title: 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: 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.
authors.affiliation: Laboratory of Molecular Oncology, N.N. Petrov Institute of Oncology, Pesochny-2, 197758, St.-Petersburg, Russia.
authors.forename: Ekatherina Sh
authors.initials: ESh
authors.lastname: Kuligina
authors.forename: Anna P
authors.initials: AP
authors.lastname: Sokolenko
authors.forename: Nathalia V
authors.initials: NV
authors.lastname: Mitiushkina
authors.forename: Svetlana N
authors.initials: SN
authors.lastname: Abysheva
authors.forename: Elena V
authors.initials: EV
authors.lastname: Preobrazhenskaya
authors.forename: Tatiana V
authors.initials: TV
authors.lastname: Gorodnova
authors.forename: Grigoriy A
authors.initials: GA
authors.lastname: Yanus
authors.forename: Alexandr V
authors.initials: AV
authors.lastname: Togo
authors.forename: Nadezhda V
authors.initials: NV
authors.lastname: Cherdyntseva
authors.forename: Svetlana A
authors.initials: SA
authors.lastname: Bekhtereva
authors.forename: J Michael
authors.initials: JM
authors.lastname: Dixon
authors.forename: Alexey A
authors.initials: AA
authors.lastname: Larionov
authors.forename: Sergey G
authors.initials: SG
authors.lastname: Kuznetsov
authors.forename: Evgeny N
authors.initials: EN
authors.lastname: Imyanitov
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000483:Alleles; D001943:Breast Neoplasms / Q000235:genetics*; D005260:Female; D005808:Genes, Recessive; D020022:Genetic Predisposition to Disease; D045565:Holliday Junction Resolvases / Q000235:genetics*; D006720:Homozygote; D006801:Humans; D008875:Middle Aged; D009154:Mutation; D009386:Neoplastic Syndromes, Hereditary / Q000235:genetics*; D012307:Risk Factors
chemical_list: C533748:GEN1 protein, human; D045565:Holliday Junction Resolvases