Focal gains of VEGFA and molecular classification of hepatocellular carcinoma.
Hepatocellular carcinomas represent the third leading cause of cancer-related deaths worldwide. The vast majority of cases arise in the context of chronic liver injury due to hepatitis B virus or hepatitis C virus infection. To identify genetic mechanisms of hepatocarcinogenesis, we characterized copy number alterations and gene expression profiles from the same set of tumors associated with hepatitis C virus. Most tumors harbored 1q gain, 8q gain, or 8p loss, with occasional alterations in 13 additional chromosome arms. In addition to amplifications at 11q13 in 6 of 103 tumors, 4 tumors harbored focal gains at 6p21 incorporating vascular endothelial growth factor A (VEGFA). Fluorescence in situ hybridization on an independent validation set of 210 tumors found 6p21 high-level gains in 14 tumors, as well as 2 tumors with 6p21 amplifications. Strikingly, this locus overlapped with copy gains in 4 of 371 lung adenocarcinomas. Overexpression of VEGFA via 6p21 gain in hepatocellular carcinomas suggested a novel, non-cell-autonomous mechanism of oncogene activation. Hierarchical clustering of gene expression among 91 of these tumors identified five classes, including "CTNNB1", "proliferation", "IFN-related", a novel class defined by polysomy of chromosome 7, and an unannotated class. These class labels were further supported by molecular data; mutations in CTNNB1 were enriched in the "CTNNB1" class, whereas insulin-like growth factor I receptor and RPS6 phosphorylation were enriched in the "proliferation" class. The enrichment of signaling pathway alterations in gene expression classes provides insights on hepatocellular carcinoma pathogenesis. Furthermore, the prevalence of VEGFA high-level gains in multiple tumor types suggests indications for clinical trials of antiangiogenic therapies.
Chiang
Derek Y
DY
Department of Medical Oncology and Center for Cancer Genome Discovery, Dana-Farber Cancer Institute, Boston, MA 02115, USA.
Villanueva
Augusto
A
Hoshida
Yujin
Y
Peix
Judit
J
Newell
Philippa
P
Minguez
Beatriz
B
LeBlanc
Amanda C
AC
Donovan
Diana J
DJ
Thung
Swan N
SN
Solé
Manel
M
Tovar
Victoria
V
Alsinet
Clara
C
Ramos
Alex H
AH
Barretina
Jordi
J
Roayaie
Sasan
S
Schwartz
Myron
M
Waxman
Samuel
S
Bruix
Jordi
J
Mazzaferro
Vincenzo
V
Ligon
Azra H
AH
Najfeld
Vesna
V
Friedman
Scott L
SL
Sellers
William R
WR
Meyerson
Matthew
M
Llovet
Josep M
JM
D000230:Adenocarcinoma / Q000235:genetics / Q000473:pathology; D014408:Biomarkers, Tumor / Q000235:genetics / Q000378:metabolism; D006528:Carcinoma, Hepatocellular / Q000145:classification / Q000235:genetics* / Q000821:virology; D002869:Chromosome Aberrations; D002896:Chromosomes, Human, Pair 6 / Q000235:genetics; D002897:Chromosomes, Human, Pair 7 / Q000235:genetics; D018628:Gene Dosage; D020869:Gene Expression Profiling; D019694:Hepatitis B, Chronic / Q000150:complications / Q000235:genetics; D019698:Hepatitis C, Chronic / Q000150:complications / Q000235:genetics; D006801:Humans; D007124:Immunoenzyme Techniques; D017404:In Situ Hybridization, Fluorescence; D007621:Karyotyping; D008113:Liver Neoplasms / Q000145:classification / Q000235:genetics* / Q000821:virology; D008175:Lung Neoplasms / Q000235:genetics / Q000556:secondary; D009367:Neoplasm Staging; D009693:Nucleic Acid Hybridization; D020411:Oligonucleotide Array Sequence Analysis; D011379:Prognosis; D015398:Signal Transduction; D015996:Survival Rate; D046888:Tissue Array Analysis; D042461:Vascular Endothelial Growth Factor A / Q000235:genetics* / Q000378:metabolism
D014408:Biomarkers, Tumor; C467484:VEGFA protein, human; D042461:Vascular Endothelial Growth Factor A