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Manchester study recommends unselected screening for Lynch syndrome in endometrial cancer

A study led by the University of Manchester has concluded that women with endometrial cancer (EC) should be screened for Lynch syndrome (LS).

The prospective cross-sectional study was carried out at a large UK gynaecological cancer centre between October 2015 and January 2017. Women diagnosed with EC or atypical hyperplasia (AH) were offered LS testing.

Tumours underwent mismatch-repair (MMR) immunohistochemistry (IHC), microsatellite instability (MSI), and targeted MLH1-methylation testing.

Women <50 years, with strong family histories and/or indicative tumour molecular features, underwent MMR germline sequencing. Somatic MMR sequencing was performed when indicative molecular features were unexplained by LS or MLH1-hypermethylation.

In total, 500 women participated in the study. Germline sequencing was indicated and conducted for 136 and 135 women, respectively. A total of 16/500 women (3.2%; 95% CI 1.8%-5.1%) had LS, and 11 more (2.2%) had MMR variants of uncertain significance.

Restricting testing to age <50 years, indicative family history (revised Bethesda guidelines or Amsterdam II criteria) or endometrioid histology alone would have missed 9/16 (56%), 8/13 (62%) or 9/13 (69%), and 5/16 (31%) cases of LS, respectively.

In total 132/500 tumours were MMR deficient by IHC, of which 83/132 (63%) had MLH1-hypermethylation, and 16/49 (33%) of the remaining patients had LS (16/132 with MMR deficiency; 12%).

MMR-IHC with targeted MLH1-methylation testing was more discriminatory for LS than MSI with targeted methylation testing, with 100% versus 56.3% sensitivity (P=0.016) and equal 97.5% specificity. Approximately 64% of MSI-H and 73% MMR of deficient tumours unexplained by LS or MLH1-hypermethylation had somatic MMR mutations.

The study did not conduct MMR germline sequencing for the whole study population, which means that the sensitivity and specificity of tumour triage strategies for LS detection may be overestimated, although the risk of LS in women with no clinical or tumour predictors is expected to be extremely low.

The authors say the 3.2% proportion of LS-EC is similar to colorectal cancer, supporting unselected screening of EC for LS.


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