Genomic profiling identifies GATA6 as a candidate oncogene amplified in pancreatobiliary cancer.
Pancreatobiliary cancers have among the highest mortality rates of any cancer type. Discovering the full spectrum of molecular genetic alterations may suggest new avenues for therapy. To catalogue genomic alterations, we carried out array-based genomic profiling of 31 exocrine pancreatic cancers and 6 distal bile duct cancers, expanded as xenografts to enrich the tumor cell fraction. We identified numerous focal DNA amplifications and deletions, including in 19% of pancreatobiliary cases gain at cytoband 18q11.2, a locus uncommonly amplified in other tumor types. The smallest shared amplification at 18q11.2 included GATA6, a transcriptional regulator previously linked to normal pancreas development. When amplified, GATA6 was overexpressed at both the mRNA and protein levels, and strong immunostaining was observed in 25 of 54 (46%) primary pancreatic cancers compared to 0 of 33 normal pancreas specimens surveyed. GATA6 expression in xenografts was associated with specific microarray gene-expression patterns, enriched for GATA binding sites and mitochondrial oxidative phosphorylation activity. siRNA mediated knockdown of GATA6 in pancreatic cancer cell lines with amplification led to reduced cell proliferation, cell cycle progression, and colony formation. Our findings indicate that GATA6 amplification and overexpression contribute to the oncogenic phenotypes of pancreatic cancer cells, and identify GATA6 as a candidate lineage-specific oncogene in pancreatobiliary cancer, with implications for novel treatment strategies.
Kwei
Kevin A
KA
Department of Pathology, Stanford University, Stanford, California, United States of America.
Bashyam
Murali D
MD
Kao
Jessica
J
Ratheesh
Raman
R
Reddy
Edumakanti C
EC
Kim
Young H
YH
Montgomery
Kelli
K
Giacomini
Craig P
CP
Choi
Yoon-La
YL
Chatterjee
Sreejata
S
Karikari
Collins A
CA
Salari
Keyan
K
Wang
Pei
P
Hernandez-Boussard
Tina
T
Swarnalata
Gowrishankar
G
van de Rijn
Matt
M
Maitra
Anirban
A
Pollack
Jonathan R
JR
D000818:Animals; D001661:Biliary Tract Neoplasms / Q000235:genetics* / Q000378:metabolism; D002453:Cell Cycle; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D002887:Chromosomes, Human, Pair 18 / Q000235:genetics; D050993:GATA6 Transcription Factor / Q000235:genetics* / Q000378:metabolism; D005784:Gene Amplification; D020869:Gene Expression Profiling; D006801:Humans; D017404:In Situ Hybridization, Fluorescence; D051379:Mice; D010190:Pancreatic Neoplasms / Q000235:genetics* / Q000378:metabolism; D014183:Transplantation, Heterologous / Q000473:pathology / Q000662:veterinary
D050993:GATA6 Transcription Factor; C494759:GATA6 protein, human