Gene panel sequencing in familial breast/ovarian cancer patients identifies multiple novel mutations also in genes others than BRCA1/2

Abstract

Breast and ovarian cancer (BC/OC) predisposition has been attributed to a number of high-and moderate to low-penetrance susceptibility genes. With the advent of next generation sequencing (NGS) simultaneous testing of these genes has become feasible. In this monocentric study, we report results of panel-based screening of 14 BC/OC susceptibility genes (BRCA1, BRCA2, RAD51C, RAD51D, CHEK2, PALB2, ATM, NBN, CDH1, TP53, MLH1, MSH2, MSH6 and PMS2) in a group of 581 consecutive individuals from a German population with BC and/or OC fulfilling diagnostic criteria for BRCA1 and BRCA2 testing including 179 with a triple-negative tumor. Altogether we identified 106 deleterious mutations in 105 (18%) patients in 10 different genes, including seven different exon deletions. Of these 106 mutations, 16 (15%) were novel and only six were found in BRCA1/2. To further characterize mutations located in or nearby splicing consensus sites we performed RT-PCR analysis which allowed confirmation of pathogenicity in 7 of 9 mutations analyzed. In PALB2, we identified a deleterious variant in six cases. All but one were associated with early onset BC and a positive family history indicating that penetrance for PALB2 mutations is comparable to BRCA2. Overall, extended testing beyond BRCA1/2 identified a deleterious mutation in further 6% of patients. As a downside, 89 variants of uncertain significance were identified highlighting the need for comprehensive variant databases. In conclusion, panel testing yields more accurate information on genetic cancer risk than assessing BRCA1/2 alone and wide-spread testing will help improve penetrance assessment of variants in these risk genes.With some 70,000 new cases currently being diagnosed annually, breast cancer (BC) is by far the most common form of cancer among women in Germany. 1 Increasingly genetic information is not only used for disease risk management in healthy individuals, but also for treatment decisions in patients with breast and ovarian cancer. 2,3 A family history of BC is considered a significant risk factor to develop the disease and about 15% of women diagnosed with BC have at least one first degree relative with breast cancer. 4 Germline mutations in BRCA1 and BRCA2 can be found in approximately 24% of families with hereditary breast and/or ovarian cancer (BC/OC) with highest mutation frequencies in families with at least two OCs (41.9%) and families with at least one BC and one OC (41.6%). 5 Therefore, a large portion of this patient population with BC/OC has another cause of hereditary cancer, likely

The identification of pathogenic variants in BRCA1/2 negative, high risk, hereditary breast and/or ovarian cancer patients: High frequency of FANCM pathogenic variants

“…High throughput NGS‐based multiple gene panel analyses are routinely used for genetic risk assessment in HBOC. Several studies have confirmed the suitability of the commercially available TSCP for HBOC diagnostics . In our study, we performed a systematic screen for PVs in 94 cancer predisposing genes via NGS and CGH.…”

Detection of novel germline mutations in six breast cancer predisposition genes by targeted next-generation sequencing

“…According to a previous study, the mutation prevalence of BRCA1/2 in Han Chinese patients with early‐onset or familial breast cancer was 15.0% and a 7.5% mutation rate of non‐ BRCA genes was found in women who tested negative for BRCA1/2 mutations (Lin et al., ). In another study of German breast cancer patients, extended testing beyond BRCA1/2 also identified a deleterious mutation in a further 6% of patients (Kraus et al., ). Therefore, although BRCA1/2 genes were the most important susceptibility genes in breast cancer, multiple gene sequencing significantly increased the detection rate of possible disease‐causing mutation carriers.…”

Next-Generation Sequencing in Oncology: Genetic Diagnosis, Risk Prediction and Cancer Classification

“…The technical validity of gene-panel/NGS in comparison with the reference technology was thoroughly assessed in different studies [29,36,42,66,67,68,69,70]. In particular, one of these assessed the sensitivity and specificity of NGS compared with standard Sanger sequencing and MLPA (multiplex ligation-probe amplification) and also confirmed the performance of three different panel designs for HBOC (Custom Design by Castera et al [29]: Table 1 and Table 2).…”