Mutant allele-specific imbalance modulates prognostic impact of KRAS mutations in colorectal adenocarcinoma and is associated with worse overall survival

• Published in: International journal of cancer 2012-10, Vol.131 (8), p.1810-1817
• Main Authors: Hartman, D. J., Davison, J. M., Foxwell, T. J., Nikiforova, M. N., Chiosea, S. I.
• Format: Article
• Language: English
• Subjects: Adenocarcinoma - genetics; Adenocarcinoma - mortality; Adenocarcinoma - pathology; Alleles; allelic imbalance; Biological and medical sciences; Biomarkers, Tumor - genetics; Biomarkers, Tumor - metabolism; Cancer; Codon - genetics; colon adenocarcinoma; Colorectal cancer; Colorectal Neoplasms - genetics; Colorectal Neoplasms - mortality; Colorectal Neoplasms - pathology; Exons - genetics; Female; Follow-Up Studies; Gastroenterology. Liver. Pancreas. Abdomen; Humans; In Situ Hybridization, Fluorescence; KRAS; Male; Medical prognosis; Medical research; Medical sciences; Microsatellite Instability; Microsatellite Repeats - genetics; Middle Aged; Mortality; Mutation; Mutation - genetics; Neoplasm Grading; Neoplasm Staging; Prognosis; Prospective Studies; Proto-Oncogene Proteins - genetics; Proto-Oncogene Proteins p21(ras); ras Proteins - genetics; Stomach. Duodenum. Small intestine. Colon. Rectum. Anus; Survival Rate; Tumors
• ISSN: 0020-7136; 1097-0215
• DOI: 10.1002/ijc.27461

The prognostic impact of distinct KRAS mutations in colorectal carcinomas is not fully characterized. We hypothesized that the prognostic impact of KRAS mutations is modulated by KRAS mutant allele‐specific imbalance (MASI). KRAS MASI was assessed by sequencing electropherograms in KRAS‐mutated colorectal carcinomas (N = 394, prospectively tested). The mechanism of KRAS MASI was studied by fluorescence in situ hybridization (FISH; N = 50). FISH showed that KRAS MASI developed by chromosome 12 hyperploidy (9/18, 50%) or KRAS amplification (1/18, 5.5%). KRAS MASI was more common in tumors with KRAS codon 13 than with codon 12 mutations [24/81, 30% vs. 54/313, 17%; odds ratio (OR), 2.0, 95% confidence interval (CI), 1.2–3.5; p = 0.01]. KRAS MASI was correlated with overall survival (N = 358, median follow‐up = 21 months). In a multivariate analysis, KRAS codon 13 MASI was an independent adverse prognostic factor (compared to codon 13 mutants without MASI combined with all codon 12 mutants; adjusted hazard ratio, 2.2, 95% CI: 1.2–3.9; p = 0.01). KRAS MASI arises through chromosome 12 hyperploidy or KRAS amplification and, when affects KRAS codon 13, is associated with worse overall survival.