Abstract
CDH1 pathogenic variants confer a markedly elevated lifetime risk of developing diffuse gastric cancer (DGC) and lobular breast cancer (LBC). The aim of this study was to evaluate the prevalence and clinical impact of CDH1 pathogenic variants in the unselected and ancestrally diverse BioMe Biobank. We evaluated exome sequence data from 30,223 adult BioMe participants to identify CDH1 positive individuals, defined as those harboring a variant previously classified as pathogenic or likely pathogenic or a predicted loss-of-function variant in CDH1. We reviewed electronic health records and BioMe enrollment surveys for personal and family history of malignancy and evidence of prior clinical genetic testing. Using a genomics-first approach, we identified 6 CDH1 positive individuals in BioMe (~ 1 in 5000). CDH1 positive individuals had a median age of 42 years (range 35–62 years), all were non-European by self-report, and one was female. None had evidence of either a personal or family history of DGC or LBC. Our findings suggest a low risk of DGC and LBC in unselected patients harboring a pathogenic variant in CDH1. Knowledge of CDH1-related cancer risk in individuals with no personal or family history may better inform surveillance and prophylactic measures.
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References
Blair VR et al (2020) Hereditary diffuse gastric cancer: updated clinical practice guidelines. Lancet Oncol 21(8):e386–e397
van der Post RS et al (2015) Hereditary diffuse gastric cancer: updated clinical guidelines with an emphasis on germline CDH1 mutation carriers. J Med Genet 52(6):361–374
Caldas C et al (1999) Familial gastric cancer: overview and guidelines for management. J Med Genet 36(12):873–880
Katona BW, Clark DF, Domchek SM (2020) CDH1 on Multigene Panel Testing: Look Before You Leap. J Natl Cancer Inst 112(4):330–334
Roberts ME et al (2019) Comparison of CDH1 penetrance estimates in clinically ascertained families vs families ascertained for multiple gastric cancers. JAMA Oncol 5:1325
Kalia SS et al (2017) Recommendations for reporting of secondary findings in clinical exome and genome sequencing, 2016 update (ACMG SF v2.0): a policy statement of the American College of Medical Genetics and Genomics. Genet Med 19(2):249–255
Abul-Husn NS et al (2019) Exome sequencing reveals a high prevalence of BRCA1 and BRCA2 founder variants in a diverse population-based biobank. Genome Med 12(1):2
Karczewski KJ et al (2020) The mutational constraint spectrum quantified from variation in 141,456 humans. Nature 581(7809):434–443
van Dieren JM et al (2020) Gastroscopic surveillance with targeted biopsies compared with random biopsies in CDH1 mutation carriers. Endoscopy 52(10):839–846
Kumar S et al (2019) The role of endoscopy in the management of hereditary diffuse gastric cancer syndrome. World J Gastroenterol 25(23):2878–2886
Acknowledgements
We thank participants of the BioMe Biobank for their permission to use their health and genomic information.
Funding
This study was supported by dedicated funding to the Institute for Genomic Health by the Icahn School of Medicine at Mount Sinai. A.B.-M. received support from the Digestive Disease Research Foundation. E.E.K., N.S.A-H., and G.M.B. are supported by the National Institutes of Health; National Human Genome Research Institute (NHGRI) and National Institute on Minority Health and Health Disparities (U01 HG009610). E.E.K. and N.S.A.-H. are supported by NHGRI (U01 HG011176). E.E.K. is supported by NHGRI (R01 HG010297, U01 HG009080, UM1 HG0089001, U01 HG007417), the National Heart, Lung, Blood Institute (R01 HL104608, X01 HL1345), the National Institute of Diabetes and Kidney and Digestive Disease (R01 DK110113). A.L.L. is supported by the American Cancer Society (129387-MRSG-16–015-01-CPHPS).
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E.E.K., A.L.L., and N.S.A.-H. conceived and designed the study. G.M.B. and S.C. performed sequence data QC and annotation. E.R.S. and N.S.A.-H. interpreted sequence data. A.B.-M., E.R.S., A.L.L., and N.S.A.-H. conducted medical record review, analysis, and interpretation. A.B.-M., E.R.S., and N.S.A.-H. drafted the manuscript. All authors reviewed and approved the final manuscript.
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Conflicts of interest
Dr. Abul-Husn was previously employed by Regeneron Pharmaceuticals and has received a speaker honorarium from Genentech. E.E.K. has received speaker honoraria from Illumina and Regeneron Pharmaceuticals. The remaining authors have no relevant financial or non-financial interests to disclose.
Ethical approval
The Icahn School of Medicine at Mount Sinai’s Institutional Review Board approved this study (protocol number 18-1771), including a waiver of informed consent and a HIPAA waiver of authorization. The study population consisted of 30,223 participants aged 18 years or older from Mount Sinai’s BioMe Biobank (protocol number 07-0529). This study was performed in accordance with the ethical standards as laid down in the 1964 Declaration of Helsinki and its later amendments or comparable ethical standards.
Consent to participate
All participants of the Mount Sinai BioMe Biobank provided written informed consent.
Availability of data and material
All expected pathogenic variants in CDH1 are reported in this paper. Exome sequencing and genotyping of BioMe was performed in collaboration with the Regeneron Genetics Center. Individual-level data generated via this collaboration are not publicly available due to the terms of the BioMe biospecimen and data access agreement but may be requested directly from the corresponding author.
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Bar-Mashiah, A., Soper, E.R., Cullina, S. et al. CDH1 pathogenic variants and cancer risk in an unselected patient population. Familial Cancer 21, 235–239 (2022). https://doi.org/10.1007/s10689-021-00257-x
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DOI: https://doi.org/10.1007/s10689-021-00257-x