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Cancer genetics
Original research
Validation of the NCCN/Yale criteria for the identification of CDH1 pathogenic variant carriers
  1. Benjamin A Lerner1,
  2. Mar Giner-Calabuig2,
  3. Cassidy Carraway3,
  4. Marcy Richardson4,
  5. Karl Krahn5,
  6. Lisa Susswein5,
  7. Sarah M Nielsen6,
  8. Rachid Karam7,
  9. Rosa M Xicola8,
  10. Xavier Llor2
  1. 1Department of Medicine, Yale University, New Haven, Connecticut, USA
  2. 2Department of Medicine, Yale School of Medicine, New Haven, Connecticut, USA
  3. 3Ambry Genetics Corporation, Aliso Viejo, California, USA
  4. 4Clinical Research, Ambry Genetics, Aliso Viejo, California, USA
  5. 5GeneDx, Stamford, Connecticut, USA
  6. 6Labcorp Genetics, Burlington, North Carolina, USA
  7. 7Ambry Genetics, Aliso Viejo, California, USA
  8. 8Genetics, Yale University, New Haven, CT, USA
  1. Correspondence to Dr Xavier Llor; xavier.llor{at}yale.edu

Abstract

Background Diffuse gastric and lobular breast cancer (LBC) syndrome is an autosomal-dominant syndrome characterised by early-onset diffuse gastric cancer and LBC most often caused by germline pathogenic variants (PVs) in CDH1. We previously showed the International Gastric Cancer Linkage Consortium (IGCLC) criteria for genetic testing to have poor sensitivity for CDH1 PV and proposed our own simpler and more sensitive Yale criteria. The European Reference Network on Genetic Tumour Risk Syndromes subsequently proposed expanding the IGCLC criteria and showed its LBC-expanded criteria to be more sensitive than the IGCLC criteria in a European cohort of CDH1 PV carriers.

Methods We aggregated demographic and clinical data of all CDH1 PV carriers identified at three US commercial laboratories. These data were used to calculate the sensitivity of the IGCLC, LBC-expanded and National Comprehensive Cancer Network (NCCN)/Yale criteria.

Results Data on 708 probands and their 4318 family members were included in the analysis. In this cohort, the sensitivities for detecting CDH1 PVs were 23.6% for IGCLC criteria, 35.7% for LBC-expanded criteria and 82.2% for NCCN/Yale criteria.

Conclusion In a large cohort of CDH1 PV carriers to date, the IGCLC and LBC-expanded criteria called for genetic testing in a minority of CDH1 PV carriers while the Yale criteria detected the large majority. Along with their superior sensitivity, the NCCN/Yale criteria address critical practical challenges in cancer genetics by not depending heavily on pathology information from family members which is often lacking and by incorporating recommendations from other cancer genetics guidelines.

  • Gastrointestinal Diseases
  • Genetic Carrier Screening

Data availability statement

All data relevant to the study are included in the article or uploaded as supplementary information. All data is included in the manuscript and supplementary tables.

https://doi.org/10.1136/jmg-2024-110446

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    Data availability statement

    All data relevant to the study are included in the article or uploaded as supplementary information. All data is included in the manuscript and supplementary tables.

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    Footnotes

    • BAL and MG-C are joint first authors.

    • X @rachidkaram

    • BAL and MG-C contributed equally.

    • Contributors Conceptualisation, supervision of the overall project and edition of the final manuscript draft: BAL, RMX, RK and XL. Data curation: MG-C, CC, MR, KK, LS, SMN. Formal analysis: MG-C, BAL, RMX. Validation, writing—original draft: BAL and XL. Writing—review and editing: BAL, RMX, MG-C, CC, MR, KK, LS, SMN, RK. All authors critically revised the manuscript for important intellectual content. They take full responsibility for the integrity of the data and the accuracy of the data analysis. XL is the guarantor.

    • Funding This work was supported in part by the C Richard Boland Fund (XL) and internal funds. 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; or in the decision to submit the manuscript for publication.

    • Competing interests None declared.

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

    • Supplemental material This content has been supplied by the author(s). It has not been vetted by BMJ Publishing Group Limited (BMJ) and may not have been peer-reviewed. Any opinions or recommendations discussed are solely those of the author(s) and are not endorsed by BMJ. BMJ disclaims all liability and responsibility arising from any reliance placed on the content. Where the content includes any translated material, BMJ does not warrant the accuracy and reliability of the translations (including but not limited to local regulations, clinical guidelines, terminology, drug names and drug dosages), and is not responsible for any error and/or omissions arising from translation and adaptation or otherwise.