MMR Deficiency Defines Distinct Molecular Subtype of Breast Cancer with Unique Proteomic Networks and Variable Clinical Significance

Mismatch repair (MMR) alterations are important prognostic and predictive biomarkers in a variety of cancer subtypes including colorectal and endometrial. However, in breast cancer (BC), the distinction and clinical significance of MMR is largely unknown. This may be due in part to the fact that genetic alterations in MMR genes are rare, and only seen to occur in around 3% of BCs. In the present study we analyzed TCGA data using a multi-sample protein-protein interactions (PPI) analysis tool, Proteinarium, and showed a distinct separation in the MMR deficient and intact specific networks. MMR deficient tumor specific networks have a highly connected cluster of histone genes, identified by unique PPI. We also found that distribution of MMR deficient breast cancer is more prevalent in HER2-enriched and triple-negative (TN) BC subtypes compared to luminal BCs. Poorer survival was seen in patients with HER2-enriched BCs with MMR deficiency, whereas an improved survival was seen in TNBCs with MMR deficiency. We recommend defining MMR deficient breast cancer by next generation sequencing (NGS) when any somatic mutation is detected in one of the 7 MMR genes found in our study. Our recommendations include labeling patients with variants of undetermined significance (VUS) as MMR deficient supported by findings from distinct clusters of patients based on our network analysis. MMR may have a role in guiding the use of immunotherapy for both TN as well as HER2-enriched BC.