Disease Spectrum of Breast Cancer Susceptibility Genes

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.

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Disease Spectrum of Breast Cancer Susceptibility Genes

10.1101/2020.08.11.20172007 ◽

2020 ◽

Author(s):

Jin Wang ◽

Preeti Singh ◽

Kanhua Yin ◽

Jingan Zhou ◽

Yujia Bao ◽

...

Keyword(s):

Breast Cancer ◽

Genetic Resources ◽

Language Processing ◽

Cancer Susceptibility ◽

Breast Cancer Susceptibility ◽

Susceptibility Genes ◽

Disease Spectrum ◽

Cancer Susceptibility Genes ◽

Breast Cancer Susceptibility Genes ◽

Disease Associations

Background Pathogenic variants in cancer susceptibility genes can increase the risk of a spectrum of diseases. We aim to evaluate the disease spectrum of breast cancer susceptibility genes (BCSGs) to develop a comprehensive resource of gene-disease associations for clinicians. Methods Thirteen genes (ATM, BARD1, BRCA1, BRCA2, CDH1, CHEK2, NBN, NF1, PALB2, PTEN, RECQL, STK11, and TP53), that have been conclusively established as BCSGs by the Clinical Genome Resource (ClinGen) and the NCCN guidelines, were investigated. For these thirteen genes, potential gene-disease associations were identified 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. Results A total of 40 diseases were confirmed as being associated with one or more of the 13 BCSGs by our evaluation. Malignant diseases including prostate cancer, pancreatic cancer, colorectal cancer, brain tumor, gastric cancer, ovarian cancer, and sarcoma were associated with at least 3 BCSGs. Furthermore, a total of 87 gene-disease associations were confirmed by our evaluation, of which 85% (74/87) were confirmed by ClinGen and/or NCCN. Conversely, 9 gene-disease associations absent from both ClinGen and NCCN were confirmed in the other four genetic resources (≥3) and 4 gene-disease associations were confirmed by the NLP-based procedure. Conclusion This is the first study to systematically investigate the reported disease spectrum of BCSGs in multiple sources. Our innovative approach provides a general guide for evaluating gene-disease associations and improves the clinical management for at-risk individuals.

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