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Updated: Apr 23, 2026
Deficient Pms2, ERCC1, Ku86, CcOI in Field Defects During Progression to Colon Cancer
Published on: July 28, 2010
Molecular Lineages of Sporadic Mismatch Repair-Deficient Colorectal Cancer
Michael B Foote1, Guilherme Harada2, Somer Abdelfattah1
1Division of Solid Tumor Oncology, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York.
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.
Insights
Four subtypes of mismatch-repair deficient colorectal cancer (MMRd CRC) were identified based on MAPK and fusion drivers. These subtypes correlate with distinct molecular lineages, clinical outcomes, and treatment responses, guiding personalized CRC therapy.
Area of Science:
- Oncology
- Genomics
- Molecular Biology
Background:
- Mismatch-repair deficient (MMRd) colorectal cancer (CRC) is often classified by MMR protein loss and BRAF-V600E mutations.
- BRAF-wild-type (wt) sporadic MMRd tumors present a complex landscape of alternative oncogenes, including gene fusions, whose biological and clinical significance remains unclear.
Purpose of the Study:
- To evaluate mutually-exclusive subtypes of sporadic MMRd tumors defined by oncogenic MAPK variants and gene fusions.
- To determine the relationship between the predominant genomic driver, the mechanism of mismatch repair deficiency, and clinical outcomes in CRC.
Main Methods:
- Analysis of 6,789 CRC patients sequenced by MSK-IMPACT to identify 518 patients with sporadic MMRd CRC.
- Definition of mutually-exclusive oncogenic alteration subtypes and assessment of differences in MMR-inactivating events, co-occurring variants, and patient outcomes.
- Validation of findings in an independent Italian cohort (n=69).
Main Results:
- Four distinct sporadic MMRd CRC subtypes were identified: oncogenic fusion-positive, RAS-mutant, BRAF-V600E-mutant, and MAPK/fusion driver-negative.
- These subtypes exhibited conserved molecular lineages of MMR gene inactivation and WNT signaling variants, with distinct demographic and clinical associations (e.g., fusions in non-Caucasians, BRAF-mut in smokers).
- Oncogene-defined lineages predicted patient outcomes and response to immunotherapy and tyrosine kinase inhibitors; fusion-positive patients showed improved survival and benefited from immunotherapy and fusion inhibitors, while MAPK/fusion driver-negative tumors responded poorly to immunotherapy but were sensitive to EGFR blockade.
Conclusions:
- MAPK and fusion oncogenic drivers effectively distinguish MMRd CRC molecular lineages.
- These molecular lineages inform distinct molecular and clinical phenotypes, paving the way for targeted therapeutic strategies.
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