N56: Incorporating Somatic Sequencing Into Current Molecular Testing Strategies For Lynch Syndrome

B. Desouza, G. Norbury, A. Kulkarni, D. Ruddy, V. Tripathi, L. Izatt, A. Shaw

Guy’s Regional Genetics Service


Background: UK guidelines recommend that all newly diagnosed colorectal cancers (CRCs) be screened for mismatch repair deficiency (MMR-D) that may be indicative of Lynch syndrome (LS). Current diagnostic approaches, will fail to detect MLH1 promoter hypermethylation or a germline mutation in approximately 60% of suspected LS cases. In most cases the diagnosis of LS can be excluded by somatic sequencing through the demonstration of double somatic mismatch repair (MMR) mutations.

Method: We have used our clinical data from over 1100 families to model costs for different diagnostic strategies for LS that integrate germline and somatic testing.   Outcomes were correlated to family history category of either revised Bethesda guidelines or modified Amsterdam criteria.

Results: Modelling shows that for Bethesda families, performing concurrent germline and somatic testing would be more cost-effective than sequential germline and somatic testing (£523 vs. £940 per proband). For Amsterdam families, however, performing sequential testing would be more cost-effective than concurrent testing (£617 vs. £1256 per proband).

Conclusion: LS diagnostic strategies for CRC cases could be accelerated and simplified by concurrent germline and somatic testing. Moreover, our data suggests that this approach is more cost-effective than sequential testing in Bethesda families.