title: Mutant allele-specific imbalance modulates prognostic impact of KRAS mutations in colorectal adenocarcinoma and is associated with worse overall survival.
abstract: 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.
authors.affiliation: Department of Pathology, University of Pittsburgh Medical Center, Pittsburgh, PA, USA.
authors.forename: D J
authors.initials: DJ
authors.lastname: Hartman
authors.forename: J M
authors.initials: JM
authors.lastname: Davison
authors.forename: T J
authors.initials: TJ
authors.lastname: Foxwell
authors.forename: M N
authors.initials: MN
authors.lastname: Nikiforova
authors.forename: S I
authors.initials: SI
authors.lastname: Chiosea
mesh_terms: D000230:Adenocarcinoma / Q000235:genetics* / Q000401:mortality* / Q000473:pathology; D000483:Alleles; D014408:Biomarkers, Tumor / Q000235:genetics / Q000378:metabolism; D003062:Codon / Q000235:genetics; D015179:Colorectal Neoplasms / Q000235:genetics* / Q000401:mortality* / Q000473:pathology; D005091:Exons / Q000235:genetics; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D017404:In Situ Hybridization, Fluorescence; D008297:Male; D053842:Microsatellite Instability; D018895:Microsatellite Repeats / Q000235:genetics*; D008875:Middle Aged; D009154:Mutation / Q000235:genetics*; D060787:Neoplasm Grading; D009367:Neoplasm Staging; D011379:Prognosis; D011446:Prospective Studies; D011518:Proto-Oncogene Proteins / Q000235:genetics; D016283:Proto-Oncogene Proteins p21(ras); D015996:Survival Rate; D018631:ras Proteins / Q000235:genetics
chemical_list: D014408:Biomarkers, Tumor; D003062:Codon; C117307:KRAS protein, human; D011518:Proto-Oncogene Proteins; D016283:Proto-Oncogene Proteins p21(ras); D018631:ras Proteins