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Clinical features and cancer risk in families with pathogenic CDH1 variants irrespective of clinical criteria
  1. Rosa M Xicola1,
  2. Shuwei Li2,
  3. Nicolette Rodriguez1,
  4. Patrick Reinecke2,
  5. Rachid Karam3,
  6. Virginia Speare2,
  7. Mary Helen Black4,
  8. Holly LaDuca2,
  9. Xavier Llor1
  1. 1 Medicine, Yale University School of Medicine, New Haven, Connecticut, USA
  2. 2 Clinical Diagnostics, Ambry Genetics Corporation, Aliso Viejo, California, USA
  3. 3 Ambry Translational Genomics (ATG) Lab. Ambry Genetics Corporation, Aliso Viejo, California, USA
  4. 4 Statistical Genetics, Ambry Genetics Corporation, Aliso Viejo, California, USA
  1. Correspondence to Dr Xavier Llor, Medicine, Yale University School of Medicine, New Haven, CT 06520-8019, USA; xavier.llor{at}


Background The clinical phenotype of CDH1 pathogenic variant carriers has mostly been studied in families that fulfil criteria of hereditary diffuse gastric cancer (HDGC). We aimed at determining cancer phenotype and cancer risk estimation among families with CDH1 pathogenic variants not selected by HDGC clinical criteria.

Methods Patients were all consecutively identified CDH1 pathogenic variant carriers from a clinical laboratory tested with multigene panel testing and from an academic cancer genetics programme. Clinical and demographic features, cancer phenotypes and genotype–phenotype correlations were determined among CDH1 families. Age-specific cumulative cancer risks (penetrance) were calculated based on 38 families with available pedigrees.

Results Within the 113 CDH1 pathogenic variant probands and 476 relatives, 113 had gastric cancer, 177 breast cancer and 196 other cancers. Mean age at diagnosis was 47 for gastric and 54 for breast cancer. Forty-six per cent fulfilled criteria of HDGC. While 36% of families had both gastric and breast cancers, 36% had breast but no gastric cancers and 16% had gastric but not breast cancers. Cumulative risk of cancer by age 80 was 37.2% for gastric and 42.9% for breast cancer.

Conclusion In unselected CDH1 pathogenic variant carrier families, gastric cancer risks were lower and age at diagnosis higher than previously reported in families pre-selected for HDGC criteria. A substantial proportion of families did not present with any gastric cancers and their cancers were limited to breast. Thus, clinical criteria for CDH1 testing should be widened, including breast cancer families only, and a consideration for delayed prophylactic gastrectomy/surveillance should be evaluated.

  • hereditary diffuse gastric cancer (hdgc)
  • cdh1pathogenic variants
  • cdh1cumulative cancer risk
  • cdh1cancer phenotypes

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  • RMX and SL are joint first authors.

  • Contributors RMX, HL and XL designed and supervised the overall project. RMX, NR, SL, RK, VS and PR compiled and analysed the data and performed the statistical analysis. RMX and XL interpreted the data and drafted the manuscript. They take full responsibility for the integrity of the data and the accuracy of the data analysis. MHB, NR and SL critically revised the manuscript for important intellectual content.

  • Funding This work was supported by internal funds from the Yale Cancer Center (XL). RMX was supported by the Prevent Cancer Foundation.

  • Disclaimer The study sponsors had no role in the design of the study; in the collection, analysis or interpretation of the data; in the writing of the manuscript; and in the decision to submit the manuscript for publication.

  • Competing interests SL, PR, RK, VS, MHB and HL work at Ambry Genetics. There are no competing interests for any author.

  • Patient consent for publication Not required.

  • Provenance and peer review Not commissioned; externally peer reviewed.

  • Data availability statement All data relevant to the study are included in the article or uploaded as online supplementary information.

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