High prevalence of unusual KRAS, NRAS, and BRAF mutations in POLE-hypermutated colorectal cancers.
Mol Oncol
; 16(17): 3055-3065, 2022 09.
Article
in En
| MEDLINE
| ID: mdl-35624529
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.
Key words
Full text:
1
Collection:
01-internacional
Database:
MEDLINE
Main subject:
Colorectal Neoplasms
/
Proto-Oncogene Proteins B-raf
/
DNA Polymerase II
/
Poly-ADP-Ribose Binding Proteins
Type of study:
Diagnostic_studies
/
Prevalence_studies
/
Prognostic_studies
/
Risk_factors_studies
Limits:
Humans
/
Male
Language:
En
Journal:
Mol Oncol
Journal subject:
BIOLOGIA MOLECULAR
/
NEOPLASIAS
Year:
2022
Document type:
Article
Affiliation country:
Francia