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Analyses of clinicopathological, molecular, and prognostic associations of KRAS codon 61 and codon 146 mutations in colorectal cancer: cohort study and literature review.

AbstractBACKGROUND:
KRAS mutations in codons 12 and 13 are established predictive biomarkers for anti-EGFR therapy in colorectal cancer. Previous studies suggest that KRAS codon 61 and 146 mutations may also predict resistance to anti-EGFR therapy in colorectal cancer. However, clinicopathological, molecular, and prognostic features of colorectal carcinoma with KRAS codon 61 or 146 mutation remain unclear.
METHODS:
We utilized a molecular pathological epidemiology database of 1267 colon and rectal cancers in the Nurse's Health Study and the Health Professionals Follow-up Study. We examined KRAS mutations in codons 12, 13, 61 and 146 (assessed by pyrosequencing), in relation to clinicopathological features, and tumor molecular markers, including BRAF and PIK3CA mutations, CpG island methylator phenotype (CIMP), LINE-1 methylation, and microsatellite instability (MSI). Survival analyses were performed in 1067 BRAF-wild-type cancers to avoid confounding by BRAF mutation. Cox proportional hazards models were used to compute mortality hazard ratio, adjusting for potential confounders, including disease stage, PIK3CA mutation, CIMP, LINE-1 hypomethylation, and MSI.
RESULTS:
KRAS codon 61 mutations were detected in 19 cases (1.5%), and codon 146 mutations in 40 cases (3.2%). Overall KRAS mutation prevalence in colorectal cancers was 40% (=505/1267). Of interest, compared to KRAS-wild-type, overall, KRAS-mutated cancers more frequently exhibited cecal location (24% vs. 12% in KRAS-wild-type; P < 0.0001), CIMP-low (49% vs. 32% in KRAS-wild-type; P < 0.0001), and PIK3CA mutations (24% vs. 11% in KRAS-wild-type; P < 0.0001). These trends were evident irrespective of mutated codon, though statistical power was limited for codon 61 mutants. Neither KRAS codon 61 nor codon 146 mutation was significantly associated with clinical outcome or prognosis in univariate or multivariate analysis [colorectal cancer-specific mortality hazard ratio (HR) = 0.81, 95% confidence interval (CI) = 0.29-2.26 for codon 61 mutation; colorectal cancer-specific mortality HR = 0.86, 95% CI = 0.42-1.78 for codon 146 mutation].
CONCLUSIONS:
Tumors with KRAS mutations in codons 61 and 146 account for an appreciable proportion (approximately 5%) of colorectal cancers, and their clinicopathological and molecular features appear generally similar to KRAS codon 12 or 13 mutated cancers. To further assess clinical utility of KRAS codon 61 and 146 testing, large-scale trials are warranted.
AuthorsYu Imamura, Paul Lochhead, Mai Yamauchi, Aya Kuchiba, Zhi Rong Qian, Xiaoyun Liao, Reiko Nishihara, Seungyoun Jung, Kana Wu, Katsuhiko Nosho, Yaoyu E Wang, Shouyong Peng, Adam J Bass, Kevin M Haigis, Jeffrey A Meyerhardt, Andrew T Chan, Charles S Fuchs, Shuji Ogino
JournalMolecular cancer (Mol Cancer) Vol. 13 Pg. 135 (May 31 2014) ISSN: 1476-4598 [Electronic] England
PMID24885062 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, Non-P.H.S.)
Chemical References
  • Codon
  • KRAS protein, human
  • Proto-Oncogene Proteins
  • Phosphatidylinositol 3-Kinases
  • Class I Phosphatidylinositol 3-Kinases
  • PIK3CA protein, human
  • EGFR protein, human
  • ErbB Receptors
  • BRAF protein, human
  • Proto-Oncogene Proteins B-raf
  • Proto-Oncogene Proteins p21(ras)
  • ras Proteins
Topics
  • Aged
  • Class I Phosphatidylinositol 3-Kinases
  • Codon
  • Cohort Studies
  • Colorectal Neoplasms (diagnosis, genetics, mortality, pathology)
  • CpG Islands
  • DNA Methylation
  • ErbB Receptors (genetics)
  • Female
  • Gene Expression
  • Humans
  • Long Interspersed Nucleotide Elements (genetics)
  • Male
  • Middle Aged
  • Mutation
  • Phosphatidylinositol 3-Kinases (genetics)
  • Proportional Hazards Models
  • Proto-Oncogene Proteins (genetics)
  • Proto-Oncogene Proteins B-raf (genetics)
  • Proto-Oncogene Proteins p21(ras)
  • Survival Analysis
  • ras Proteins (genetics)

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