Lessons learnt from implementation of a Lynch syndrome screening program for patients with gynaecological malignancy

Fedaa Najdawi, Ashley Crook, Jayne Maidens, Christopher McEvoy, Andrew Fellowes, Justine Pickett, Musei Ho, David Nevell, Kirsten McIlroy, Amy Sheen, Loretta Sioson, Mahsa Ahadi, John Turchini, Adele Clarkson, Russell Hogg, Sue Valmadre, Greg Gard, Susan J. Dooley, Rodney J. Scott, Stephen B. Fox & 2 others Michael Field, Anthony J. Gill*

*Corresponding author for this work

Research output: Contribution to journalArticle

15 Citations (Scopus)


Despite a trend towards universal testing, best practice to screen patients presenting with gynaecological malignancy for Lynch syndrome (LS) is uncertain. We report our institutional experience of a co-ordinated gynaecological LS screening program. All patients with endometrial carcinoma or carcinosarcoma, or gynaecological endometrioid or clear cell carcinomas undergo reflex four panel immunohistochemistry (IHC) for MLH1, PMS2, MSH2 and MSH6 followed by cascade somatic hypermethylation analysis of the MLH1 promoter locus for dual MLH1/PMS2 negative tumours. On the basis of these results, genetic counselling and targeted germline mutation testing is then offered to patients considered at high risk of LS. From 1 August 2013 to 31 December 2015, 124 patients were screened (mean age 64.6 years). Thirty-six (29.0%) demonstrated abnormal MMR IHC: 26 (72.2%) showed dual loss of MLH1/PMS2, five (13.9%) dual loss of MSH2/MSH6, three (8.3%) isolated loss of MSH6, and two (5.6%) isolated loss of PMS2. Twenty-five of 26 (96.1%) patients with dual MLH1/PMS2 loss demonstrated MLH1 promoter methylation. Therefore, 11 (8.9%) patients screened were classified as high risk for LS, of whom nine (81.8%) accepted germline mutation testing. Three (2.4% of total screened) were confirmed to have LS, two with germline PMS2 and one with germline MSH2 mutation. Massive parallel sequencing of tumour tissue demonstrated somatic mutations which were concordant with the IHC results in the remainder. Interestingly, the one MLH1/PMS2 IHC negative but not hypermethylated tumour harboured only somatic MLH1 mutations, indicating that universal cascade methylation testing in MLH1/PMS2 IHC negative tumours is very low yield and could be reconsidered in a resource-poor setting.In conclusion, universal screening for LS in patients presenting with gynaecological malignancy using the algorithm described above identified LS in three of 124 (2.4%) of our population. Only three of nine (33.3%) patients considered at high risk for LS by combined IHC and hypermethylation analysis were proven to have LS. Only one of the LS patients was less than 50 years of age and none of these patients would have been identified had more restrictive Amsterdam or Bethesda criteria been applied.

Original languageEnglish
Pages (from-to)457-464
Number of pages8
Issue number5
Publication statusPublished - Aug 2017
Externally publishedYes


  • Lynch syndrome
  • Lynch-like syndrome
  • Mismatch repair

Fingerprint Dive into the research topics of 'Lessons learnt from implementation of a Lynch syndrome screening program for patients with gynaecological malignancy'. Together they form a unique fingerprint.

  • Cite this