Challenging Standard Protocols: A New Perspective on MMR Deficiency from a Longitudinal Regional Study

The role of DNA mismatch repair (MMR) tumor testing in colon and endometrial carcinomas is well-established, yet the universal application of this testing faces challenges due to limited data on its efficacy in diverse populations. This retrospective study at a community hospital in Northern Indiana examined MMR immunohistochemistry (IHC) results across 549 cases. Our analysis found intact MMR expression in 469 cases, while 80 demonstrated MMR deficiency, translating to MMR deficiency rates of 10% in colon cancers and 22% in uterine carcinomas. Notably, only 16 patients (2.9%) were categorized as high microsatellite instability (MSI-H), a rate significantly lower than the 3-5-fold higher incidences reported in other Midwestern populations, including Ohio. These findings suggest that the benefits of universal cascade methylation testing, particularly in MLH1/PMS2 IHC-negative tumors, may vary significantly based on regional demographics. Given the notably lower MSI-H incidence in this study, re-evaluating reflex testing protocols in low-resource settings could lead to more targeted, cost-effective approaches without compromising diagnostic accuracy. This study challenges the one-size-fits-all approach to MMR testing, highlighting the need for tailored strategies that consider regional variations in cancer genetics.