title: VEGFA gene locus (6p12) amplification identifies a small but highly aggressive subgroup of colorectal cancer [corrected] patients.
abstract: The aim of this study was to determine: (1) the frequency of VEGFA gene locus (6p12) amplification in colorectal cancers, (2) the effect of gene amplification on clinical outcome using two independent colorectal cancer patient cohorts and (3) the relationship between amplification and KRAS or BRAF gene mutation as well as with other RAS/MAPK signalling proteins. Single-punch (n=1280; cohort 1) and multiple-punch (n=195; cohort 2) tissue microarrays were used for dual-labelling fluorescence in situ hybridization (FISH). Amplification was defined as a ratio >2 times for 6p12/centromere 6 signals. Mutation analysis of KRAS (codons 12 and 13) and BRAF (codon V600E) and immunohistochemistry for p-MAPK3/MAPK1, PEBP1, HMMR, p-AKT, PLAU, PLAUR, TP53 and VEGFA were performed on cohort 1. In cohort 1, VEGFA amplification was found in 39/1280 (3%) cases and linked to higher pT stage (P=0.022), higher tumor grade (P=0.024) and vascular invasion (P=0.003). The 5-year disease-specific survival rates were 31% (95% CI 17-46) and 57% (95% CI 54-60) for amplified and nonamplified cases, respectively (P<0.001). Results were confirmed in cohort 2. In multivariable analysis, the relative risk for amplification was 2.09 (95% CI 1.4-3.1; P<0.001) and linked to more frequent BRAF mutation (P=0.015), overexpression of p-MAPK3/MAPK1 (P=0.012) and PLAU (P=0.048) and loss of metastasis suppressor protein PEBP1 (P=0.047). VEGFA gene locus amplification highlights a small but remarkably aggressive subgroup of colorectal cancers. Further studies are needed to elucidate the potential role of amplification as a prognostic or predictive biomarker in both metastatic and nonmetastatic patients.
authors: Institute of Pathology, University Hospital Basel, Basel, Switzerland.
authors: Tatjana
authors: T
authors: Vlajnic
authors: Maria Carla
authors: MC
authors: Andreozzi
authors: Sandra
authors: S
authors: Schneider
authors: Luigi
authors: L
authors: Tornillo
authors: Eva
authors: E
authors: Karamitopoulou
authors: Alessandro
authors: A
authors: Lugli
authors: Christian
authors: C
authors: Ruiz
authors: Inti
authors: I
authors: Zlobec
authors: Luigi
authors: L
authors: Terracciano
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D016009:Chi-Square Distribution; D002896:Chromosomes, Human, Pair 6; D015331:Cohort Studies; D015179:Colorectal Neoplasms / Q000737:chemistry / Q000235:genetics* / Q000401:mortality / Q000473:pathology; D004252:DNA Mutational Analysis; D005260:Female; D005784:Gene Amplification; D006115:Greece; D006801:Humans; D007150:Immunohistochemistry; D017404:In Situ Hybridization, Fluorescence; D047908:Intracellular Signaling Peptides and Proteins / Q000032:analysis; D053208:Kaplan-Meier Estimate; D008297:Male; D008875:Middle Aged; D009154:Mutation; D060787:Neoplasm Grading; D009361:Neoplasm Invasiveness; D009367:Neoplasm Staging; D011379:Prognosis; D016016:Proportional Hazards Models; D011518:Proto-Oncogene Proteins / Q000235:genetics; D048493:Proto-Oncogene Proteins B-raf / Q000235:genetics; D016283:Proto-Oncogene Proteins p21(ras); D018570:Risk Assessment; D012307:Risk Factors; D015398:Signal Transduction; D015996:Survival Rate; D013557:Switzerland; D046888:Tissue Array Analysis; D042461:Vascular Endothelial Growth Factor A / Q000235:genetics*; D018631:ras Proteins / Q000235:genetics
chemical_list: D047908:Intracellular Signaling Peptides and Proteins; C117307:KRAS protein, human; D011518:Proto-Oncogene Proteins; C467484:VEGFA protein, human; D042461:Vascular Endothelial Growth Factor A; C482119:BRAF protein, human; D048493:Proto-Oncogene Proteins B-raf; D016283:Proto-Oncogene Proteins p21(ras); D018631:ras Proteins