Molecular lineages of sporadic mismatch-repair deficient colorectal cancer

PURPOSE: Mismatch-repair deficient (MMRd) colorectal cancers (CRC) are classified based on MMR protein loss and BRAF-V600E mutations. BRAF-wild-type(wt) sporadic MMRd tumors exhibit a diverse landscape of alternative oncogenes, including gene fusions, with unclear biologic and clinical significance. We evaluated mutually-exclusive subtypes of sporadic MMRd tumors defined by oncogenic MAPK variants and gene fusions to determine the relationship between predominant genomic driver, MMR deficiency mechanism, and clinical outcomes. PATIENTS AND METHODS: We assessed 6,789 patients with CRC sequenced by MSK-IMPACT to identify 518 patients with sporadic MMRd CRC. We defined mutually-exclusive oncogenic alteration subtypes, then assessed differences in allele-specific MMR-inactivating events, co-occurring oncogenic variants, and patient outcomes. We validated findings in an Italian cohort (n=69). RESULTS: We identify four sporadic MMRd CRC subtypes: (i) oncogenic fusion-positive, (ii) RAS-mutant(mut), (iii) BRAF-V600E-mut, and (iv) MAPK/fusion driver-negative. These mutually-exclusive subtypes were associated with conserved molecular lineages of MMR gene inactivation and WNT signaling variants. Oncogenic fusions were disproportionately prevalent in non-Caucasians, non-smokers and in the transverse colon, compared to subtypes that were enriched in smokers (BRAF-mut) and male, younger patients (RAS-mut and MAPK/fusion-driverless). Oncogene-defined molecular lineages were strong predictors of patient outcomes and response to immunotherapy and tyrosine kinase inhibition for metastatic disease. Fusion-positive patients demonstrated improved survival compared to BRAF mutant cancers and benefitted from immunotherapy and fusion inhibitors. MAPK/fusion driver negative tumors were aneuploid, responded poorly to immunotherapy, and were sensitive to EGFR blockade. CONCLUSIONS: Overall, MAPK and fusion oncogenic drivers distinguish MMRd CRC molecular lineages that inform molecular and clinical phenotypes.