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The proportion of endometrial tumours associated with Lynch syndrome (PETALS): A prospective cross-sectional study

  • 0Division of Cancer Sciences, Faculty of Biology, Medicine and Health, University of Manchester, St Mary's Hospital, Manchester, United Kingdom.
Plos Medicine +

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September 17, 2020

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September 17, 2020

View abstract on PubMed

Summary

This summary is machine-generated.

Lynch syndrome (LS) is found in 3.2% of endometrial cancer (EC) patients. Unselected screening of EC for LS is recommended, as clinical factors alone are insufficient for diagnosis.

Area Of Science

  • Oncology
  • Genetics
  • Gynaecological Oncology

Background

  • Lynch syndrome (LS) significantly increases the risk of endometrial cancer (EC) and other malignancies due to inherited mismatch-repair (MMR) gene variants.
  • Diagnosing LS in women with EC facilitates crucial interventions like colonoscopic surveillance, aspirin chemoprevention, and cascade testing for relatives, reducing cancer mortality.
  • Current LS screening strategies for EC lack definitive validation regarding test positivity rates and optimal testing pathways, particularly in unselected populations.

Purpose Of The Study

  • To determine the prevalence of Lynch syndrome (LS) in an unselected cohort of women diagnosed with endometrial cancer (EC).
  • To evaluate the diagnostic accuracy of various clinical and tumor-based testing strategies for identifying LS in EC patients.
  • To establish an optimal testing strategy for risk stratification of EC patients for MMR germline sequencing.

Main Methods

  • A prospective cross-sectional study involving 500 women with EC or atypical hyperplasia (AH) at a UK gynaecological cancer center.
  • Tumor analysis included MMR immunohistochemistry (IHC), microsatellite instability (MSI) testing, and MLH1-methylation analysis.
  • MMR germline sequencing was performed for women meeting specific criteria (age <50, strong family history, indicative tumor features); somatic MMR sequencing was also conducted.

Main Results

  • The prevalence of LS in the unselected EC population was 3.2% (16/500), with an additional 2.2% having MMR variants of uncertain significance.
  • Clinical risk factors (age, family history, histology) were imprecise, missing a significant proportion of LS cases (31-69%).
  • MMR-IHC combined with MLH1-methylation testing demonstrated higher sensitivity (100%) and comparable specificity (97.5%) for LS detection compared to MSI testing.

Conclusions

  • Age, family history, and histology are unreliable predictors for Lynch syndrome in endometrial cancer patients.
  • MMR immunohistochemistry (IHC) is a superior method for tumor triage in LS screening compared to MSI testing.
  • The 3.2% prevalence of LS in EC supports the implementation of unselected LS screening in all EC patients.