Association of Pathogenic Variants in Hereditary Cancer Genes With Additional Cancers and Non-neoplastic Diseases

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In a study reported in JAMA Oncology, Zeng et al found that germline pathogenic variants in 23 hereditary cancer genes were associated with an increased risk of cancers not previously associated with the variants, as well as an increased risk of multiple non-neoplastic diseases.

Study Details

The phenome-wide association study used health data from a total of 214,020 participants in three cohorts:

  • The Electronic Medical Records and Genomics Sequencing (eMERGEseq) dataset (n = 23,544) recruited predominantly healthy individuals from 10 U.S. medical centers from July 2016 to February 2018 with a mean follow-up through electronic health records (EHRs) of 12.7 years.
  • The UK Biobank cohort (n = 187,234) recruited participants from March 2006 to August 2010, with a mean follow-up through multiple sources of health-related data of 12.4 years.
  • The Hereditary Cancer Registry (n = 3,242) recruited patients undergoing clinical genetic testing at Vanderbilt University Medical Center from May 2012 to December 2019, with a mean follow-up through EHRs of 8.8 years.

A meta-analysis was performed to identify associations of germline variants in 23 hereditary cancer genes with increased risk of cancers not known to be associated with the variants and increased risk of non-neoplastic diseases.  

Key Findings

The established associations of the 23 gene variants with significantly increased risk of 38 cancers were replicated.

A total of seven new associations with statistically significant increased risks for cancers were identified: CHEK2 with leukemia (odds ratio [OR] = 3.81) and plasma cell neoplasms (OR = 3.12); ATM with gastric cancer (OR = 4.27) and pancreatic cancer (OR = 4.44); MUTYH (biallelic) with kidney cancer (OR = 32.28); MSH6 with bladder cancer (OR = 5.63); and APC with benign liver/intrahepatic bile duct tumors (OR = 52.01).  

A total of 12 associations with increased risk for nonneoplastic diseases were identified: BRCA1/2 with ovarian cysts (OR = 3.15 and 3.12, respectively); MEN1 with acute pancreatitis (OR = 33.45); APC with gastritis and duodenitis (OR = 4.66); PTEN with chronic gastritis (OR = 15.68); MUTYH with polycystic ovaries (OR = 44.57); MLH1 with lower gastrointestinal ulcer (OR = 18.97); PMS2 with spermatocele (OR = 20.09) and cannabis dependence (OR = 29.34); RET with diplopia (OR = 9.46); and VHL with splenic anomalies (OR = 119.45).

The investigators concluded, “The findings of this genetic association study analyzing the EHRs of three large cohorts suggest that these new phenotypes associated with hereditary cancer genes may facilitate early detection and better management of cancers. This study highlights the potential benefits of using EHR data in genomic medicine.”

Joshua C. Denny, MD, MS, of the National Human Genome Research Institute, National Institutes of Health, is the corresponding author for the JAMA Oncology article.

Disclosure: The study was supported by a grant from the National Library of Medicine, grants from the National Institutes of Health, and others. For full disclosures of the study authors, visit

The content in this post has not been reviewed by the American Society of Clinical Oncology, Inc. (ASCO®) and does not necessarily reflect the ideas and opinions of ASCO®.