Molecular Lineages of Sporadic Mismatch Repair-Deficient Colorectal Cancer.

PURPOSE: Mismatch repair-deficient (MMRd) colorectal cancers are classified based on MMR protein loss and BRAFV600E mutations. BRAF wild-type sporadic MMRd tumors exhibit a diverse landscape of alternative oncogenes, including gene fusions, with unclear biological and clinical significance. We evaluated mutually exclusive subtypes of sporadic MMRd tumors defined by oncogenic mitogen-activated protein kinase (MAPK) variants and gene fusions to determine the relationship among predominant genomic driver, MMR deficiency mechanism, and clinical outcomes.

EXPERIMENTAL

DESIGN

We assessed 6,789 patients with colorectal cancer sequenced by MSK-IMPACT to identify 518 patients with sporadic MMRd colorectal cancer. We defined mutually exclusive oncogenic alteration subtypes and 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 4 sporadic MMRd colorectal cancer subtypes: (i) oncogenic fusion-positive, (ii) RAS-mutant (mut), (iii) BRAFV600E-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, among nonsmokers, and in the transverse colon, compared with 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 with BRAF-mut cancers and benefited 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 colorectal cancer molecular lineages that inform molecular and clinical phenotypes.