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Original research
Systems approach to enhance Lynch syndrome diagnosis through tumour testing
  1. Vinit Singh1,
  2. Catherine Mezzacappa1,
  3. Peter Gershkovich2,
  4. Jessica Di Giovanna3,
  5. Amanda Ganzak3,
  6. Joanna Gibson2,
  7. John Sinard2,
  8. Rosa M Xicola1,
  9. Xavier Llor1
  1. 1 Department of Medicine, Yale University, New Haven, Connecticut, USA
  2. 2 Department of Pathology, Yale University, New Haven, Connecticut, USA
  3. 3 Cancer Genetics and Prevention Program, Yale–New Haven Hospital, New Haven, Connecticut, USA
  1. Correspondence to Dr Xavier Llor, Department of Medicine, Yale University, New Haven, USA; xavier.llor{at}


Background Guidelines recommend universal mismatch repair (MMR) tumour testing of colorectal adenocarcinomas (CRCs) to screen for Lynch syndrome (LS). However, its implementation remains disjointed and referral for genetic testing dismal, particularly among minorities. We aimed to increase referral, cancer genetic testing and eventually LS diagnosis by developing the CLEAR LS (Closed Loop Enhanced Assessment and Referral for Lynch Syndrome) intervention, a systems approach which in the second phase was automated.

Methods This is a cohort study of all patients diagnosed with CRC at an academic centre between 1 January 2012, when implementation of universal CRC testing began, and 31 January 2021. The original cohort spanned through 31 May 2015. Tumour testing included MMR immunohistochemistry, followed by BRAF V600E/MLH1 promoter methylation testing when indicated. The intervention included a manual phase (1 June 2015 through 31 July 2018), which systematised pathology screening and cancer genetics (CG) referral mechanisms, and an automated phase (1 August 2018 through 31 January 2021) using computer programming.

Results A total of 249/1541 CRC (17.38%) had MMR loss of expression and 129 (8.37%) qualified for CG evaluation. Referral was 27.58% in the original cohort and 92.1% in the intervention (p<0.001). Patients seen by CG among referred were 27.58% in the original cohort and 74.3% in the intervention (p two-sided<0.001). The distribution of race/ethnicity among patients qualifying and referred for CG evaluation was not significantly different across cohorts. LS diagnosis increased from 0.56% (original cohort) to 1.43% (intervention). Cost per new diagnosis of LS decreased from US$173 675 to $87 960 from original cohort to intervention.

Conclusion Implementation of systematic case identification and referral support mechanisms significantly increased the proportion of patients undergoing genetic testing and doubled the percentage of patients diagnosed with LS with no referral differences across racial/ethnic groups.

  • diagnosis
  • gastroenterology
  • health services research

Data availability statement

All data relevant to the study are included in the article or uploaded as online supplemental information.

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Data availability statement

All data relevant to the study are included in the article or uploaded as online supplemental information.

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  • RMX and XL are joint senior authors.

  • Correction notice This article has been corrected since it was published online first. A statement about co-senior authorship between RMX and XL has been added.

  • Contributors Conceptualisation, supervision of the overall project and edition of the final manuscript draft: RMX, XL. Data curation: JDG, AG, JS, JG, PG, CM, VS. Software: JS, PG. Formal analysis: VS, CM, RMX, XL. Validation, writing—original draft: VS, CM, RMX, XL. Writing—review and editing: VS, CM, RMX, XL, JS, JG. 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. Guarantors: RMX and XL.

  • Funding This work was supported by the C. Richard Boland Fund (XL); and the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDKO): T32DK007356 (CM).

  • 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.