Article Text

Download PDFPDF
Original article
Associations of CDH1 germline variant location and cancer phenotype in families with hereditary diffuse gastric cancer (HDGC)
  1. Winifred Lo1,
  2. Bin Zhu2,
  3. Arvind Sabesan1,
  4. Ho-Hsiang Wu2,
  5. Astin Powers3,
  6. Rebecca A Sorber1,4,
  7. Sarangan Ravichandran5,
  8. Ina Chen1,6,
  9. Lucas A McDuffie1,4,
  10. Humair S Quadri1,7,
  11. Joal D Beane1,4,
  12. Kathleen Calzone8,
  13. Markku M Miettinen3,
  14. Stephen M Hewitt9,
  15. Christopher Koh10,
  16. Theo Heller10,
  17. Sholom Wacholder2,
  18. Udo Rudloff1,11
  1. 1 Thoracic and Surgical Oncology Branch, National Cancer Institute, Bethesda, Maryland, USA
  2. 2 Biostatistics Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institute of Health, Bethesda, Maryland, USA
  3. 3 Laboratory of Pathology, Center for Cancer Research, National Cancer Institute, Bethesda, Maryland, USA
  4. 4 Department of Surgery, Indiana University School of Medicine, Indianapolis, Indiana, USA
  5. 5 Advanced Biomedical Computing Center, Frederick National Laboratory for Cancer Research, Frederick, Maryland, USA
  6. 6 Department of Surgery, Washington University School of Medicine, St. Louis, Missouri, USA
  7. 7 Department of Surgery, MedStar Georgetown University Hospital, Washington, District of Columbia, USA
  8. 8 Genetics Branch, Center for Cancer Research, National Cancer Institute, Bethesda, Maryland, USA
  9. 9 Experimental Pathology Laboratory, National Cancer Institute, Bethesda, Maryland, USA
  10. 10 Liver Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases, Bethesda, Maryland, USA
  11. 11 Rare Tumor Initiative, Pediatric Oncology Branch, National Cancer Institute, Bethesda, Maryland, USA
  1. Correspondence to Dr Udo Rudloff, Center for Cancer Research, National Cancer Institute, Bethesda, MD 20892, USA; rudloffu{at}


Introduction Hereditary diffuse gastric cancer (HDGC) is a cancer syndrome associated with variants in E-cadherin (CDH1), diffuse gastric cancer and lobular breast cancer. There is considerable heterogeneity in its clinical manifestations. This study aimed to determine associations between CDH1 germline variant status and clinical phenotypes of HDGC.

Methods One hundred and fifty-two HDGC families, including six previously unreported families, were identified. CDH1 gene-specific guidelines released by the Clinical Genome Resource (ClinGen) CDH1 Variant Curation Expert Panel were applied for pathogenicity classification of truncating, missense and splice site CDH1 germline variants. We evaluated ORs between location of truncating variants of CDH1 and incidence of colorectal cancer, breast cancer and cancer at young age (gastric cancer at <40 or breast cancer <50 years of age).

Results Frequency of truncating germline CDH1 variants varied across functional domains of the E-cadherin receptor gene and was highest in linker (0.05785 counts/base pair; p=0.0111) and PRE regions (0.10000; p=0.0059). Families with truncating CDH1 germline variants located in the PRE-PRO region were six times more likely to have family members affected by colorectal cancer (OR 6.20, 95% CI 1.79 to 21.48; p=0.004) compared with germline variants in other regions. Variants in the intracellular E-cadherin region were protective for cancer at young age (OR 0.2, 95% CI 0.06 to 0.64; p=0.0071) and in the linker regions for breast cancer (OR 0.35, 95% CI 0.12 to 0.99; p=0.0493). Different CDH1 genotypes were associated with different intracellular signalling activation levels including different p-ERK, p-mTOR and β-catenin levels in early submucosal T1a lesions of HDGC families with different CDH1 variants.

Conclusion Type and location of CDH1 germline variants may help to identify families at increased risk for concomitant cancers that might benefit from individualised surveillance and intervention strategies.

  • cancer: gastric
  • clinical genetics

Statistics from

Request Permissions

If you wish to reuse any or all of this article please use the link below which will take you to the Copyright Clearance Center’s RightsLink service. You will be able to get a quick price and instant permission to reuse the content in many different ways.


  • WL, BZ and AS contributed equally.

  • Contributors BZ, SW and UR designed the study. WL, AS, RS, SR, IC, LM, HQ and JB performed the systematic review, identified the HDGC families and captured clinicopathological and genetic information. KC, CK, TH and UR were responsible for the familial gastric cancer registry and accuracy of genetic information of novel HDGC families included into the studies. SR conducted all molecular predictions, BZ and HW performed the statistical analysis. AP, MM and SH performed the pathology review, histopathological sectioning and immunostaining of T1a lesions. WL, BZ, AS, HW, SR and UR wrote the manuscript, which was approved by all authors.

  • Funding This work was supported by the intramural research program from the National Cancer Institute, National Institutes of Health, under contract HHSN261200800001E.

  • Disclaimer The content of this publication does not reflect the views of policies of the Department of Health and Human Services, nor does mention of trade names, commercial products, or organizations imply endorsement by the U.S. government.

  • Competing interests None declared.

  • Patient consent Not required.

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

  • Data sharing statement Data are available upon reasonable request to the corresponding author.