Deficient mismatch repair: Read all about it (Review) Lynch Syndrome

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 Affiliations: Department of Pathology and Tumour Biology, Leeds Institute of Cancer and Pathology, St. James University Hospital, Leeds, LS9 7TF, UK

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Abstract

Defects in the DNA mismatch repair (MMR) proteins, result in a phenotype called microsatellite instability (MSI), occurring in up to 15% of sporadic colorectal cancers. Approximately one quarter of colon cancers with deficient MMR (dMMR) develop as a result of an inherited predisposition syndrome, Lynch syndrome (formerly known as HNPCC). It is essential to identify patients who potentially have Lynch syndrome, as not only they, but also family members, may require screening and monitoring. Diagnostic criteria have been developed, based primarily on Western populations, and several methodologies are available to identify dMMR tumours, including immunohistochemistry and microsatellite testing. These criteria have provided evidence supporting the introduction of reflex testing. Yet, it is becoming increasingly clear that tests have a limited sensitivity and specificity and may yet be superseded by next generation sequencing. In this review, the limitations of diagnostic criteria are discussed, and current and emerging screening technologies explained. There is now useful evidence supporting the prognostic and predictive value of dMMR status in colorectal tumours, but much less is known about their value in extracolonic tumours, that may also feature in Lynch syndrome. This review assesses current literature relating to dMMR in endometrial, ovarian, gastric and melanoma cancers, which it would seem, may benefit from large-scale clinical trials in order to further close the gap in knowledge between colorectal and extracolonic tumours.

 Contents
1. Introduction
2. dMMR in sporadic colorectal cancer
3. dMMR in Lynch syndrome
4. Who (and how) to test for mismatch repair deficiencies?
5. Does ‘one size’ really fit all?
6. Reflex testing
7. MMR immunohistochemistry (IHC)
8. Microsatellite (MSI) testing
9. Next generation sequencing (NGS)
10. Deficient MMR and clinical outcomes
11. Conclusion

Ovarian Cancer:  .....One feature common to most studies was the fact that there was an overrepresentation of the non-serous tumours within the MSI cohorts, which parallels the overrepresentation of mucinous and endometrioid histologies in CRC and endometrial cancers respectively. In terms of data relating to the effect of dMMR or MSI on prognosis or response to chemotherapy, very little has been published, and the results are varied.....Extracolonic cancers trail far behind in terms of what is known of the prognostic and predictive value of MMR, and, our understanding will remain limited unless large controlled trials are performed.