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.

RECQL5: Another DNA helicase potentially involved in hereditary breast cancer susceptibility

“…It has been suggested for years that a percentage of the BC families could be explained by a recessive model of inheritance (Cui et al, ; Kaufman, Beaty, & Struewing, ; Kuligina et al, ), but this hypothesis has not been investigated so far. With the aim to explore new approaches, we have performed WES in two BRCAX families that were compatible with the presence of a recessive high‐risk gene, however, we have not found any suitable candidate under this model.…”

Whole-exome sequencing of a rare case of familial childhood acute lymphoblastic leukemia reveals putative predisposing mutations in Fanconi anemia genes

“…Efficient DNA damage repair and simultaneous regulation of cell cycle progression is critical for genomic stability. Interestingly, a rare recessive homozygous variant in GEN1 has been associated with bilateral breast cancer [ 40 ] and the depletion of GEN1 or FANCP/SLX4 in Bloom’s syndrome cells results in defects in chromosome condensation and severe chromosome abnormalities, such as nondisjunction of sister chromatids and abnormal mitosis leading to aneuploidy [ 41 , 42 ], highlighting their important role in maintaining genome stability. Thus, mutated FANCP/SLX4 and GEN1 , in combination with the rare allele of PRDM9 also segregating within this family, could alter Holliday junction resolution leading to nondisjunction of chromosomes and segregation defects.…”

Analysis of Tumor Suppressor Genes Based on Gene Ontology and the KEGG Pathway

“…In Bloom’s syndrome cells, depletion of GEN1 results in severe chromosome abnormalities [114]. It has been identified rare recessive at-risk alleles of GEN1 in breast cancer by Ekatherina Sh [115]−[117], and two somatic frameshift mutations in breast cancer cell lines and primary tumors through exome sequencing [114]. Above all, GEN1 is a novel tumor suppressor akin to some other DNA repair genes, BRCA1 and BRCA2 in breast cancer, although there is rare study prove GEN1 make a high-appreciable contribution to breast cancer.…”