Microsatellite Instability in Lynch Syndrome Extra-Colonic Cancers: Why is there a Greater Incidence of MSS in Endometrial Cancers?

Peter Gawthorpe1, Christine Hayes1, Richard Gallon1, Shaun Prior1, Rachel Jones1, Harsh Sheth1,2, Neil Rajan1, Gillian Borthwick1, Mauro Santibanez-Koref1, Michael Jackson1, John Burn1

1Institute of Genetic Medicine – Newcastle University, Newcastle, United Kingdom. 2FRIGE’s Institute of Genetics, Ahmedabad, India


Objectives: Current guidelines recommend testing all colorectal cancers (CRCs) for mismatch repair deficiency (MMRd) and/or microsatellite instability (MSI) to screen for Lynch syndrome (LS) (1-3). Although recently proposed for endometrial tumours (4), testing of extra-colonic cancers (ECCs) is not currently recommended. Recently, we have developed an accurate sequencing-based MSI assay using molecular inversion probes (MIPs), suitable for high-throughput, low-cost diagnostics (5). Here, we apply this to a cohort of ECCs from LS patients.


Methods: DNA was extracted from 92 independent ECCs from LS patients, sourced from the CaPP3 tissue resource (www.capp3.org). Using our MSI assay, 24 mononucleotide repeat markers were amplified and sequenced to a target depth of 2000 reads, before MSI status was determined using our automated classifier (5).


Results: 71% of the ECCs exhibited an MSI-High phenotype. Within LS-spectrum ECCs, 29/39 (74%) endometrial, 6/7 (86%) ovarian, 5/5 (100%) urothelial, and 7/7 (100%) sebaceous cancers were classified as MSI-High. 4/8 (50%) breast, and 14/23 (61%) other skin cancers were also classified MSI-High.


Conclusion: Our assay detected MSI in the majority of samples analysed, including those not typically of the LS spectrum. The frequencies observed are comparable with literature findings (6-9), except for urothelial cancers where we observed a higher frequency than the 46% previously reported (10). Given our assay’s sensitivity (5), the frequency of MSS raises the possibility of diverse pathways of tumorigenesis in LS endometrial cancers. However, these findings suggest our assay could provide an effective, high-throughput screening tool for LS detection within a range of ECCs.

Abstract references

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