Association of Pathogenic Variants in Hereditary Cancer Genes With Multiple Diseases

Chenjie Zeng; Lisa A. Bastarache; Ran Tao; Eric Venner; Scott Hebbring; Justin D. Andujar; Sarah T. Bland; David R. Crosslin; Siddharth Pratap; Ayorinde Cooley; Jennifer A. Pacheco; Kurt D. Christensen; Emma Perez; Carrie L. Blout Zawatsky; Leora Witkowski; Hana Zouk; Chunhua Weng; Kathleen A. Leppig; Patrick M.A. Sleiman; Hakon Hakonarson; Marc S. Williams; Yuan Luo; Gail P. Jarvik; Robert C. Green; Wendy K. Chung; Ali G. Gharavi; Niall J. Lennon; Heidi L. Rehm; Richard A. Gibbs; Josh F. Peterson; Dan M. Roden; Georgia L. Wiesner; Joshua C. Denny

doi:10.1001/jamaoncol.2022.0373

Association of Pathogenic Variants in Hereditary Cancer Genes With Multiple Diseases

Chenjie Zeng, Lisa A. Bastarache, Ran Tao, Eric Venner, Scott Hebbring, Justin D. Andujar, Sarah T. Bland, David R. Crosslin, Siddharth Pratap, Ayorinde Cooley, Jennifer A. Pacheco, Kurt D. Christensen, Emma Perez, Carrie L. Blout Zawatsky, Leora Witkowski, Hana Zouk, Chunhua Weng, Kathleen A. Leppig, Patrick M.A. Sleiman, Hakon HakonarsonMarc S. Williams, Yuan Luo, Gail P. Jarvik, Robert C. Green, Wendy K. Chung, Ali G. Gharavi, Niall J. Lennon, Heidi L. Rehm, Richard A. Gibbs, Josh F. Peterson, Dan M. Roden, Georgia L. Wiesner, Joshua C. Denny^*

^*Corresponding author for this work

Preventive Medicine

Research output: Contribution to journal › Article › peer-review

25 Scopus citations

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 214020 participants were identified, including 23544 in eMERGEseq cohort (mean [SD] age, 47.8 [23.7] years; 12611 women [53.6%]), 187234 in the UKB cohort (mean [SD] age, 56.7 [8.1] years; 104055 [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.

Original language	English (US)
Pages (from-to)	835-844
Number of pages	10
Journal	JAMA Oncology
Volume	8
Issue number	6
DOIs	https://doi.org/10.1001/jamaoncol.2022.0373
State	Published - Jun 2022

Funding

Funding/Support: This study was supported by grant R01LM010685 from the National Library of Medicine and funding to the eMERGE sites through the following: grants U01HG8657, U01HG006375, and U01HG004610 (Kaiser Permanente Washington/University of Washington); U01HG8685 (Brigham and Women’s Hospital); U01HG8672, U01HG006378, and U01HG004608 (Vanderbilt University Medical Center); U01HG8666 and U01HG006828 (Cincinnati Children’s Hospital Medical Center); U01HG6379 and U01HG04599 (Mayo Clinic); U01HG8679 and U01HG006382 (Geisinger Clinic); U01HG008680 (Columbia University Health Sciences); U01HG8684 and U01HG006830 (Children’s Hospital of Philadelphia); U01HG8673, U01HG006388, and U01HG004609 (Northwestern University); U54MD007593 and U54MD007586 (Meharry Medical College); U01HG8676 (Partners Healthcare/Broad Institute); U01HG8664 (Baylor College of Medicine); U01HG006389 (Essentia Institute of Rural Health, Marshfield Clinic Research Foundation and Pennsylvania State University); U01HG006380 (Icahn School of Medicine at Mount Sinai); U01HG8701, U01HG006385, and U01HG04603 (Vanderbilt University Medical Center serving as the Coordinating Center) from the NHGRI; funding to eMERGE genotyping centers through grants U01HG004438 (CIDR) and U01HG004424 (the Broad Institute); funding for Vanderbilt University Medical Center’s Synthetic Derivative, Research Derivative, and BioVU by institutional funding and Clinical and Translational Science Awards grant ULTR000445 from National Center for Advancing Translational Sciences/NIH; by grant HG200417-01 from the Intramural Research Program of the NHGRI; by funds from the Vanderbilt-Ingram Cancer Center Ingram Professorship program (Dr Wiesner); and by grant HG200417 from the Intramural Research Program of the National Human Genome Research Institute (Drs Zeng and Denny since joining the NIH). 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

ASJC Scopus subject areas

Oncology
Cancer Research

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1001/jamaoncol.2022.0373

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Zeng, C., Bastarache, L. A., Tao, R., Venner, E., Hebbring, S., Andujar, J. D., Bland, S. T., Crosslin, D. R., Pratap, S., Cooley, A., Pacheco, J. A., Christensen, K. D., Perez, E., Blout Zawatsky, C. L., Witkowski, L., Zouk, H., Weng, C., Leppig, K. A., Sleiman, P. M. A., ... Denny, J. C. (2022). Association of Pathogenic Variants in Hereditary Cancer Genes With Multiple Diseases. JAMA Oncology, 8(6), 835-844. https://doi.org/10.1001/jamaoncol.2022.0373

@article{66af8afafc1a46609b87a9ac5eec7f0a,

title = "Association of Pathogenic Variants in Hereditary Cancer Genes With Multiple Diseases",

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 214020 participants were identified, including 23544 in eMERGEseq cohort (mean [SD] age, 47.8 [23.7] years; 12611 women [53.6%]), 187234 in the UKB cohort (mean [SD] age, 56.7 [8.1] years; 104055 [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.",

author = "Chenjie Zeng and Bastarache, {Lisa A.} and Ran Tao and Eric Venner and Scott Hebbring and Andujar, {Justin D.} and Bland, {Sarah T.} and Crosslin, {David R.} and Siddharth Pratap and Ayorinde Cooley and Pacheco, {Jennifer A.} and Christensen, {Kurt D.} and Emma Perez and {Blout Zawatsky}, {Carrie L.} and Leora Witkowski and Hana Zouk and Chunhua Weng and Leppig, {Kathleen A.} and Sleiman, {Patrick M.A.} and Hakon Hakonarson and Williams, {Marc S.} and Yuan Luo and Jarvik, {Gail P.} and Green, {Robert C.} and Chung, {Wendy K.} and Gharavi, {Ali G.} and Lennon, {Niall J.} and Rehm, {Heidi L.} and Gibbs, {Richard A.} and Peterson, {Josh F.} and Roden, {Dan M.} and Wiesner, {Georgia L.} and Denny, {Joshua C.}",

note = "Publisher Copyright: {\textcopyright} 2022 American Medical Association.",

year = "2022",

month = jun,

doi = "10.1001/jamaoncol.2022.0373",

language = "English (US)",

volume = "8",

pages = "835--844",

journal = "JAMA Oncology",

issn = "2374-2437",

publisher = "American Medical Association",

number = "6",

}

Zeng, C, Bastarache, LA, Tao, R, Venner, E, Hebbring, S, Andujar, JD, Bland, ST, Crosslin, DR, Pratap, S, Cooley, A, Pacheco, JA, Christensen, KD, Perez, E, Blout Zawatsky, CL, Witkowski, L, Zouk, H, Weng, C, Leppig, KA, Sleiman, PMA, Hakonarson, H, Williams, MS, Luo, Y, Jarvik, GP, Green, RC, Chung, WK, Gharavi, AG, Lennon, NJ, Rehm, HL, Gibbs, RA, Peterson, JF, Roden, DM, Wiesner, GL & Denny, JC 2022, 'Association of Pathogenic Variants in Hereditary Cancer Genes With Multiple Diseases', JAMA Oncology, vol. 8, no. 6, pp. 835-844. https://doi.org/10.1001/jamaoncol.2022.0373

TY - JOUR

T1 - Association of Pathogenic Variants in Hereditary Cancer Genes With Multiple Diseases

AU - Zeng, Chenjie

AU - Bastarache, Lisa A.

AU - Tao, Ran

AU - Venner, Eric

AU - Hebbring, Scott

AU - Andujar, Justin D.

AU - Bland, Sarah T.

AU - Crosslin, David R.

AU - Pratap, Siddharth

AU - Cooley, Ayorinde

AU - Pacheco, Jennifer A.

AU - Christensen, Kurt D.

AU - Perez, Emma

AU - Blout Zawatsky, Carrie L.

AU - Witkowski, Leora

AU - Zouk, Hana

AU - Weng, Chunhua

AU - Leppig, Kathleen A.

AU - Sleiman, Patrick M.A.

AU - Hakonarson, Hakon

AU - Williams, Marc S.

AU - Luo, Yuan

AU - Jarvik, Gail P.

AU - Green, Robert C.

AU - Chung, Wendy K.

AU - Gharavi, Ali G.

AU - Lennon, Niall J.

AU - Rehm, Heidi L.

AU - Gibbs, Richard A.

AU - Peterson, Josh F.

AU - Roden, Dan M.

AU - Wiesner, Georgia L.

AU - Denny, Joshua C.

PY - 2022/6

Y1 - 2022/6

N2 - 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 214020 participants were identified, including 23544 in eMERGEseq cohort (mean [SD] age, 47.8 [23.7] years; 12611 women [53.6%]), 187234 in the UKB cohort (mean [SD] age, 56.7 [8.1] years; 104055 [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.

AB - 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 214020 participants were identified, including 23544 in eMERGEseq cohort (mean [SD] age, 47.8 [23.7] years; 12611 women [53.6%]), 187234 in the UKB cohort (mean [SD] age, 56.7 [8.1] years; 104055 [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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Association of Pathogenic Variants in Hereditary Cancer Genes With Multiple Diseases

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