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

Autor: Favre L; Département de Pathologie, AP-HP, Centre Hospitalier Universitaire Henri Mondor, Créteil, France.; INSERM, IMRB, Univ Paris Est Creteil, France., Cohen J; Département de Pathologie, AP-HP, Centre Hospitalier Universitaire Henri Mondor, Créteil, France., Calderaro J; Département de Pathologie, AP-HP, Centre Hospitalier Universitaire Henri Mondor, Créteil, France.; INSERM, IMRB, Univ Paris Est Creteil, France., Pécriaux A; Département de Pathologie, AP-HP, Centre Hospitalier Universitaire Henri Mondor, Créteil, France., Nguyen CT; INSERM, IMRB, Univ Paris Est Creteil, France., Bourgoin R; Département de Pathologie, AP-HP, Centre Hospitalier Universitaire Henri Mondor, Créteil, France., Larnaudie L; Département de Pathologie, AP-HP, Centre Hospitalier Universitaire Henri Mondor, Créteil, France., Dupuy A; INSERM, IMRB, Univ Paris Est Creteil, France., Ollier M; Département de Pathologie, AP-HP, Centre Hospitalier Universitaire Henri Mondor, Créteil, France., Lechapt E; Département de Pathologie, AP-HP, Centre Hospitalier Universitaire Henri Mondor, Créteil, France.; INSERM, IMRB, Univ Paris Est Creteil, France., Sloma I; INSERM, IMRB, Univ Paris Est Creteil, France.; Département d'Hématologie Biologique, AP-HP, Centre Hospitalier Universitaire Henri Mondor, Créteil, France., Tournigand C; INSERM, IMRB, Univ Paris Est Creteil, France.; Service d'Oncologie Médicale, AP-HP, Centre Hospitalier Universitaire Henri Mondor, Créteil, France., Rousseau B; Service d'Oncologie Médicale, AP-HP, Centre Hospitalier Universitaire Henri Mondor, Créteil, France.; Mortimer B. Zuckerman Research Center, Memorial Sloan Kettering Cancer Center, New York, NY, USA., Pujals A; Département de Pathologie, AP-HP, Centre Hospitalier Universitaire Henri Mondor, Créteil, France.; INSERM, IMRB, Univ Paris Est Creteil, France.
Jazyk: angličtina
Zdroj: Molecular oncology [Mol Oncol] 2022 Sep; Vol. 16 (17), pp. 3055-3065. Date of Electronic Publication: 2022 Jul 14.
DOI: 10.1002/1878-0261.13257
Abstrakt: 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.)
Databáze: MEDLINE
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