RNA sequencing of pancreatic adenocarcinoma tumors yields novel expression patterns associated with long‐term survival and reveals a role for ANGPTL4
Background Pancreatic adenocarcinoma patients have low survival rates due to late‐stage diagnosis and high rates of cancer recurrence even after surgical resection. It is important to understand the molecular characteristics associated with survival differences in pancreatic adenocarcinoma tumors th...
| Main Authors: | , , , , , , , , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Wiley
2016-10-01
|
| Series: | Molecular Oncology |
| Subjects: | |
| Online Access: | https://doi.org/10.1016/j.molonc.2016.05.004 |
| _version_ | 1827329589240659968 |
|---|---|
| author | Marie K. Kirby Ryne C. Ramaker Jason Gertz Nicholas S. Davis Bobbi E. Johnston Patsy G. Oliver Katherine C. Sexton Edward W. Greeno John D. Christein Martin J. Heslin James A. Posey William E. Grizzle Selwyn M. Vickers Donald J. Buchsbaum Sara J. Cooper Richard M. Myers |
| author_facet | Marie K. Kirby Ryne C. Ramaker Jason Gertz Nicholas S. Davis Bobbi E. Johnston Patsy G. Oliver Katherine C. Sexton Edward W. Greeno John D. Christein Martin J. Heslin James A. Posey William E. Grizzle Selwyn M. Vickers Donald J. Buchsbaum Sara J. Cooper Richard M. Myers |
| author_sort | Marie K. Kirby |
| collection | DOAJ |
| description | Background Pancreatic adenocarcinoma patients have low survival rates due to late‐stage diagnosis and high rates of cancer recurrence even after surgical resection. It is important to understand the molecular characteristics associated with survival differences in pancreatic adenocarcinoma tumors that may inform patient care. Results RNA sequencing was performed for 51 patient tumor tissues extracted from patients undergoing surgical resection, and expression was associated with overall survival time from diagnosis. Our analysis uncovered 323 transcripts whose expression correlates with survival time in our pancreatic patient cohort. This genomic signature was validated in an independent RNA‐seq dataset of 68 additional patients from the International Cancer Genome Consortium. We demonstrate that this transcriptional profile is largely independent of markers of cellular division and present a 19‐transcript predictive model built from a subset of the 323 transcripts that can distinguish patients with differing survival times across both the training and validation patient cohorts. We present evidence that a subset of the survival‐associated transcripts is associated with resistance to gemcitabine treatment in vitro, and reveal that reduced expression of one of the survival‐associated transcripts, Angiopoietin‐like 4, impairs growth of a gemcitabine‐resistant pancreatic cancer cell line. Conclusions Gene expression patterns in pancreatic adenocarcinoma tumors can distinguish patients with differing survival outcomes after undergoing surgical resection, and the survival difference could be associated with the intrinsic gemcitabine sensitivity of primary patient tumors. Thus, these transcriptional differences may impact patient care by distinguishing patients who would benefit from a non‐gemcitabine based therapy. |
| first_indexed | 2024-03-07T15:42:16Z |
| format | Article |
| id | doaj.art-18b28309935b4450822c1557f59a1f5b |
| institution | Directory Open Access Journal |
| issn | 1574-7891 1878-0261 |
| language | English |
| last_indexed | 2024-03-07T15:42:16Z |
| publishDate | 2016-10-01 |
| publisher | Wiley |
| record_format | Article |
| series | Molecular Oncology |
| spelling | doaj.art-18b28309935b4450822c1557f59a1f5b2024-03-05T07:31:03ZengWileyMolecular Oncology1574-78911878-02612016-10-011081169118210.1016/j.molonc.2016.05.004RNA sequencing of pancreatic adenocarcinoma tumors yields novel expression patterns associated with long‐term survival and reveals a role for ANGPTL4Marie K. Kirby0Ryne C. Ramaker1Jason Gertz2Nicholas S. Davis3Bobbi E. Johnston4Patsy G. Oliver5Katherine C. Sexton6Edward W. Greeno7John D. Christein8Martin J. Heslin9James A. Posey10William E. Grizzle11Selwyn M. Vickers12Donald J. Buchsbaum13Sara J. Cooper14Richard M. Myers15HudsonAlpha Institute for Biotechnology, Huntsville, AL, USAHudsonAlpha Institute for Biotechnology, Huntsville, AL, USAHudsonAlpha Institute for Biotechnology, Huntsville, AL, USAHudsonAlpha Institute for Biotechnology, Huntsville, AL, USAHudsonAlpha Institute for Biotechnology, Huntsville, AL, USAUniversity of Alabama at Birmingham, Birmingham, AL, USAUniversity of Alabama at Birmingham, Birmingham, AL, USAUniversity of Minnesota, Minneapolis, MN, USAUniversity of Alabama at Birmingham, Birmingham, AL, USAUniversity of Alabama at Birmingham, Birmingham, AL, USAUniversity of Alabama at Birmingham, Birmingham, AL, USAUniversity of Alabama at Birmingham, Birmingham, AL, USAUniversity of Alabama at Birmingham, Birmingham, AL, USAUniversity of Alabama at Birmingham, Birmingham, AL, USAHudsonAlpha Institute for Biotechnology, Huntsville, AL, USAHudsonAlpha Institute for Biotechnology, Huntsville, AL, USABackground Pancreatic adenocarcinoma patients have low survival rates due to late‐stage diagnosis and high rates of cancer recurrence even after surgical resection. It is important to understand the molecular characteristics associated with survival differences in pancreatic adenocarcinoma tumors that may inform patient care. Results RNA sequencing was performed for 51 patient tumor tissues extracted from patients undergoing surgical resection, and expression was associated with overall survival time from diagnosis. Our analysis uncovered 323 transcripts whose expression correlates with survival time in our pancreatic patient cohort. This genomic signature was validated in an independent RNA‐seq dataset of 68 additional patients from the International Cancer Genome Consortium. We demonstrate that this transcriptional profile is largely independent of markers of cellular division and present a 19‐transcript predictive model built from a subset of the 323 transcripts that can distinguish patients with differing survival times across both the training and validation patient cohorts. We present evidence that a subset of the survival‐associated transcripts is associated with resistance to gemcitabine treatment in vitro, and reveal that reduced expression of one of the survival‐associated transcripts, Angiopoietin‐like 4, impairs growth of a gemcitabine‐resistant pancreatic cancer cell line. Conclusions Gene expression patterns in pancreatic adenocarcinoma tumors can distinguish patients with differing survival outcomes after undergoing surgical resection, and the survival difference could be associated with the intrinsic gemcitabine sensitivity of primary patient tumors. Thus, these transcriptional differences may impact patient care by distinguishing patients who would benefit from a non‐gemcitabine based therapy.https://doi.org/10.1016/j.molonc.2016.05.004Pancreatic adenocarcinomaANGPTL4GemcitabineRNA-seq |
| spellingShingle | Marie K. Kirby Ryne C. Ramaker Jason Gertz Nicholas S. Davis Bobbi E. Johnston Patsy G. Oliver Katherine C. Sexton Edward W. Greeno John D. Christein Martin J. Heslin James A. Posey William E. Grizzle Selwyn M. Vickers Donald J. Buchsbaum Sara J. Cooper Richard M. Myers RNA sequencing of pancreatic adenocarcinoma tumors yields novel expression patterns associated with long‐term survival and reveals a role for ANGPTL4 Molecular Oncology Pancreatic adenocarcinoma ANGPTL4 Gemcitabine RNA-seq |
| title | RNA sequencing of pancreatic adenocarcinoma tumors yields novel expression patterns associated with long‐term survival and reveals a role for ANGPTL4 |
| title_full | RNA sequencing of pancreatic adenocarcinoma tumors yields novel expression patterns associated with long‐term survival and reveals a role for ANGPTL4 |
| title_fullStr | RNA sequencing of pancreatic adenocarcinoma tumors yields novel expression patterns associated with long‐term survival and reveals a role for ANGPTL4 |
| title_full_unstemmed | RNA sequencing of pancreatic adenocarcinoma tumors yields novel expression patterns associated with long‐term survival and reveals a role for ANGPTL4 |
| title_short | RNA sequencing of pancreatic adenocarcinoma tumors yields novel expression patterns associated with long‐term survival and reveals a role for ANGPTL4 |
| title_sort | rna sequencing of pancreatic adenocarcinoma tumors yields novel expression patterns associated with long term survival and reveals a role for angptl4 |
| topic | Pancreatic adenocarcinoma ANGPTL4 Gemcitabine RNA-seq |
| url | https://doi.org/10.1016/j.molonc.2016.05.004 |
| work_keys_str_mv | AT mariekkirby rnasequencingofpancreaticadenocarcinomatumorsyieldsnovelexpressionpatternsassociatedwithlongtermsurvivalandrevealsaroleforangptl4 AT rynecramaker rnasequencingofpancreaticadenocarcinomatumorsyieldsnovelexpressionpatternsassociatedwithlongtermsurvivalandrevealsaroleforangptl4 AT jasongertz rnasequencingofpancreaticadenocarcinomatumorsyieldsnovelexpressionpatternsassociatedwithlongtermsurvivalandrevealsaroleforangptl4 AT nicholassdavis rnasequencingofpancreaticadenocarcinomatumorsyieldsnovelexpressionpatternsassociatedwithlongtermsurvivalandrevealsaroleforangptl4 AT bobbiejohnston rnasequencingofpancreaticadenocarcinomatumorsyieldsnovelexpressionpatternsassociatedwithlongtermsurvivalandrevealsaroleforangptl4 AT patsygoliver rnasequencingofpancreaticadenocarcinomatumorsyieldsnovelexpressionpatternsassociatedwithlongtermsurvivalandrevealsaroleforangptl4 AT katherinecsexton rnasequencingofpancreaticadenocarcinomatumorsyieldsnovelexpressionpatternsassociatedwithlongtermsurvivalandrevealsaroleforangptl4 AT edwardwgreeno rnasequencingofpancreaticadenocarcinomatumorsyieldsnovelexpressionpatternsassociatedwithlongtermsurvivalandrevealsaroleforangptl4 AT johndchristein rnasequencingofpancreaticadenocarcinomatumorsyieldsnovelexpressionpatternsassociatedwithlongtermsurvivalandrevealsaroleforangptl4 AT martinjheslin rnasequencingofpancreaticadenocarcinomatumorsyieldsnovelexpressionpatternsassociatedwithlongtermsurvivalandrevealsaroleforangptl4 AT jamesaposey rnasequencingofpancreaticadenocarcinomatumorsyieldsnovelexpressionpatternsassociatedwithlongtermsurvivalandrevealsaroleforangptl4 AT williamegrizzle rnasequencingofpancreaticadenocarcinomatumorsyieldsnovelexpressionpatternsassociatedwithlongtermsurvivalandrevealsaroleforangptl4 AT selwynmvickers rnasequencingofpancreaticadenocarcinomatumorsyieldsnovelexpressionpatternsassociatedwithlongtermsurvivalandrevealsaroleforangptl4 AT donaldjbuchsbaum rnasequencingofpancreaticadenocarcinomatumorsyieldsnovelexpressionpatternsassociatedwithlongtermsurvivalandrevealsaroleforangptl4 AT sarajcooper rnasequencingofpancreaticadenocarcinomatumorsyieldsnovelexpressionpatternsassociatedwithlongtermsurvivalandrevealsaroleforangptl4 AT richardmmyers rnasequencingofpancreaticadenocarcinomatumorsyieldsnovelexpressionpatternsassociatedwithlongtermsurvivalandrevealsaroleforangptl4 |