PMID- 21743435
OWN - NLM
STAT- MEDLINE
DCOM- 20120207
LR  - 20230210
IS  - 1530-0285 (Electronic)
IS  - 0893-3952 (Linking)
VI  - 24
IP  - 10
DP  - 2011 Oct
TI  - VEGFA gene locus (6p12) amplification identifies a small but highly aggressive 
      subgroup of colorectal cancer [corrected] patients.
PG  - 1404-12
LID - 10.1038/modpathol.2011.96 [doi]
AB  - 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.
FAU - Vlajnic, Tatjana
AU  - Vlajnic T
AD  - Institute of Pathology, University Hospital Basel, Basel, Switzerland.
FAU - Andreozzi, Maria Carla
AU  - Andreozzi MC
FAU - Schneider, Sandra
AU  - Schneider S
FAU - Tornillo, Luigi
AU  - Tornillo L
FAU - Karamitopoulou, Eva
AU  - Karamitopoulou E
FAU - Lugli, Alessandro
AU  - Lugli A
FAU - Ruiz, Christian
AU  - Ruiz C
FAU - Zlobec, Inti
AU  - Zlobec I
FAU - Terracciano, Luigi
AU  - Terracciano L
LA  - eng
PT  - Journal Article
PT  - Multicenter Study
DEP - 20110708
PL  - United States
TA  - Mod Pathol
JT  - Modern pathology : an official journal of the United States and Canadian Academy 
      of Pathology, Inc
JID - 8806605
RN  - 0 (Intracellular Signaling Peptides and Proteins)
RN  - 0 (KRAS protein, human)
RN  - 0 (Proto-Oncogene Proteins)
RN  - 0 (VEGFA protein, human)
RN  - 0 (Vascular Endothelial Growth Factor A)
RN  - EC 2.7.11.1 (BRAF protein, human)
RN  - EC 2.7.11.1 (Proto-Oncogene Proteins B-raf)
RN  - EC 3.6.5.2 (Proto-Oncogene Proteins p21(ras))
RN  - EC 3.6.5.2 (ras Proteins)
SB  - IM
EIN - Mod Pathol. 2011 Nov;24(11):1530
MH  - Adult
MH  - Aged
MH  - Aged, 80 and over
MH  - Chi-Square Distribution
MH  - *Chromosomes, Human, Pair 6
MH  - Cohort Studies
MH  - Colorectal Neoplasms/chemistry/*genetics/mortality/pathology
MH  - DNA Mutational Analysis
MH  - Female
MH  - *Gene Amplification
MH  - Greece
MH  - Humans
MH  - Immunohistochemistry
MH  - In Situ Hybridization, Fluorescence
MH  - Intracellular Signaling Peptides and Proteins/analysis
MH  - Kaplan-Meier Estimate
MH  - Male
MH  - Middle Aged
MH  - Mutation
MH  - Neoplasm Grading
MH  - Neoplasm Invasiveness
MH  - Neoplasm Staging
MH  - Prognosis
MH  - Proportional Hazards Models
MH  - Proto-Oncogene Proteins/genetics
MH  - Proto-Oncogene Proteins B-raf/genetics
MH  - Proto-Oncogene Proteins p21(ras)
MH  - Risk Assessment
MH  - Risk Factors
MH  - Signal Transduction
MH  - Survival Rate
MH  - Switzerland
MH  - Tissue Array Analysis
MH  - Vascular Endothelial Growth Factor A/*genetics
MH  - ras Proteins/genetics
EDAT- 2011/07/12 06:00
MHDA- 2012/02/09 06:00
CRDT- 2011/07/12 06:00
PHST- 2011/07/12 06:00 [entrez]
PHST- 2011/07/12 06:00 [pubmed]
PHST- 2012/02/09 06:00 [medline]
AID - S0893-3952(22)01804-X [pii]
AID - 10.1038/modpathol.2011.96 [doi]
PST - ppublish
SO  - Mod Pathol. 2011 Oct;24(10):1404-12. doi: 10.1038/modpathol.2011.96. Epub 2011 
      Jul 8.