Distribution of KRAS G12C Somatic Mutations across Race, Sex, and Cancer Type
Open accessAbstract
To the Editor: Hong et al. (Sept.24 issue) 1 present results of an early-phase clinical trial of sotorasib, which showed promising clinical benefit.Patients had non-small-cell lung cancer (NSCLC; 46%) or colorectal cancer (33%), and White patients constituted 76% of the cohort.As drugs are being developed for the previously "undruggable" KRAS G12C mutation, it is imperative to study the distribution of this mutation across sex, race, 2 and all cancers.We extracted data from the registry of the American Association for Cancer Research Project Genomics Evidence Neoplasia Information Exchange (GENIE), version 8.0 3 (see the Methods section in Supplementary Appendix 1).We studied the distribution of KRAS G12C mutations in 32,138 patients with cancer across race (Asian, Black, and White) and sex and in 10 cancer types (Table S1.1 in Supplementary Appendix 2).A total of 2045 patients (6.4%) were Asian, 2355 (7.3%) were Black, and 27,738 (86.3%) were White.KRAS G12C mutations were compared according to race and sex, and P values were corrected by the Benjamini-Hochberg method to determine false discovery rate-corrected Q values, which were considered significant when Q was less than 0.05.KRAS G12C mutations were identified in 1867 samples, most frequently in patients with NSCLC (1443 of 10,444 [13.8%]).KRAS G12C mutations were identified in 3.5% of patients (74 of 2105) with cancer of unknown primary site, 3.3% of patients (12 of 368) with appendiceal cancer, 3.2% of patients (234 of 7402) with colorectal cancer, and 3.1% of patients (7 of 223) with small-bowel cancer (Fig. 1A, and Table S1.2 in Supplementary Appendix 2).Among patients
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KRAS G12C occurs in 3 to 4% of colorectal cancer patients and impairs GTP hydrolysis, shifting KRAS to its active GTP-binding state.
“The KRAS glycine-to-cysteine mutation at codon 12 (KRAS G12C) occurs in 3 to 4% of patients with colorectal cancer and impairs GTP hydrolysis, which shifts KRAS to the active GTP-binding state to drive protumorigenic effector signaling.8,10–12”
From Adagrasib with or without Cetuximab in Colorectal Cancer with Mutated <i>KRAS</i> G12C (2023) · cites this paper as [10]
The mutation-distribution paragraph reports KRAS G12C in 234 of 7,402 patients with colorectal cancer (3.2%), supporting the 3–4% figure. The paper does not address impaired GTP hydrolysis, the active GTP-bound state, or effector signaling. (LLM, conf=0.88)
Experimental — accuracy not yet measuredLung adenocarcinomas in Black or Asian patients tend to exhibit KRAS mutations other than G12C more frequently than White patients, who are more likely to have tumors driven by the clinically targetable KRAS G12C.
“Lung adenocarcinomas in Black or Asian patients tend to exhibit KRAS mutations other than G12C more frequently than White patients, who are more likely to have tumors driven by the clinically targetable KRAS G12C [38].”
From KRAS: Biology, Inhibition, and Mechanisms of Inhibitor Resistance (2024) · cites this paper as [38]
The correspondence passage (page not specified in our copy) reports KRAS G12C in 13% of White, 10.9% of Black, and 3.6% of Asian patients with non-small-cell lung cancer. That supports the lower G12C frequency in Black and Asian patients, but the paper does not report whether other KRAS mutations are more frequent in those groups, and its figures are for non-small-cell lung cancer rather than lung adenocarcinoma specifically. (LLM, conf=0.88)
Experimental — accuracy not yet measuredKRAS G12C mutations occur in approximately 4% of patients with colorectal cancer.
“Oncogenic KRAS G12C mutations occur in ~4% of patients with CRC, and are associated with poor prognosis3–7.”
From Divarasib plus cetuximab in KRAS G12C-positive colorectal cancer: a phase 1b trial (2024) · cites this paper as [6]
In colorectal cancer, the KRAS G12C allele is associated with worse survival than other KRAS mutations and KRAS wild-type tumors.
“KRAS mutations have historically been considered to be “undruggable,” and retrospective series of clinical data suggest that the presence of the KRAS G12C allele is associated with worse survival outcomes than other KRAS mutations in patients with colorectal cancer.12,17”
From Adagrasib with or without Cetuximab in Colorectal Cancer with Mutated <i>KRAS</i> G12C (2023) · cites this paper as [10]
The letter’s GENIE analysis reports the frequency of KRAS G12C in colorectal cancer and differences by sex and race (page not provided). Our copy does not report survival outcomes or compare KRAS G12C with other KRAS mutations or KRAS wild-type tumors for survival; searches for those comparisons found no passage addressing them. (LLM, conf=0.76)
Experimental — accuracy not yet measuredKRAS G12C mutation is associated with poor prognosis in colorectal cancer.
“Oncogenic KRAS G12C mutations occur in ~4% of patients with CRC, and are associated with poor prognosis3–7.”
From Divarasib plus cetuximab in KRAS G12C-positive colorectal cancer: a phase 1b trial (2024) · cites this paper as [6]
The paper’s mutation-distribution results report KRAS G12C in 3.2% of patients with colorectal cancer, but do not assess prognosis. Searches for poor prognosis and survival outcomes found no passage linking the mutation to worse outcomes in colorectal cancer. (LLM, conf=0.77)
Experimental — accuracy not yet measured
KRAS G12C mutations are associated with poor prognosis in colorectal cancer.
“KRAS G12C mutations occur in 3% to 4% of colorectal cancer cases and are associated with poor prognosis (1, 2).”
From Efficacy and Safety of Adagrasib plus Cetuximab in Patients with <i>KRAS</i> G12C-Mutated Metastatic Colorectal Cancer (2024) · cites this paper as [1]
KRAS G12C mutations occur in 3% to 4% of colorectal cancer cases.
“KRAS G12C mutations occur in 3% to 4% of colorectal cancer cases and are associated with poor prognosis (1, 2).”
From Efficacy and Safety of Adagrasib plus Cetuximab in Patients with <i>KRAS</i> G12C-Mutated Metastatic Colorectal Cancer (2024) · cites this paper as [1]
KRAS codon 12 mutations most commonly yield G12C, G12V or G12D, accounting for 40%, 19% and 15% of KRAS mutations in NSCLC, respectively; KRASG12C prevalence is about 14% in NSCLC, 3% in colorectal cancer and 1% in pancreatic ductal adenocarcinoma.
“Recurrent KRAS codon 12 mutations most commonly result in G12C, G12V or G12D substitutions, which account for 40%, 19% and 15% of KRAS mutations in NSCLCs, respectively. Although much attention has been focused on KRASG12C mutations in NSCLCs (prevalence of ~14%), these mutations are not unique to NSCLC and also occur less commonly in colorectal cancers (CRCs; 3%) and pancreatic ductal adenocarcin”
From The current state of the art and future trends in RAS-targeted cancer therapies (2022) · cites this paper as [28]
Within a subgroup analysis, both Caucasian and African American populations can be more often diagnosed with KRAS G12C NSCLC than Asian populations; white females harbor KRAS G12C NSCLC mutations more often than their male counterparts; and Asian males more frequently have NSCLC G12C mutations than Asian females.
“Within a subgroup analysis of those who are more frequently diagnosed with KRAS G12C NSCLC, both Caucasian and African American populations can be more often diagnosed than Asian populations. Interestingly, white females harbor KRAS G12C NSCLC mutations more often than their male counterparts. This trend is opposite for Asian populations, as Asian males more frequently have NSCLC G12C mutations11.”
From Selective KRAS G12C inhibitors in non-small cell lung cancer: chemistry, concurrent pathway alterations, and clinical outcomes (2021) · cites this paper as [11]
A recent report found no difference in the distribution of KRAS G12C mutation in colorectal cancer between Asian and Western populations, unlike non-small cell lung cancer.
“However, a recent report has revealed no difference in the distribution of KRAS G12C mutation in CRC between Asian and Western populations, unlike non-small cell lung cancer [18].”
From The Prognostic Impact of <i>KRAS</i> G12C Mutation in Patients with Metastatic Colorectal Cancer: A Multicenter Retrospective Observational Study (2021) · cites this paper as [18]
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- Authors
- Nassar, A. H., Adib, E., & Kwiatkowski, D. J.
- Affiliations
- Brigham and Women's Hospital (US)
- Venue
- New England Journal of Medicine
- Publisher
- Massachusetts Medical Society
- Published
- 2021-01-14
- Volume
- 384
- Issue
- 2
- Pages
- 185-187
- ISSN
- 0028-4793 (ISSN-L)
- 1533-4406
- OpenAlex
- W3120172300
- Semantic Scholar
- 026a3973a5d536e100cebc3e42f5fc012d589979
- Cited by
- 210
- References
- 3
- Citations by year
- 2026: 28 · 2025: 37 · 2024: 51 · 2023: 33 · 2022: 36 · 2021: 25
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- New England Journal of Medicine (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer Genomics and Diagnostics
- Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Lung Cancer Treatments and Mutations
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Kinase Regulation and GTPase Signaling
- Keywords
- KRAS G12C mutation, somatic mutations, racial distribution, sex differences, non-small cell lung cancer, colorectal cancer, cancer of unknown primary, appendiceal neoplasms, small intestine neoplasms, sotorasib, precision oncology
- MeSH terms
- Carcinoma, Non-Small-Cell Lung, Humans, Lung Neoplasms, Mutation, Piperazines, Pyridines, Pyrimidines, Proto-Oncogene Proteins p21(ras)
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