primarily based on the comparison of DNA sequences between affected and non-affected individuals. Many contemporary gene-seeking studies, be it genome-wide association scans or mutation analysis of candidate genes, utilize genetically enriched cancer cases. Genetic enrichment is usually achieved by selection of patients with clinical signs of hereditary cancer predisposition, e.g. family history of the disease or presence of multiple primary tumors. We suggest that the preference towards familial vs. multiple primary cancer cases may in fact be indeed disadvantageous under certain circumstances. Let's consider for example the transmission of a recessive cancer predisposing allele (a), which has a frequency of 0.1 and a penetrance of 100%. In accordance with the Hardy-Weinberg distribution (p^2 + 2pq + q^2), only 1% of this population will be homozygous for this allele and therefore bear the at-risk genotype (aa). Notably, only 19% of cancer patients with the aa genotype will have one or both parents with the same genotype and hence report a history of cancer disease in their mother or father. Therefore, while the focus on familial cancer clustering is a powerful tool for identifying dominant predisposing mutations, the disease cases caused by the homozygous recessive at-risk alleles may be easily missed. On the other hand, non-selected patients with multiple primary tumors, being strongly enriched for cancer associated genotypes, are unlikely to have a bias towards accumulation of dominant vs. recessive alleles; in addition, a deliberate exclusion of the family history-positive patients from this group may further increase the proportion of recessively inherited cases.
We considered the c.2515_2519delAAGTT mutation in a Holliday junction resolvase, GEN1, as an interesting candidate to test this hypothesis on breast cancer (BC) cases. We observed noticeably high frequency of the c.2515_2519delAAGTT frame-shift in Russian subjects, that permitted us to consider BC-predisposing impact of the homozygosity for this allele. Strikingly, we observed an overrepresentation of the c.2515_2519delAAGTT homozygotes in patients with bilateral breast cancer (biBC) versus healthy controls (11/360 (3.1%) vs. 18/1305 (1.4%); OR = 2.3 (1.02-4.75); p = 0.031). In accordance with the calculations outlined above, all patients with the biallelic c.2515_2519delAAGTT mutation belonged to the group with no evidence for the vertical transmission of the disease predisposition. The analysis of unilateral BC cases did not reveal an excess of c.2515_2519delAAGTT homozygotes (23/1851 (1.2%) vs. 18/1305 (1.4%); OR = 0.9 (0.49-1.69); p = 0.738), however this comparison lacked the power to detect the effect for a low-penetrance rare genotype. Interestingly, as in case of biBC, biallelic c.2515_2519delAAGTT genotype occurred only in patients whose mothers were not affected by this disease (21/1558 (1.3%) vs. 0/215 (0%); p = 0.087). When the data on bilateral and unilateral BC were combined, the association between the c.2515_2519delAAGTT homozygosity and the absence of BC in mother reached the formal level of statistical significance (Mantel-Haenszel p = 0.041).
We acknowledge that the obtained data are insufficient to claim the BC predisposing role for the c.2515_2519delAAGTT homozygous genotype. However, this study indicates, that the consideration of patients with multiple cancers may be particularly fruitful for the identification of recessive determinants of cancer predisposition.
Citation Format: Ekaterina S. Kuligina, Anna P. Sokolenko, Nathalia V. Mitiushkina, Svetlana N. Abysheva, Elena V. Preobrazhenskaya, Tatiana V. Gorodnova, Grigoriy A. Yanus, Alexandr V. Togo, Nadezhda V. Cherdyntseva, Alexey A. Larionov, Sergey G. Kuznetsov, Evgeny N. Imyanitov. Value of bilateral breast cancer for identification of rare recessive at-risk alleles: evidence for the role of homozygous GEN1 c.2515_2519delAAGTT mutation. [abstract]. In: Proceedings of the AACR Special Conference on Post-GWAS Horizons in Molecular Epidemiology: Digging Deeper into the Environment; 2012 Nov 11-14; Hollywood, FL. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2012;21(11 Suppl):Abstract nr 74.