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Ann Oncol. 2014 Oct;25(10):2008-14. doi: 10.1093/annonc/mdu252. Epub 2014 Jul 9.

Clinicopathologic characteristics and gene expression analyses of non-KRAS 12/13, RAS-mutated metastatic colorectal cancer.

Author information

1
Department of Cancer Medicine, The University of Texas-MD Anderson Cancer Center, Houston.
2
Graduate School of Biomedical Sciences, University of Texas Health Science Center, Houston, USA.
3
Department of Gastrointestinal Medical Oncology, The University of Texas-MD Anderson Cancer Center, Houston.
4
Department of Hematopathology, The University of Texas-MD Anderson Cancer Center, Houston.
5
Department of Surgical Oncology, The University of Texas-MD Anderson Cancer Center, Houston.
6
Department of Pathology, The University of Texas-MD Anderson Cancer Center, Houston.
7
Department of Epidemiology, The University of Texas-MD Anderson Cancer Center, Houston.
8
Department of Gastrointestinal Medical Oncology, The University of Texas-MD Anderson Cancer Center, Houston Graduate School of Biomedical Sciences, University of Texas Health Science Center, Houston, USA.
9
Department of Gastrointestinal Medical Oncology, The University of Texas-MD Anderson Cancer Center, Houston Clinical Cancer Prevention, The University of Texas-MD Anderson Cancer Center, Houston evilar@mdanderson.org.

Abstract

BACKGROUND:

KRAS mutations in codons 12 and 13 are present in ∼40% of all colorectal cancers (CRC). Activating mutations in codons 61 and 146 of KRAS and in codons 12, 13, and 61 of NRAS also occur but are less frequent. The clinicopathologic features and gene expression profiles of this latter subpopulation of RAS-mutant colorectal tumors have not yet been clearly defined but in general are treated similarly to those with KRAS 12 or 13 mutations.

PATIENTS AND METHODS:

Records of patients with metastatic CRC (mCRC) treated at MD Anderson Cancer Center between December 2000 and August 2012 were reviewed for RAS (KRAS or NRAS) and BRAF mutation status, clinical characteristics, and survival outcomes. To study further with an independent cohort, data from The Cancer Genome Atlas were analyzed to define a gene expression signature for patients whose tumors feature these atypical RAS mutations and explore differences with KRAS 12/13-mutated colorectal tumors.

RESULTS:

Among the 484 patients reviewed, KRAS 12/13, KRAS 61/146, NRAS, and BRAF mutations were detected in 47.7%, 3.0%, 4.1%, and 7.4%, respectively, of patients who were tested for each of these aberrations. Lung metastases were more common in both the KRAS 12/13-mutated and atypical RAS-mutated cohorts relative to patients with RAS/BRAF wild-type tumors. Gene expression analyses revealed similar patterns regardless of the site of RAS mutation, and in silico functional algorithms predicted that KRAS and NRAS mutations in codons 12, 13, 61, and 146 alter the protein function and drive tumorgenesis.

CONCLUSIONS:

Clinicopathologic characteristics, survival outcomes, functional impact, and gene expression profiling were similar between patients with KRAS 12/13 and those with NRAS or KRAS 61/146-mutated mCRC. These clinical and bioinformatic findings support the notion that colorectal tumors driven by these RAS mutations are phenotypically similar.

KEYWORDS:

KRAS; colorectal cancer; gene expression; next-generation sequencing; survival

PMID:
25009008
PMCID:
PMC4176451
DOI:
10.1093/annonc/mdu252
[Indexed for MEDLINE]
Free PMC Article

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