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Lessons learnt from implementation of a Lynch syndrome screening program for patients with gynaecological malignancy
Fedaa Najdawi1, Ashley Crook2, Jayne Maidens3
1Cancer Diagnosis and Pathology Group, Kolling Institute of Medical Research, St Leonards, NSW, Australia; Department of Anatomical Pathology, Royal North Shore Hospital, St Leonards, NSW, Australia.
Pathology
|July 4, 2017
Summary
Universal screening for Lynch syndrome (LS) in gynecological cancer patients identified LS in 2.4% of cases. This approach detected LS cases missed by traditional criteria, highlighting its value in early cancer detection.
Area of Science:
- Oncology
- Genetics
- Pathology
Background:
- Lynch syndrome (LS) is an inherited disorder increasing cancer risk.
- Optimal screening strategies for LS in gynecological malignancies remain debated.
- Current guidelines may miss LS cases in this patient population.
Purpose of the Study:
- To evaluate the effectiveness of a coordinated institutional program for Lynch syndrome screening in patients with gynecological malignancies.
- To determine the yield of a specific screening algorithm involving immunohistochemistry and methylation analysis.
- To assess the concordance of molecular findings with clinical presentation and traditional LS diagnostic criteria.
Main Methods:
- Implementation of a four-panel immunohistochemistry (IHC) for MMR proteins (MLH1, PMS2, MSH2, MSH6) in patients with specific gynecological cancers.
- Cascade analysis including MLH1 promoter methylation testing for dual MLH1/PMS2 negative tumors.
- Germline mutation testing and genetic counseling offered to high-risk individuals based on IHC and methylation results.
- Massive parallel sequencing for tumor somatic mutation analysis.
Main Results:
- 124 patients were screened; 29% showed abnormal MMR IHC.
- MLH1/PMS2 loss was most common (72.2%), with 96.1% showing MLH1 promoter methylation.
- The screening algorithm identified 11 high-risk patients (8.9%), leading to germline testing for 9.
- Lynch syndrome was confirmed in 3 patients (2.4%), including one under 50, and none would have met Amsterdam or Bethesda criteria.
Conclusions:
- The described universal screening algorithm effectively identifies Lynch syndrome in gynecological malignancy patients.
- This comprehensive approach detects LS cases missed by restrictive criteria like Amsterdam or Bethesda.
- MLH1 promoter methylation testing is crucial for MLH1/PMS2 deficient tumors, but its universal application in all IHC-negative tumors warrants reconsideration in resource-limited settings.
