Targeted sequencing of crucial cancer causing genes of breast cancer in Saudi patients
SAUDI JOURNAL OF BIOLOGICAL SCIENCES
Authors: Alanazi, Mohammad; Parine, Narasimha Reddy; Shaik, Jilani Purusottapatnam; Al Naeem, Abdulrahman; Aldhaian, Sooad
Abstract
Breast cancer is the most common cancer among women worldwide, causing 15% of cancer-related deaths among women. Breast cancer incidence rate is increasing in most countries. In Saudi Arabia, breast cancer constitutes nearly 22% of the newly diagnosed cancer cases in women. Breast cancer incidence in the women population of Saudi Arabia is 25.9%, with 18.2% mortality. In this study, targeted sequencing of 164 selected genes was performed on germline and somatic DNA derived from the blood and tissue samples of 50 breast cancer patients using customized panel on Ion torrent platform. This study focused on the identification of genetic variations of different cancer-causing genes, raising the hope for identification of personalized prognosis. After final filtration and validation, we found protein-truncating, non-synonymous missense, and splice site mutations in the known susceptibility genes for breast cancer. We identified a total of 14 point mutations and one deletion in BRCA1, BRCA2, and RAD50 genes from the BRCA panel analysis of breast cancer samples. In the customized panel analysis, we identified 37 potential mutations in 25 breast cancer risk associated genes. Out of these, most mutations were observed in TP53. After filtration, we observed 7 mutations in TP53 genes (n = 7:- one stop gain (p.R81X), four non-synonymous (p.R81X, p.Y88C, p.R141H, and p.V25D), and two deletions (c.59delC and c.327delC)). Among the mutations detected in our study, TP53 (p.R81X), VHL (p.E52X), and BRCA2 (p.K3326X) mutations, which lead to an aberrant transcript with a premature stop codon, were reported for the first time in breast cancer patients from Saudi Arabia. Our study will help in identifying the damaging mutations and predisposing genes in Saudi breast cancer patients. (C) 2020 The Authors. Published by Elsevier B.V. on behalf of King Saud University.
Molecular profile of BRCA-mutated biliary tract cancers
ESMO OPEN
Authors: Spizzo, Gilbert; Puccini, Alberto; Xiu, Joanne; Goldberg, Richard M.; Grothey, Axel; Shields, Anthony F.; Arora, Sukeshi Patel; Khushmann, Moh'd; Salem, Mohamed E.; Battaglin, Francesca; Baca, Yasmine; El-Deiry, Wafik S.; Philip, Philip A.; Nassem, Madiha; Hall, Michael; Marshall, John L.; Kocher, Florian; Amann, Arno; Wolf, Dominik; Korn, W. Michael; Lenz, Heinz; Seeber, Andreas
Abstract
Introduction Prognosis of biliary tract cancers (BTC) remains dismal and novel treatment strategies are needed to improve survival. BRCA mutations are known to occur in BTC but their frequency and the molecular landscape in which they are observed in distinct sites of BTC remain unknown. Material and methods Tumour samples from 1292 patients with BTC, comprising intrahepatic cholangiocarcinoma (IHC, n=746), extrahepatic cholangiocarcinoma (EHC, n=189) and gallbladder cancer (GBC, n=353), were analysed using next-generation sequencing (NGS). Tumour mutational burden (TMB) was calculated based on somatic non-synonymous missense mutations. Determination of tumour mismatch repair (MMR) or microsatellite instability (MSI) status was done by fragment analysis, immunohistochemistry and the evaluation of known microsatellite loci by NGS. Programmed death ligand 1 expression was analysed using immunohistochemistry. Results Overall, BRCA mutations were detected in 3.6% (n=46) of samples (BRCA1: 0.6%, BRCA2: 3%) with no significant difference in frequency observed based on tumour site. In GBC and IHC, BRCA2 mutations (4.0% and 2.7%) were more frequent than BRCA1 (0.3% and 0.4%, p<0.05) while in EHC, similar frequency was observed (2.6% for BRCA2 vs 2.1% for BRCA1). BRCA mutations were associated with a higher rate in subjects with MSI-H/deficient mismatch repair (19.5% vs 1.7%, p<0.0001) and tumours with higher TMB, regardless of the MMR or MSI status (p<0.05). Conclusions BRCA mutations are found in a subgroup of patients with BTC and are characterised by a distinct molecular profile. These data provide a rationale testing poly(ADP-ribose)polymeraseinhibitors and other targeted therapies in patients with BRCA-mutant BTC.