Abstract
Virtually all known tumor predisposing genes have been identified via the analysis of familial cancer cases. Here we argue that this approach is likely to miss recessively acting cancer genes and suggest the analysis of family history-negative patients with multiple primary malignancies for identifying homozygous at-risk genotypes. We performed calculations showing that the homozygous carriers of rare recessive cancer predisposing alleles are unlikely to report a family history of the disease. We further revealed that the c.2515_2519delAAGTT homozygous mutation in a Holliday junction resolvase, GEN1, was overrepresented in women with bilateral breast cancer (BC) as compared to healthy controls [11/360 (3.1 %) vs. 18/1305 (1.4 %); odds ratio (OR) = 2.25 (1.02–4.75); p = 0.031], although this trend was not maintained in unilateral BC patients [23/1851 (1.2 %)]. Noticeably, presence of biallelic c.2515_2519delAAGTT mutation was associated with the absence of BC in mother both in bilateral and unilateral BC cases [7/239 (3.0 %) vs. 0/41 (0 %) and 21/1,558 (1.3 %) vs. 0/215 (0 %), respectively; Mantel–Haenszel p = 0.041]. Thus, this study suggests that identification of dominant and recessive cancer predisposing genes may require distinct study groups.
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Acknowledgments
We cordially thank Olga A Zaitseva, Olga S Yatsuk and Tatiana P Kutilova for their technical assistance. This work has been supported by the Russian Federation for Basic Research (grants 10-04-00260, 11-04-00227, 12-04-00928 and 12-04-01490), the Federal Agency for Science and Innovations, Russia (grant agreement 8780), the Government of Moscow, Russia (grant 15/12), The President Research Council for Support of Young Russian Scientists (grant MK-261.2012.7) and the Breakthrough Breast Cancer, UK. Sergey G Kuznetsov is supported by the Academy of Finland, Cancer Society of Finland, Sigrid Jusélius Foundation and Finnish Medical Foundation.
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The authors declare that they have no conflict of interest.
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Ekatherina Sh. Kuligina and Anna P. Sokolenko contributed equally to this work.
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Kuligina, E.S., Sokolenko, A.P., Mitiushkina, N.V. et al. Value of bilateral breast cancer for identification of rare recessive at-risk alleles: evidence for the role of homozygous GEN1 c.2515_2519delAAGTT mutation. Familial Cancer 12, 129–132 (2013). https://doi.org/10.1007/s10689-012-9575-x
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DOI: https://doi.org/10.1007/s10689-012-9575-x