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...
Autores principales: | , , , , , , , , , , , , , , , , , |
---|---|
Formato: | Texto |
Lenguaje: | English |
Publicado: |
Public Library of Science
2008
|
Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2413204/ https://www.ncbi.nlm.nih.gov/pubmed/18535672 http://dx.doi.org/10.1371/journal.pgen.1000081 |
_version_ | 1782156027606597632 |
---|---|
author | Kwei, Kevin A. Bashyam, Murali D. Kao, Jessica Ratheesh, Raman Reddy, Edumakanti C. Kim, Young H. Montgomery, Kelli Giacomini, Craig P. Choi, Yoon-La Chatterjee, Sreejata Karikari, Collins A. Salari, Keyan Wang, Pei Hernandez-Boussard, Tina Swarnalata, Gowrishankar van de Rijn, Matt Maitra, Anirban Pollack, Jonathan R. |
author_facet | Kwei, Kevin A. Bashyam, Murali D. Kao, Jessica Ratheesh, Raman Reddy, Edumakanti C. Kim, Young H. Montgomery, Kelli Giacomini, Craig P. Choi, Yoon-La Chatterjee, Sreejata Karikari, Collins A. Salari, Keyan Wang, Pei Hernandez-Boussard, Tina Swarnalata, Gowrishankar van de Rijn, Matt Maitra, Anirban Pollack, Jonathan R. |
author_sort | Kwei, Kevin A. |
collection | PubMed |
description | 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. |
format | Text |
id | pubmed-2413204 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2008 |
publisher | Public Library of Science |
record_format | MEDLINE/PubMed |
spelling | pubmed-24132042008-06-06 Genomic Profiling Identifies GATA6 as a Candidate Oncogene Amplified in Pancreatobiliary Cancer Kwei, Kevin A. Bashyam, Murali D. Kao, Jessica Ratheesh, Raman Reddy, Edumakanti C. Kim, Young H. Montgomery, Kelli Giacomini, Craig P. Choi, Yoon-La Chatterjee, Sreejata Karikari, Collins A. Salari, Keyan Wang, Pei Hernandez-Boussard, Tina Swarnalata, Gowrishankar van de Rijn, Matt Maitra, Anirban Pollack, Jonathan R. PLoS Genet Research Article 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. Public Library of Science 2008-05-23 /pmc/articles/PMC2413204/ /pubmed/18535672 http://dx.doi.org/10.1371/journal.pgen.1000081 Text en Kwei et al. http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are properly credited. |
spellingShingle | Research Article Kwei, Kevin A. Bashyam, Murali D. Kao, Jessica Ratheesh, Raman Reddy, Edumakanti C. Kim, Young H. Montgomery, Kelli Giacomini, Craig P. Choi, Yoon-La Chatterjee, Sreejata Karikari, Collins A. Salari, Keyan Wang, Pei Hernandez-Boussard, Tina Swarnalata, Gowrishankar van de Rijn, Matt Maitra, Anirban Pollack, Jonathan R. Genomic Profiling Identifies GATA6 as a Candidate Oncogene Amplified in Pancreatobiliary Cancer |
title | Genomic Profiling Identifies GATA6 as a Candidate Oncogene Amplified in Pancreatobiliary Cancer |
title_full | Genomic Profiling Identifies GATA6 as a Candidate Oncogene Amplified in Pancreatobiliary Cancer |
title_fullStr | Genomic Profiling Identifies GATA6 as a Candidate Oncogene Amplified in Pancreatobiliary Cancer |
title_full_unstemmed | Genomic Profiling Identifies GATA6 as a Candidate Oncogene Amplified in Pancreatobiliary Cancer |
title_short | Genomic Profiling Identifies GATA6 as a Candidate Oncogene Amplified in Pancreatobiliary Cancer |
title_sort | genomic profiling identifies gata6 as a candidate oncogene amplified in pancreatobiliary cancer |
topic | Research Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2413204/ https://www.ncbi.nlm.nih.gov/pubmed/18535672 http://dx.doi.org/10.1371/journal.pgen.1000081 |
work_keys_str_mv | AT kweikevina genomicprofilingidentifiesgata6asacandidateoncogeneamplifiedinpancreatobiliarycancer AT bashyammuralid genomicprofilingidentifiesgata6asacandidateoncogeneamplifiedinpancreatobiliarycancer AT kaojessica genomicprofilingidentifiesgata6asacandidateoncogeneamplifiedinpancreatobiliarycancer AT ratheeshraman genomicprofilingidentifiesgata6asacandidateoncogeneamplifiedinpancreatobiliarycancer AT reddyedumakantic genomicprofilingidentifiesgata6asacandidateoncogeneamplifiedinpancreatobiliarycancer AT kimyoungh genomicprofilingidentifiesgata6asacandidateoncogeneamplifiedinpancreatobiliarycancer AT montgomerykelli genomicprofilingidentifiesgata6asacandidateoncogeneamplifiedinpancreatobiliarycancer AT giacominicraigp genomicprofilingidentifiesgata6asacandidateoncogeneamplifiedinpancreatobiliarycancer AT choiyoonla genomicprofilingidentifiesgata6asacandidateoncogeneamplifiedinpancreatobiliarycancer AT chatterjeesreejata genomicprofilingidentifiesgata6asacandidateoncogeneamplifiedinpancreatobiliarycancer AT karikaricollinsa genomicprofilingidentifiesgata6asacandidateoncogeneamplifiedinpancreatobiliarycancer AT salarikeyan genomicprofilingidentifiesgata6asacandidateoncogeneamplifiedinpancreatobiliarycancer AT wangpei genomicprofilingidentifiesgata6asacandidateoncogeneamplifiedinpancreatobiliarycancer AT hernandezboussardtina genomicprofilingidentifiesgata6asacandidateoncogeneamplifiedinpancreatobiliarycancer AT swarnalatagowrishankar genomicprofilingidentifiesgata6asacandidateoncogeneamplifiedinpancreatobiliarycancer AT vanderijnmatt genomicprofilingidentifiesgata6asacandidateoncogeneamplifiedinpancreatobiliarycancer AT maitraanirban genomicprofilingidentifiesgata6asacandidateoncogeneamplifiedinpancreatobiliarycancer AT pollackjonathanr genomicprofilingidentifiesgata6asacandidateoncogeneamplifiedinpancreatobiliarycancer |