Beyond BRCA1 and BRCA2: Deleterious Variants in DNA Repair Pathway Genes in Italian Families with Breast/Ovarian and Pancreatic Cancers

Abstract

The 5–10% of breast/ovarian cancers (BC and OC) are inherited, and germline pathogenic (P) variants in DNA damage repair (DDR) genes BRCA1 and BRCA2 explain only 10–20% of these cases. Currently, new DDR genes have been related to BC/OC and to pancreatic (PC) cancers, but the prevalence of P variants remains to be explored. The purpose of this study was to investigate the spectrum and the prevalence of pathogenic variants in DDR pathway genes other than BRCA1/2 and to correlate the genotype with the clinical phenotype. A cohort of 113 non-BRCA patients was analyzed by next-generation sequencing using a multigene panel of the 25 DDR pathways genes related to BC, OC, and PC. We found 43 unique variants in 18 of 25 analyzed genes, 14 classified as P/likely pathogenic (LP) and 28 as variants of uncertain significance (VUS). Deleterious variants were identified in 14% of index cases, whereas a VUS was identified in 20% of the probands. We observed a high incidence of deleterious variants in the CHEK2 gene, and a new pathogenic variant was detected in the RECQL gene. These results supported the clinical utility of multigene panel to increase the detection of P/LP carriers and to identify new actionable pathogenic gene variants useful for preventive and therapeutic approaches.

Impact of deleterious variants in other genes beyond BRCA1/2 detected in breast/ovarian and pancreatic cancer patients by NGS-based multi-gene panel testing: looking over the hedge

“…Recently, Germani et al. 9 carried out a multi-gene panel testing on 113 BRCA -negative patients with BC, OC, or PC, by identifying in 14 patients a PV or a likely pathogenic variant (LPV) beyond BRCA1/2 genes, such as CHEK2 , RAD51C , ATM , MLH1 , MSH2 , and RECQL . Our recent study 10 conducted on patients with bilateral breast cancer (BBC) showed that 14.4% of PVs in high- and moderate-penetrance BC susceptibility genes, such as PTEN , PALB2 , CHEK2 , ATM , and RAD51C , would have been lost in the absence of an analysis carried out via multi-gene panel.…”

“…8 In spite of BRCA1 and BRCA2 being the two high-penetrance genes primarily associated with increased risk of hereditary BC/OC and PC, several studies have helped identify many other predisposition genes for these tumours. 9,10 Other hereditary cancer syndromes could be associated with germline PVs in several high-and moderate-risk susceptibility genes such as CDH1, PALB2, PTEN, STK11, TP53, ATM, CHEK2, BARD1, BRIP1, RAD51C, and RAD51D. 10,11 Recently, it has become necessary to study several genes in a short time and in an inexpensive way.…”

“…13 Kurian et al 14 showed an increased BC risk associated with several genes such as ATM, BARD1, BRCA1, BRCA2, CHEK2, PALB2, PTEN, and TP53, as well as an OC risk associated with various genes including ATM, BRIP1, RAD51C, RAD51D, MLH1, MSH6, MSH2, NBN, and STK11. Recently, Germani et al 9 carried out a multi-gene panel testing on 113 BRCA-negative patients with BC, OC, or PC, by identifying in 14 patients a PV or a likely pathogenic variant (LPV) beyond BRCA1/2 genes, such as CHEK2, RAD51C, ATM, MLH1, MSH2, and RECQL. Our recent study 10 conducted on patients with bilateral breast cancer (BBC) showed that 14.4% of PVs in high-and moderatepenetrance BC susceptibility genes, such as PTEN, PALB2, CHEK2, ATM, and RAD51C, would have been lost in the absence of an analysis carried out via multi-gene panel.…”

Genomic Breakpoints’ Characterization of a Large CHEK2 Duplication in an Italian Family with Hereditary Breast Cancer

“…To the best of our knowledge, the penetrance of large intragenic duplications has not been evaluated or compared to that of other variants. Unfortunately, due to the reduced penetrance and variable expressivity of the cancer susceptibility condition, the absence of large families available for molecular testing and the lack of functional studies, most variants are classified as VUS [ 2 ]. Recently, adjustments of the ACMG variant classification were proposed for CHEK2 [ 12 ].…”

“…The role of heterozygous point mutations and intragenic rearrangements of high penetrance genes BRCA1 and BRCA2 in cancer susceptibility (especially, but not only, breast and ovarian cancer) is well established, and international guidelines addressing molecular testing indications and clinical management are available [ 1 ]. Variants in other genes with high and moderate penetrance whose products are involved in the same DNA damage sensing and repair pathway can result in similar cancer susceptibility conditions [ 2 ]. CHEK2 (checkpoint kinase 2; MIM# 604373) is a tumor suppressor gene encoding a serine–threonine kinase involved in DNA repair, cell cycle regulation, senescence and apoptosis [ 3 ].…”