Multigene Panel Sequencing Identifies a Novel Germline Mutation Profile in Male Breast Cancer Patients

Al Saati, Ayman; Vande Perre, Pierre; Plenecassagnes, Julien; Gilhodes, Julia; Monselet, Nils; Cabarrou, Bastien; Lignon, Norbert; Filleron, Thomas; Telly, Dominique; Perello-Lestrade, Emilie; Feillel, Viviane; Staub, Anne; Martinez, Mathilde; Chipoulet, Edith; Collet, Gaëlle; Thomas, Fabienne; Gladieff, Laurence; Toulas, Christine

doi:10.3390/ijms241814348

Cited by 2 publications

(1 citation statement)

References 50 publications

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“…Based on the observation that PALB2 PV carriers were fourfold more likely to have a male relative with BC than non-carriers [86], several studies have investigated the presence of PALB2 PVs in MBC cases by candidate single-gene sequencing, and more recently by gene-panel sequencing approaches [25,[27][28][29]31,32,85,[87][88][89][90][91][92][93][94][95][96]. These studies showed a variable PALB2 PV frequency, ranging from about 0.8% to 1.8%, depending on the characteristics and the size of the population analyzed [25,27,29,31,32,93].…”

Section: Palb2mentioning

confidence: 99%

Gender-Specific Genetic Predisposition to Breast Cancer: BRCA Genes and Beyond

Valentini,

Bucalo,

Conti

et al. 2024

Cancers

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Among neoplastic diseases, breast cancer (BC) is one of the most influenced by gender. Despite common misconceptions associating BC as a women-only disease, BC can also occur in men. Additionally, transgender individuals may also experience BC. Genetic risk factors play a relevant role in BC predisposition, with important implications in precision prevention and treatment. The genetic architecture of BC susceptibility is similar in women and men, with high-, moderate-, and low-penetrance risk variants; however, some sex-specific features have emerged. Inherited high-penetrance pathogenic variants (PVs) in BRCA1 and BRCA2 genes are the strongest BC genetic risk factor. BRCA1 and BRCA2 PVs are more commonly associated with increased risk of female and male BC, respectively. Notably, BRCA-associated BCs are characterized by sex-specific pathologic features. Recently, next-generation sequencing technologies have helped to provide more insights on the role of moderate-penetrance BC risk variants, particularly in PALB2, CHEK2, and ATM genes, while international collaborative genome-wide association studies have contributed evidence on common low-penetrance BC risk variants, on their combined effect in polygenic models, and on their role as risk modulators in BRCA1/2 PV carriers. Overall, all these studies suggested that the genetic basis of male BC, although similar, may differ from female BC. Evaluating the genetic component of male BC as a distinct entity from female BC is the first step to improve both personalized risk assessment and therapeutic choices of patients of both sexes in order to reach gender equality in BC care. In this review, we summarize the latest research in the field of BC genetic predisposition with a particular focus on similarities and differences in male and female BC, and we also discuss the implications, challenges, and open issues that surround the establishment of a gender-oriented clinical management for BC.

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Section: Palb2mentioning

confidence: 99%

Gender-Specific Genetic Predisposition to Breast Cancer: BRCA Genes and Beyond

Valentini,

Bucalo,

Conti

et al. 2024

Cancers

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Next generation sequencing identifies a pattern of novel germline variants in early-onset colorectal cancer

Vande Perre,

Al Saati,

Cabarrou

et al. 2024

Preprint

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Early-onset colorectal cancer (EOCRC) incidence is increasing rapidly worldwide. However, the majority of EOCRCs are not substantiated by germline variants in the main colorectal cancer (CRC) predisposition genes (the “DIGE” panel). To investigate a potential genetic transmission of EOCRC (dominant, recessive and oligogenic hypotheses) and thus identify potentially novel EOCRC-specific predisposition genes, we conducted an analysis of 585 cancer pathway genes on an EOCRC patient cohort (n=87 patients diagnosed at ≤ 40 years of age, DIGE-) with or without a CRC family history. By comparing this germline variant spectrum to the GnomAD cancer-free database, we identified high impact variants (HVs) in 15 genes significantly over-represented in the EOCRC cohort. Among the 32 unrelated patients with a CRC family history (i.e.with a potentially dominant transmission pattern), nine presented HVs in ten of the genes tested, four of these genes had a DNA repair function. A potentially recessive transmission of EOCRC in patients without a CRC family history cannot be supported by our results nor can an oligogenic transmission.We subsequently sequenced these 15 genes in a cohort of 82 late-onset CRCs (cancer diagnosis ≥50 years, DIGE-) and found variants in 11 of these genes to be specific to EOCRC. To evaluate whether variants in these 11 genes would allow to specifically detect EOCRC patients, we screened our patient database (n=6482), which only contained 2% of EOCRCs (DIGE-), and identified two other EOCRC cases diagnosed after the constitution of our cohort, with individual HVs inRECQL4andNUTM1. Altogether, we showed that 37.5% and 18.75% of heterozygousNUTM1andRECQL4HVs of our database were diagnosed with EOCRC.Our work has identified a pattern of germline gene variants not previously associated with EOCRC. This paves the way to addressing the contribution of these variants to EOCRC risk and oncogenesis.Author SummaryEarly-onset colorectal cancer (diagnosed at ≤ 40 years of age) is a rare disease that can in part be explained by a hereditary genetic predisposition. To identify novel gene variants potentially associated with EOCRC risk, we analysed a panel of 585 genes in 87 patients with early-onset colorectal cancer unexplained by conventional genetic tests. This first analysis highlighted 15 genes of interest. To evaluate if this genetic profile is specific to early onset, we sequenced these 15 genes in a population of late-onset colorectal cancers (diagnosed after 50 years of age). Variants in 11 of these genes were specific to the early-onset population. To assess if this genetic pattern allows to identify other early-onset cases, we screened these genes in our whole database of 6482 patients and identified two new early-onset cases. Our results need to be confirmed, and validated in larger cohorts but pave the way for future research into early-onset colorectal cancer and the possibility of improving screening or treatment options for these patients and their family members.

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Multigene Panel Sequencing Identifies a Novel Germline Mutation Profile in Male Breast Cancer Patients

Cited by 2 publications

References 50 publications

Gender-Specific Genetic Predisposition to Breast Cancer: BRCA Genes and Beyond

Gender-Specific Genetic Predisposition to Breast Cancer: BRCA Genes and Beyond

Next generation sequencing identifies a pattern of novel germline variants in early-onset colorectal cancer

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