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

Satoko Ugai1,2, Qian Yao1, Yasutoshi Takashima1,3

  • 1Program in MPE Molecular Pathological Epidemiology, Department of Pathology, Brigham and Women's Hospital, and Harvard Medical School, Boston, Massachusetts, USA.

Cancer Science
|July 23, 2024
PubMed

Insights

KRAS p.G12C mutations define a distinct colorectal cancer subtype with unique molecular and clinical features. These tumors show altered methylation patterns and are associated with increased mortality, suggesting targeted therapies may be beneficial.

Area of Science:

  • Oncology
  • Molecular Biology
  • Genetics

Background:

  • KRAS p.G12C mutations are emerging targets for advanced colorectal cancer treatment.
  • The distinct biological and clinical characteristics of KRAS p.G12C-mutated colorectal carcinoma remain to be fully elucidated.

Purpose of the Study:

  • To investigate the hypothesis that KRAS c.34G>T (p.G12C)-mutated colorectal carcinoma represents a distinct tumor subtype.
  • To characterize the clinical and molecular features of KRAS c.34G>T (p.G12C)-mutated colorectal tumors.

Main Methods:

  • Utilized a prospective cohort incident tumor biobank of 1347 colorectal carcinomas.
  • Detected KRAS c.34G>T (p.G12C) mutations and other KRAS mutations using molecular assays.
  • Analyzed CpG island methylator phenotype (CIMP) status, microsatellite instability (MSI), BRAF, PIK3CA mutations, and LINE-1 methylation.
  • Assessed tumor-specific mortality in relation to KRAS mutation status.

Main Results:

  • KRAS c.34G>T (p.G12C) mutation was identified in 3.2% of cases.
  • KRAS c.34G>T mutants exhibited higher CIMP-low and CIMP-high prevalence compared to KRAS-wild-type tumors.
  • These tumors were associated with cecal location, non-microsatellite instability-high status, BRAF wild type, PIK3CA mutation, and LINE-1 hypomethylation.
  • KRAS c.34G>T mutated tumors showed a significantly increased hazard ratio for colorectal cancer-specific mortality (1.82) compared to KRAS-wild-type tumors.

Conclusions:

  • KRAS c.34G>T (p.G12C)-mutated colorectal carcinoma is a distinct subtype with unique molecular and clinical characteristics.
  • The findings support the potential for targeted therapies, such as KRAS inhibitors, in this patient population.
  • This subtype is associated with poorer prognosis, highlighting the need for further research and tailored treatment strategies.
Keywords:
KRASCpG island methylator phenotypeadagrasibcolorectal tumorsotorasib

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