Abstract
BackgroundPathogenic variants in cancer susceptibility genes can increase the risk of a spectrum of diseases, which clinicians must manage for their patients. We evaluated the disease spectrum of breast cancer susceptibility genes (BCSGs) with the aim of developing a comprehensive resource of gene-disease associations for clinicians.MethodsTwelve genes (ATM, BARD1, BRCA1, BRCA2, CDH1, CHEK2, NF1, PALB2, PTEN, RECQL, STK11, and TP53), all of which have been conclusively established as BCSGs by the Clinical Genome Resource (ClinGen) and/or the NCCN guidelines, were investigated. The potential gene-disease associations for these 12 genes were verified and evaluated based on six genetic resources (ClinGen, NCCN, OMIM, Genetics Home Reference, GeneCards, and Gene-NCBI) and an additional literature review using a semiautomated natural language processing (NLP) abstract classification procedure.ResultsForty-two diseases were found to be associated with one or more of the 12 BCSGs for a total of 86 gene-disease associations, of which 90% (78/86) were verified by ClinGen and/or NCCN. Four gene-disease associations could not be verified by either ClinGen or NCCN but were verified by at least three of the other four genetic resources. Four gene-disease associations were verified by the NLP procedure alone.ConclusionThis study is unique in that it systematically investigates the reported disease spectrum of BCSGs by surveying multiple genetic resources and the literature with the aim of developing a single consolidated, comprehensive resource for clinicians. This innovative approach provides a general guide for evaluating gene-disease associations for BCSGs, potentially improving the clinical management of at-risk individuals.
Highlights
Hereditary predisposition is found in approximately 10% of all breast cancer cases [1]
The association of breast cancer risk with NF1 was only identified in National Comprehensive Cancer Network (NCCN), and RECQL was only identified in Clinical Genome Resource (ClinGen)
To outline the disease spectrum for the twelve breast cancer susceptibility genes (BCSGs), we examined six reliable genetic resources combined with a literature review using Natural language processing (NLP)
Summary
Hereditary predisposition is found in approximately 10% of all breast cancer cases [1]. Since the identification of BRCA1 and BRCA2 [6, 7], genetic testing has become a routine part of clinical care for individuals with possible hereditary breast cancer predisposition [1]. Several BCSGs are responsible for rare hereditary cancer syndromes, such as TP53, which is responsible for Li-Fraumeni syndrome Individuals with this syndrome have a very high risk of developing multiple malignancies, including but not limited to, breast cancer, sarcoma, brain cancer, leukemia, lung cancer, and adrenocortical cancer [15,16,17,18]. Pathogenic variants in cancer susceptibility genes can increase the risk of a spectrum of diseases, which clinicians must manage for their patients. We evaluated the disease spectrum of breast cancer susceptibility genes (BCSGs) with the aim of developing a comprehensive resource of gene-disease associations for clinicians
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