Clinical usefulness of NGS multi-gene panel testing in hereditary cancer analysis

Abstract

Introduction: A considerable number of families with pedigrees suggestive of a Mendelian form of Breast Cancer (BC), Ovarian Cancer (OC), or Pancreatic Cancer (PC) do not show detectable BRCA1/2 mutations after genetic testing. The use of multi-gene hereditary cancer panels increases the possibility to identify individuals with cancer predisposing gene variants. Our study was aimed to evaluate the increase in the detection rate of pathogenic mutations in BC, OC, and PC patients when using a multi-gene panel.Methods: 546 patients affected by BC (423), PC (64), or OC (59) entered the study from January 2020 to December 2021. For BC patients, inclusion criteria were i) positive cancer family background, ii) early onset, and iii) triple negative BC. PC patients were enrolled when affected by metastatic cancer, while OC patients were all submitted to genetic testing without selection. The patients were tested using a Next-Generation Sequencing (NGS) panel containing 25 genes in addition to BRCA1/2.Results: Forty-four out of 546 patients (8%) carried germline pathogenic/likely pathogenic variants (PV/LPV) on BRCA1/2 genes, and 46 (8%) presented PV or LPV in other susceptibility genes.Discussion: Our findings demonstrate the utility of expanded panel testing in patients with suspected hereditary cancer syndromes, since this approach increased the mutation detection rate of 15% in PC, 8% in BC and 5% in OC cases. In absence of multi-gene panel analysis, a considerable percentage of mutations would have been lost.

Detection of Germline Mutations in a Cohort of 250 Relatives of Mutation Carriers in Multigene Panel: Impact of Pathogenic Variants in Other Genes beyond BRCA1/2

“…Mammalian MutY homologue (MUTYH) encodes a DNA glycosylase involved in base excision repair during DNA replication and damage repair. PVs/LPVs in MUTYH are associated with autosomal recessive colorectal adenomatous polyposis, but interestingly, monoallelic variants on this gene have been reported by both our and other groups as being associated with cancer predisposition in several patients [30,31]. An interesting case in the present study is represented by the detection of a MUTYH c.734G>A variant in one female patient with a personal history of breast cancer diagnosed at the age of 44 years, previously tested for BRCA1/2 variants at another institute and found to be negative.…”

Uncovering Pathogenic Variants in Cancer Susceptibility Genes through Genetic Testing for Pancreatic Cancer Patients

“…These syndromes encompass conditions like hereditary Breast and Ovarian cancer syndrome, Lynch syndrome, and Familial Atypical Multiple Mole Melanoma Syndrome, among others. The identification of such variant statuses can profoundly influence clinical management and treatment decisions for patients [9].…”

The Crucial Role of Hereditary Cancer Panel Testing in Unaffected Individuals with a Strong Family History of Cancer: A Retrospective Study of a Cohort of 103 Healthy Subjects

“…The present study involved around 100 unaffected individuals, selected only based on their familiar cancer history in the absence of a positive familiar member. Furthermore, we focused on the potential impact of a Next Generation Sequencing (NGS)-based multi-gene panel of 27 genes, including BRCA1/2 genes, with the aim to understand whether expanding the analysis to a larger panel of genes may result into a percentage of healthy subjects with cancer-predisposing gene variants higher than that reported in previous studies [13][14][15].…”