ObjectiveThe link between BRCA1 and homologous recombination deficiency (HRD) in cancer has gained importance with the emergence of new targeted cancer treatments, while the available data on the role of the gene in colorectal cancer (CRC) remain contradictory. The aim of this case series was to elucidate the role of known pathogenic BRCA1 variants in the development of early-onset CRC.DesignPatients were evaluated using targeted next generation sequencing, exome sequencing and chromosomal microarray analysis of the paired germline and tumor samples. These results were used to calculate the HRD score and the frequency of mutational signatures in the tumors.ResultsThree patients with metastatic CRC were heterozygous for a previously known BRCA1 nonsense variant. All tumors showed remarkably high HRD scores, and the HRD-related signature 3 had the second highest contribution to the somatic pattern of variant accumulation in the samples (23% in 1 and 2, and 13% in sample 3).ConclusionsA BRCA1 germline pathogenic variant can be involved in CRC development through HRD. Thus, BRCA1 testing should be considered in young patients with a personal history of microsatellite stable CRC as this could further allow a personalized treatment approach.
Purpose. Pathogenic variants (PVs) in BRCA2 and ATMgenes have been linked to an increased risk of various cancers. BRCA2and ATM are part of the homologous recombination pathway, but the tumor risk in patients with simultaneous PVs in both genes remains largely unknown. In this study we describe four patients from three families with multiple cancers who coinherited PVs in BRCA2 and ATM genes. Methods. PVs in the patients were identified using NGS sequencing of the DNA and were confirmed by Sanger sequencing. Results. The first family included a 67-year-old male with kidney, prostate, and pancreatic adenocarcinomas, and his daughter diagnosed with breast cancer at 29 years. In the second family, a 28-year-old female had breast cancer, while a male from the third family was diagnosed with prostate cancer at the age of 49, gastric cancer one year later and pancreatic cancer at 64. The three identified BRCA2 PVs were nonsense variants previously described as pathogenic, leading to a severely truncated or absent protein due to nonsense-mediated mRNA decay. Two of the ATM variants were previously reported as pathogenic, while the third one affects a conserved splice site. Conclusions. The early age of diagnosis and the development of multiple cancers in the reported patients indicate a very high risk of cancer in double heterozygous patients, carrying PVs in the BRCA2 and ATM genes.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.
hi@scite.ai
10624 S. Eastern Ave., Ste. A-614
Henderson, NV 89052, USA
Copyright © 2024 scite LLC. All rights reserved.
Made with 💙 for researchers
Part of the Research Solutions Family.