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. 2022 Jun 1;8(6):835-844.
doi: 10.1001/jamaoncol.2022.0373.

Association of Pathogenic Variants in Hereditary Cancer Genes With Multiple Diseases

Chenjie Zeng  1 , Lisa A Bastarache  2 , Ran Tao  3 , Eric Venner  4 , Scott Hebbring  5 , Justin D Andujar  6   7 , Sarah T Bland  2 , David R Crosslin  8 , Siddharth Pratap  9 , Ayorinde Cooley  10 , Jennifer A Pacheco  11 , Kurt D Christensen  12   13 , Emma Perez  14 , Carrie L Blout Zawatsky  14 , Leora Witkowski  15 , Hana Zouk  16   17 , Chunhua Weng  18 , Kathleen A Leppig  19 , Patrick M A Sleiman  20   21 , Hakon Hakonarson  20   21 , Marc S Williams  22 , Yuan Luo  23 , Gail P Jarvik  24   25 , Robert C Green  26 , Wendy K Chung  27   28 , Ali G Gharavi  29   30 , Niall J Lennon  31 , Heidi L Rehm  32   33   34 , Richard A Gibbs  4 , Josh F Peterson  2 , Dan M Roden  2   35   36 , Georgia L Wiesner  6   7 , Joshua C Denny  1
Affiliations

Association of Pathogenic Variants in Hereditary Cancer Genes With Multiple Diseases

Chenjie Zeng et al. JAMA Oncol. .

Abstract

Importance: Knowledge about the spectrum of diseases associated with hereditary cancer syndromes may improve disease diagnosis and management for patients and help to identify high-risk individuals.

Objective: To identify phenotypes associated with hereditary cancer genes through a phenome-wide association study.

Design, setting, and participants: This phenome-wide association study used health data from participants in 3 cohorts. The Electronic Medical Records and Genomics Sequencing (eMERGEseq) data set recruited predominantly healthy individuals from 10 US medical centers from July 16, 2016, through February 18, 2018, with a mean follow-up through electronic health records (EHRs) of 12.7 (7.4) years. The UK Biobank (UKB) cohort recruited participants from March 15, 2006, through August 1, 2010, with a mean (SD) follow-up of 12.4 (1.0) years. The Hereditary Cancer Registry (HCR) recruited patients undergoing clinical genetic testing at Vanderbilt University Medical Center from May 1, 2012, through December 31, 2019, with a mean (SD) follow-up through EHRs of 8.8 (6.5) years.

Exposures: Germline variants in 23 hereditary cancer genes. Pathogenic and likely pathogenic variants for each gene were aggregated for association analyses.

Main outcomes and measures: Phenotypes in the eMERGEseq and HCR cohorts were derived from the linked EHRs. Phenotypes in UKB were from multiple sources of health-related data.

Results: A total of 214 020 participants were identified, including 23 544 in eMERGEseq cohort (mean [SD] age, 47.8 [23.7] years; 12 611 women [53.6%]), 187 234 in the UKB cohort (mean [SD] age, 56.7 [8.1] years; 104 055 [55.6%] women), and 3242 in the HCR cohort (mean [SD] age, 52.5 [15.5] years; 2851 [87.9%] women). All 38 established gene-cancer associations were replicated, and 19 new associations were identified. These included the following 7 associations with neoplasms: CHEK2 with leukemia (odds ratio [OR], 3.81 [95% CI, 2.64-5.48]) and plasma cell neoplasms (OR, 3.12 [95% CI, 1.84-5.28]), ATM with gastric cancer (OR, 4.27 [95% CI, 2.35-7.44]) and pancreatic cancer (OR, 4.44 [95% CI, 2.66-7.40]), MUTYH (biallelic) with kidney cancer (OR, 32.28 [95% CI, 6.40-162.73]), MSH6 with bladder cancer (OR, 5.63 [95% CI, 2.75-11.49]), and APC with benign liver/intrahepatic bile duct tumors (OR, 52.01 [95% CI, 14.29-189.29]). The remaining 12 associations with nonneoplastic diseases included BRCA1/2 with ovarian cysts (OR, 3.15 [95% CI, 2.22-4.46] and 3.12 [95% CI, 2.36-4.12], respectively), MEN1 with acute pancreatitis (OR, 33.45 [95% CI, 9.25-121.02]), APC with gastritis and duodenitis (OR, 4.66 [95% CI, 2.61-8.33]), and PTEN with chronic gastritis (OR, 15.68 [95% CI, 6.01-40.92]).

Conclusions and relevance: The findings of this genetic association study analyzing the EHRs of 3 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.

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Conflict of interest statement

Conflict of Interest Disclosures: Ms Bastarache reported receiving royalties from Nashville Biotech and consulting for Galatea Bio Inc outside the submitted work. Dr Hebbring reported receiving grants from the National Institutes of Health (NIH) during the conduct of the study. Ms Bland reported receiving grants from the National Human Genomic Research Institute of the NIH (NHGRI) during the conduct of the study. Dr Crosslin reported receiving grants from the NHGRI during the conduct of the study and personal fees from UnitedHealth Group outside the submitted work. Dr Christensen reported receiving grants from Sanford Health and the NIH outside the submitted work. Dr Zouk reported receiving grants from the NHGRI during the conduct of the study. Dr Williams reported receiving grants from NIH during the conduct of the study. Dr Luo reported receiving grants from the NIH during the conduct of the study. Dr Jarvik reported receiving grants from the NHGRI during the conduct of the study. Dr Green reported receiving personal fees from Genomic Life, VinBigData, Meenta, PlumCare, OptumLabs, GRAIL, Embrome, Allelica, GenomeWeb LLC, AIA, and Verily Life Sciences outside the submitted work. Dr Gharavi reported receiving grants from the Renal Research Institute and Natera Inc, serving on the advisory boards of Novartis International AG and Travere Therapeutics, conference participation for Sanofi SA, and consulting for Goldfinch Bio Inc. Dr Rehm reported receiving grants from the NIH during the conduct of the study. Dr Peterson reported receiving grants from NHGRI during the conduct of the study. Dr Wiesner reported grants from NHGRI and being a professor for Vanderbilt Ingram Cancer Center Ingram Cancer Research during the conduct of the study. Dr Denny reported receiving royalties from Vanderbilt University Medical Center–licensed use phenome-wide association study technology on Vanderbilt’s DNA biobank to Nashville Biosciences. No other disclosures were reported.

Figures

Figure 1.
Figure 1.. Phenome-Wide Association Study to Confirm Known Gene-Phenotype Associations and Uncover New Associations for Hereditary Cancer Genes
Meta-analysis results of phenome-wide association study in the Electronic Medical Records and Genomics Sequencing, Hereditary Cancer Registry, and UK Biobank data sets are shown. Strength of the association is plotted along the y-axis as −log P value summary, and phenotypes are represented on the x-axis, grouped by each gene. Black dots represent the known associated phenotypes. Labeled phenotypes with blue dots represent new gene-phenotype associations. The dashed line indicates P = 2.5 × 10−5, representing the empirical phenome-wide significance. GI indicates gastrointestinal tract; IHBD, intrahepatic bile duct; MEN1, multiple endocrine neoplasia syndrome type 1; and MEN2, multiple endocrine neoplasia syndrome type 2.
Figure 2.
Figure 2.. New Gene-Phenotype Associations Uncovered by Phenome-Wide Association Study, Organized by Organs
Organs labeled blue represent neoplastic sites; organs labeled yellow represent nonneoplastic sites. GI indicates gastrointestinal tract, IHBD, intrahepatic bile duct.
See this image and copyright information in PMC

Comment in

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