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

Satoko Ugai^{1

2}, Qian Yao¹, Yasutoshi Takashima^{1

3}, Yuxue Zhong¹, Kosuke Matsuda¹, Hidetaka Kawamura^{1

4}, Yu Imamura⁵, Kazuo Okadome¹, Kosuke Mima⁶, Kota Arima⁶, Keisuke Kosumi⁶, Mingyang Song^{2

7

8

9}, Jeffrey A Meyerhardt³, Marios Giannakis^{3

10

11}, Jonathan A Nowak^{1

3}, Tomotaka Ugai^{1

2}, Shuji Ogino^{1

2

10

12

13}

Affiliations

¹ Program in MPE Molecular Pathological Epidemiology, Department of Pathology, Brigham and Women's Hospital, and Harvard Medical School, Boston, Massachusetts, USA.
² Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, Massachusetts, USA.
³ Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical, Boston, Massachusetts, USA.
⁴ Department of Surgery, Fukushima Medical University, Fukushima, Japan.
⁵ Department of Esophageal Surgery, The Cancer Institute Hospital of the Japanese Foundation of Cancer Research, Tokyo, Japan.
⁶ Department of Gastroenterological Surgery, Graduate School of Medical Sciences, Kumamoto University, Kumamoto, Japan.
⁷ Department of Nutrition, Harvard T.H. Chan School of Public Health, Boston, Massachusetts, USA.
⁸ Clinical and Translational Epidemiology Unit, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts, USA.
⁹ Division of Gastroenterology, Massachusetts General Hospital, Boston, Massachusetts, USA.
¹⁰ Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA.
¹¹ Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts, USA.
¹² Cancer Immunology Program, Dana-Farber/Harvard Cancer Center, Boston, Massachusetts, USA.
¹³ Tokyo Medical and Dental University (Institute of Science Tokyo), Tokyo, Japan.

PMID: 39039804
PMCID: PMC11448363
DOI: 10.1111/cas.16262

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

Satoko Ugai et al. Cancer Sci. 2024 Oct.

. 2024 Oct;115(10):3455-3465.

doi: 10.1111/cas.16262. Epub 2024 Jul 22.

Authors

Affiliations

¹ Program in MPE Molecular Pathological Epidemiology, Department of Pathology, Brigham and Women's Hospital, and Harvard Medical School, Boston, Massachusetts, USA.
² Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, Massachusetts, USA.
³ Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical, Boston, Massachusetts, USA.
⁴ Department of Surgery, Fukushima Medical University, Fukushima, Japan.
⁵ Department of Esophageal Surgery, The Cancer Institute Hospital of the Japanese Foundation of Cancer Research, Tokyo, Japan.
⁶ Department of Gastroenterological Surgery, Graduate School of Medical Sciences, Kumamoto University, Kumamoto, Japan.
⁷ Department of Nutrition, Harvard T.H. Chan School of Public Health, Boston, Massachusetts, USA.
⁸ Clinical and Translational Epidemiology Unit, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts, USA.
⁹ Division of Gastroenterology, Massachusetts General Hospital, Boston, Massachusetts, USA.
¹⁰ Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA.
¹¹ Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts, USA.
¹² Cancer Immunology Program, Dana-Farber/Harvard Cancer Center, Boston, Massachusetts, USA.
¹³ Tokyo Medical and Dental University (Institute of Science Tokyo), Tokyo, Japan.

PMID: 39039804
PMCID: PMC11448363
DOI: 10.1111/cas.16262

Abstract

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.

Keywords: KRAS; CpG island methylator phenotype; adagrasib; colorectal tumor; sotorasib.

PubMed Disclaimer

Conflict of interest statement

M.G. receives research funding from Janssen, consulting fees from Nerviano Medical Sciences, and has received Honoraria from AstraZeneca and Chroma Code. No other conflicts of interest exist. The other authors have no conflicts of interest.

Figures

**FIGURE 1**
Flow diagram of the study participants.

**FIGURE 2**
Survival analyses of 1112 *BRAF*‐wild‐type colorectal cancer patients according to the *KRAS* mutation status.

See this image and copyright information in PMC

References

1. Alzahrani SM, Al Doghaither HA, Al‐Ghafari AB. General insight into cancer: an overview of colorectal cancer (review). Mol Clin Oncol. 2021;15:271. - PMC - PubMed
1. Fanelli GN, Dal Pozzo CA, Depetris I, et al. The heterogeneous clinical and pathological landscapes of metastatic Braf‐mutated colorectal cancer. Cancer Cell Int. 2020;20:30. - PMC - PubMed
1. Zhu G, Pei L, Xia H, Tang Q, Bi F. Role of oncogenic KRAS in the prognosis, diagnosis and treatment of colorectal cancer. Mol Cancer. 2021;20:143. - PMC - PubMed
1. Misale S, Yaeger R, Hobor S, et al. Emergence of KRAS mutations and acquired resistance to anti‐EGFR therapy in colorectal cancer. Nature. 2012;486:532‐536. - PMC - PubMed
1. Karapetis CS, Khambata‐Ford S, Jonker DJ, et al. K‐ras mutations and benefit from cetuximab in advanced colorectal cancer. N Engl J Med. 2008;359:1757‐1765. - PubMed

MeSH terms

Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions

Substances

Actions
Actions
Actions
Actions
Actions
Actions

Grants and funding

LinkOut - more resources

Full Text Sources
Medical
- MedlinePlus Health Information
Research Materials
- NCI CPTC Antibody Characterization Program
Miscellaneous
- NCI CPTAC Assay Portal

Save citation to file

Email citation

Add to Collections

Add to My Bibliography

Your saved search

Create a file for external citation management software

Your RSS Feed

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

Affiliations

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

Authors

Affiliations

Abstract

Conflict of interest statement

Figures

References

MeSH terms

Substances

Grants and funding

LinkOut - more resources

Full Text Sources

Medical

Research Materials

Miscellaneous