Clinicopathological, molecular, and prognostic features of colorectal carcinomas with KRAS c.34G>T (p.G12C) mutation

• Published in: Cancer science 2024-10, Vol.115 (10), p.3455-3465
• Main Authors: Ugai, Satoko, Yao, Qian, Takashima, Yasutoshi, Zhong, Yuxue, Matsuda, Kosuke, Kawamura, Hidetaka, Imamura, Yu, Okadome, Kazuo, Mima, Kosuke, Arima, Kota, Kosumi, Keisuke, Song, Mingyang, Meyerhardt, Jeffrey A., Giannakis, Marios, Nowak, Jonathan A., Ugai, Tomotaka, Ogino, Shuji
• Format: Article
• Language: English
• Subjects: adagrasib; Adult; Aged; Aged, 80 and over; Biobanks; Cancer therapies; Cecum; Class I Phosphatidylinositol 3-Kinases - genetics; Cohort analysis; Colorectal cancer; Colorectal carcinoma; Colorectal Neoplasms - genetics; Colorectal Neoplasms - mortality; Colorectal Neoplasms - pathology; colorectal tumor; Committees; CpG island methylator phenotype; CpG islands; CpG Islands - genetics; DNA Methylation; Family medical history; Female; Genes; Humans; Hypotheses; K-Ras protein; Kinases; KRAS; Male; Medical personnel; Medical prognosis; Microsatellite Instability; Middle Aged; Mortality; Mutants; Mutation; Original; Patients; Phenotypes; Polymerase chain reaction; Prognosis; Prospective Studies; Proteins; Proto-Oncogene Proteins B-raf - genetics; Proto-Oncogene Proteins p21(ras) - genetics; sotorasib; Survival analysis; Tumors; Variables
• ISSN: 1347-9032; 1349-7006; 1349-7006
• DOI: 10.1111/cas.16262

Evidence indicates that combinations of anti‐EGFR antibodies and KRAS p.G12C (c.34G>T) inhibitors can be an effective treatment strategy for advanced colorectal cancer. We hypothesized that KRAS c.34G>T (p.G12C)‐mutated colorectal carcinoma might be a distinct tumor subtype. We utilized a prospective cohort incident tumor biobank (including 1347 colorectal carcinomas) and detected KRAS c.34G>T (p.G12C) mutation in 43 cases (3.2%) and other KRAS mutations (in codon 12, 13, 61, or 146) in 467 cases (35%). The CpG island methylator phenotype (CIMP)‐low prevalence was similarly higher in KRAS c.34G>T mutants (52%) and other KRAS mutants (49%) than in KRAS‐wild‐type tumors (31%). KRAS c.34G>T mutants showed higher CIMP‐high prevalence (14%) and lower CIMP‐negative prevalence (33%) compared with other KRAS mutants (6% and 45%, respectively; p = 0.0036). Similar to other KRAS mutants, KRAS c.34G>T‐mutated tumors were associated with cecal location, non‐microsatellite instability (MSI)‐high status, BRAF wild type, and PIK3CA mutation when compared with KRAS‐wild‐type tumors. Compared with BRAF‐mutated tumors, KRAS c.34G>T mutants showed more frequent LINE‐1 hypomethylation, a biomarker for early‐onset colorectal carcinoma. KRAS c.34G>T mutants were not associated with other features, including the tumor tissue abundance of Fusobacterium nucleatum (F. animalis), pks+ Escherichia coli, Bifidobacterium, or (enterotoxigenic) Bacteroides fragilis. Among 1122 BRAF‐wild‐type colorectal carcinomas, compared with KRAS‐wild‐type tumors, multivariable‐adjusted colorectal cancer‐specific mortality hazard ratios (95% confidence interval) were 1.82 (1.05–3.17) in KRAS c.34G>T (p.G12C)‐mutated tumors (p = 0.035) and 1.57 (1.22–2.02) in other KRAS‐mutated tumors (p = 0.0004). Our study provides novel evidence for clinical and tumor characteristics of KRAS c.34G>T (p.G12C)‐mutated colorectal carcinoma. The CpG island methylator phenotype (CIMP)‐low prevalence was similarly higher in KRAS c.34G>T mutants and other KRAS mutants than in KRAS‐wild‐type tumors. KRAS c.34G>T mutants showed higher CIMP‐high prevalence and lower CIMP‐negative prevalence compared with other KRAS mutants. Similar to other KRAS mutants, KRAS c.34G>T‐mutated tumors were associated with cecal location, non‐microsatellite instability (MSI)‐high status, BRAF wild type, and PIK3CA mutation when compared with KRAS‐wild‐type tumors.