A novel microsatellite instability test of sebaceous tumours to facilitate low cost universal screening for Lynch syndrome.

Abstract

Background: One in five sebaceous tumour (ST) patients may have Lynch syndrome (LS), a hereditary cancer predisposition. LS patients benefit from cancer surveillance and prevention programmes and immunotherapy. Whilst universal tumour mismatch repair (MMR) deficiency testing is recommended in colorectal and endometrial cancers to screen for LS, there is no consensus screening strategy for ST, leading to low testing rates and inequity of care.

Objectives: To assess a low cost and scalable, sequencing-based, microsatellite instability (MSI) assay, previously shown to enhance LS screening of colorectal cancers, for MMR deficiency detection in ST against the current clinical standard of immunohistochemistry (IHC).

Methods: One-hundred-and-seven consecutive ST cases were identified from a single pathology department. MMR protein IHC staining was interpreted by a consultant histopathologist. MSI analysis used amplicon-sequencing of 14 microsatellites and a naïve Bayesian classifier to calculate sample MSI score.

Results: Loss of MMR protein expression was observed in 49/104 ST with interpretable IHC (47.1%; 95% CI: 37.3-57.2%). MMR deficiency was less frequent in carcinoma than adenoma and sebaceoma (P = 4.74x10-3). The majority of MMR deficient ST had concurrent loss of MSH2 and MSH6 expression. The MSI score achieved a receiver operator characteristic area under curve of 0.944 relative to IHC. Lower MSI scores were associated with MSH6 deficiency.

Conclusions: These data support MSI testing as an adjunct or alternative to MMR IHC in ST. Integration of ST into established LS screening pathways using this high throughput methodology could increase testing and reduce costs.