Open AccessHigh prevalence of unusual KRAS , NRAS , and BRAF mutations in POLE ‐ hypermutated colorectal cancers
Author(s) -
Favre Loetitia,
Cohen Justine,
Calderaro Julien,
Pécriaux Adrien,
Nguyen CongTrung,
Bourgoin Rémi,
Larnaudie Laura,
Dupuy Aurélie,
Ollier Marie,
Lechapt Emmanuèle,
Sloma Ivan,
Tournigand Christophe,
Rousseau Benoit,
Pujals Anaïs
Publication year - 2022
Publication title -
molecular oncology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.332
H-Index - 88
eISSN - 1878-0261
pISSN - 1574-7891
DOI - 10.1002/1878-0261.13257
Subject(s) - kras , neuroblastoma ras viral oncogene homolog , colorectal cancer , medicine , microsatellite instability , oncology , immunotherapy , cancer research , mutation , cancer , biology , genetics , gene , microsatellite , allele
Exonucleasic domain POLE (ed POLE ) 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 ed POLE ‐mutated tumors to facilitate patient screening. Based on opensource data analysis, we compared the prevalence of ed POLE 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 ed POLE mutations were then analyzed. In total, 420 CRC patients were analyzed: 11 ed POLE ‐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 ed POLE ‐mutated tumors in the control vs the experimental screening group was, respectively, 0.45% ( n = 1) vs 5.0% ( n = 10). Among the 11 ed POLE ‐mutated cases, two had a low TMB, three were hypermutated, and six were ultramutated. Ed POLE ‐mutated cases had a high CD8 + tumor‐infiltrating lymphocyte (TIL) infiltration. These clinicopathological and molecular criteria may help to identify ed POLE mutations associated with a high TMB in CRC, and improve the selection of patients who could benefit from immunotherapy.