Molecular lineages of sporadic mismatch-repair deficient colorectal cancer.
OpenAlex 토픽 ·
Genetic factors in colorectal cancer
Colorectal Cancer Treatments and Studies
Multiple and Secondary Primary Cancers
[PURPOSE] Mismatch-repair deficient (MMRd) colorectal cancers (CRC) are classified based on MMR protein loss and BRAF-V600E mutations.
- 표본수 (n) 69
APA
Michael B. Foote, Guilherme Harada, et al. (2026). Molecular lineages of sporadic mismatch-repair deficient colorectal cancer.. Clinical cancer research : an official journal of the American Association for Cancer Research. https://doi.org/10.1158/1078-0432.CCR-26-0024
MLA
Michael B. Foote, et al.. "Molecular lineages of sporadic mismatch-repair deficient colorectal cancer.." Clinical cancer research : an official journal of the American Association for Cancer Research, 2026.
PMID
42013404
Abstract
[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.
[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.