High prevalence of unusual KRAS, NRAS, and BRAF mutations in POLE-hypermutated colorectal cancers Journal Article


Authors: Favre, L.; Cohen, J.; Calderaro, J.; Pécriaux, A.; Nguyen, C. T.; Bourgoin, R.; Larnaudie, L.; Dupuy, A.; Ollier, M.; Lechapt, E.; Sloma, I.; Tournigand, C.; Rousseau, B.; Pujals, A.
Article Title: High prevalence of unusual KRAS, NRAS, and BRAF mutations in POLE-hypermutated colorectal cancers
Abstract: Exonucleasic domain POLE (edPOLE) mutations, which are responsible for a hypermutated tumor phenotype, occur in 1–2% of colorectal cancer (CRC) cases. These alterations represent an emerging biomarker for response to immune checkpoint blockade. This study aimed to assess the molecular characteristics of edPOLE-mutated tumors to facilitate patient screening. Based on opensource data analysis, we compared the prevalence of edPOLE mutations in a control group of unselected CRC patients (n = 222) vs a group enriched for unusual BRAF/RAS mutations (n = 198). Tumor mutational burden (TMB) and immune infiltrate of tumors harboring edPOLE mutations were then analyzed. In total, 420 CRC patients were analyzed: 11 edPOLE-mutated tumors were identified, most frequently in microsatellite (MMR)-proficient young (< 70 years) male patients, with left-sided tumors harboring noncodon 12 KRAS mutation. The prevalence of edPOLE-mutated tumors in the control vs the experimental screening group was, respectively, 0.45% (n = 1) vs 5.0% (n = 10). Among the 11 edPOLE-mutated cases, two had a low TMB, three were hypermutated, and six were ultramutated. EdPOLE-mutated cases had a high CD8+ tumor-infiltrating lymphocyte (TIL) infiltration. These clinicopathological and molecular criteria may help to identify edPOLE mutations associated with a high TMB in CRC, and improve the selection of patients who could benefit from immunotherapy. © 2022 The Authors. Molecular Oncology published by John Wiley & Sons Ltd on behalf of Federation of European Biochemical Societies.
Keywords: adult; controlled study; aged; middle aged; major clinical study; genetics; mutation; cancer patient; colorectal cancer; cd8+ t lymphocyte; tumor associated leukocyte; cell infiltration; prevalence; membrane proteins; microsatellite dna; tumor marker; age; colorectal neoplasms; oncogene; immunotherapy; colorectal tumor; membrane protein; data analysis; oncogene k ras; gender; genetic screening; protein p21; proto-oncogene proteins p21(ras); b raf kinase; proto-oncogene proteins b-raf; braf protein, human; kras protein, human; gtp phosphohydrolases; hypermutation; colorectal cancers; guanosine triphosphatase; oncogene n ras; oncogene b raf; humans; human; male; female; article; polymerase epsilon; nras protein, human; biomarkers, tumor; pole; tumor mutational burden; exonucleasic domain pole
Journal Title: Molecular Oncology
Volume: 16
Issue: 17
ISSN: 1878-0261
Publisher: FEBS Press  
Date Published: 2022-09-01
Start Page: 3055
End Page: 3065
Language: English
DOI: 10.1002/1878-0261.13257
PUBMED: 35624529
PROVIDER: scopus
PMCID: PMC9441000
DOI/URL:
Notes: Article -- Export Date: 3 October 2022 -- Source: Scopus
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