Clinical study of genomic drivers in pancreatic ductal adenocarcinoma
Background: Pancreatic ductal adenocarcinoma (PDA) is a lethal cancer with complex genomes and dense fibrotic stroma. This study was designed to identify clinically relevant somatic aberrations in pancreatic cancer genomes of patients with primary and metastatic disease enrolled and treated in two c...
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| Veröffentlicht in: | British journal of cancer 2017-08, Vol.117 (4), p.572-582 |
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| creator | Barrett, Michael T Deiotte, Ray Lenkiewicz, Elizabeth Malasi, Smriti Holley, Tara Evers, Lisa Posner, Richard G Jones, Timothy Han, Haiyong Sausen, Mark Velculescu, Victor E Drebin, Jeffrey O'Dwyer, Peter Jameson, Gayle Ramanathan, Ramesh K Von Hoff, Daniel D |
| description | Background:
Pancreatic ductal adenocarcinoma (PDA) is a lethal cancer with complex genomes and dense fibrotic stroma. This study was designed to identify clinically relevant somatic aberrations in pancreatic cancer genomes of patients with primary and metastatic disease enrolled and treated in two clinical trials.
Methods:
Tumour nuclei were flow sorted prior to whole genome copy number variant (CNV) analysis. Targeted or whole exome sequencing was performed on most samples. We profiled biopsies from 68 patients enrolled in two Stand Up to Cancer (SU2C)-sponsored clinical trials. These included 38 resected chemoradiation naïve tumours (SU2C 20206-003) and metastases from 30 patients who progressed on prior therapies (SU2C 20206-001). Patient outcomes including progression-free survival (PFS) and overall survival (OS) were observed.
Results:
We defined: (a)
CDKN2A
homozygous deletions that included the adjacent
MTAP
gene, only its’ 3′ region, or excluded
MTAP
; (b)
SMAD4
homozygous deletions that included
ME2
; (c) a pancreas-specific MYC super-enhancer region; (d) DNA repair-deficient genomes; and (e) copy number aberrations present in PDA patients with long-term (⩾ 40 months) and short-term (⩽ 12 months) survival after surgical resection.
Conclusions:
We provide a clinically relevant framework for genomic drivers of PDA and for advancing novel treatments. |
| doi_str_mv | 10.1038/bjc.2017.209 |
| format | Article |
| fullrecord | <record><control><sourceid>proquest_pubme</sourceid><recordid>TN_cdi_pubmedcentral_primary_oai_pubmedcentral_nih_gov_5558689</recordid><sourceformat>XML</sourceformat><sourcesystem>PC</sourcesystem><sourcerecordid>1920393205</sourcerecordid><originalsourceid>FETCH-LOGICAL-c516t-d328d99b16ef3cf7495ac4ea571438088ccfb042ea2003669897219ca2e6c27f3</originalsourceid><addsrcrecordid>eNptkU1LAzEQhoMotlZvnmXBiwe35mN3k1wEKfUDCl70HNLZbE3ZZmuyW-i_N0trUfEyw2Qe3pnJi9AlwWOCmbibL2FMMeExyCM0JDmjKRGUH6MhxpinWFI8QGchLGMpseCnaEAFp1hkbIimk9o6C7pOQtuV26SpkoVxzcpCUnq7MT4k1iVr7cAb3favHbSR1mWkQHuwEdbn6KTSdTAX-zxC74_Tt8lzOnt9epk8zFLISdGmJaOilHJOClMxqHgmcw2Z0TknGRNYCIBqjjNqNMWYFYUUklMiQVNTAOUVG6H7ne66m69MCca1Xtdq7e1K-61qtFW_O85-qEWzUXmei0LIKHCzF_DNZ2dCq1Y2gKlr7UzTBUXiZzHJKM4jev0HXTadd_G8nuKkIFKwSN3uKPBNCN5Uh2UIVr0_Kvqjen9i6Odf_TzgAH8bEoF0B4TYcgvjf0z9T_ALcZCaYg</addsrcrecordid><sourcetype>Open Access Repository</sourcetype><iscdi>true</iscdi><recordtype>article</recordtype><pqid>1927161983</pqid></control><display><type>article</type><title>Clinical study of genomic drivers in pancreatic ductal adenocarcinoma</title><source>MEDLINE</source><source>Nature</source><source>Springer Nature - Complete Springer Journals</source><source>EZB-FREE-00999 freely available EZB journals</source><source>PubMed Central</source><creator>Barrett, Michael T ; Deiotte, Ray ; Lenkiewicz, Elizabeth ; Malasi, Smriti ; Holley, Tara ; Evers, Lisa ; Posner, Richard G ; Jones, Timothy ; Han, Haiyong ; Sausen, Mark ; Velculescu, Victor E ; Drebin, Jeffrey ; O'Dwyer, Peter ; Jameson, Gayle ; Ramanathan, Ramesh K ; Von Hoff, Daniel D</creator><creatorcontrib>Barrett, Michael T ; Deiotte, Ray ; Lenkiewicz, Elizabeth ; Malasi, Smriti ; Holley, Tara ; Evers, Lisa ; Posner, Richard G ; Jones, Timothy ; Han, Haiyong ; Sausen, Mark ; Velculescu, Victor E ; Drebin, Jeffrey ; O'Dwyer, Peter ; Jameson, Gayle ; Ramanathan, Ramesh K ; Von Hoff, Daniel D</creatorcontrib><description>Background:
Pancreatic ductal adenocarcinoma (PDA) is a lethal cancer with complex genomes and dense fibrotic stroma. This study was designed to identify clinically relevant somatic aberrations in pancreatic cancer genomes of patients with primary and metastatic disease enrolled and treated in two clinical trials.
Methods:
Tumour nuclei were flow sorted prior to whole genome copy number variant (CNV) analysis. Targeted or whole exome sequencing was performed on most samples. We profiled biopsies from 68 patients enrolled in two Stand Up to Cancer (SU2C)-sponsored clinical trials. These included 38 resected chemoradiation naïve tumours (SU2C 20206-003) and metastases from 30 patients who progressed on prior therapies (SU2C 20206-001). Patient outcomes including progression-free survival (PFS) and overall survival (OS) were observed.
Results:
We defined: (a)
CDKN2A
homozygous deletions that included the adjacent
MTAP
gene, only its’ 3′ region, or excluded
MTAP
; (b)
SMAD4
homozygous deletions that included
ME2
; (c) a pancreas-specific MYC super-enhancer region; (d) DNA repair-deficient genomes; and (e) copy number aberrations present in PDA patients with long-term (⩾ 40 months) and short-term (⩽ 12 months) survival after surgical resection.
Conclusions:
We provide a clinically relevant framework for genomic drivers of PDA and for advancing novel treatments.</description><identifier>ISSN: 0007-0920</identifier><identifier>EISSN: 1532-1827</identifier><identifier>DOI: 10.1038/bjc.2017.209</identifier><identifier>PMID: 28720843</identifier><language>eng</language><publisher>London: Nature Publishing Group UK</publisher><subject>631/208/2489/144/68 ; 692/4028/67/1504/1713 ; Adenocarcinoma ; Adult ; Aged ; Aged, 80 and over ; Antineoplastic Combined Chemotherapy Protocols - therapeutic use ; Base Sequence ; Biomedical and Life Sciences ; Biomedicine ; Biopsy ; Cancer ; Cancer Research ; Carcinoma, Pancreatic Ductal - drug therapy ; Carcinoma, Pancreatic Ductal - genetics ; Carcinoma, Pancreatic Ductal - secondary ; Chemoradiotherapy ; Clinical trials ; Copy number ; Cyclin-Dependent Kinase Inhibitor p18 - genetics ; Disease-Free Survival ; DNA Copy Number Variations ; DNA Mutational Analysis ; DNA repair ; DNA Repair - genetics ; Drug Resistance ; Enhancer Elements, Genetic ; Epidemiology ; Exome ; Female ; Genes, myc ; Genetics & Genomics ; genetics-and-genomics ; Genomes ; Homozygote ; Humans ; Malate Dehydrogenase - genetics ; Male ; Metastases ; Microtubule-Associated Proteins - genetics ; Middle Aged ; Molecular Medicine ; Myc protein ; Nuclei ; Oncology ; Pancreas ; Pancreas - pathology ; Pancreatic cancer ; Pancreatic Neoplasms - drug therapy ; Pancreatic Neoplasms - genetics ; Pancreatic Neoplasms - pathology ; Proto-Oncogene Proteins p21(ras) - genetics ; Purine-Nucleoside Phosphorylase - genetics ; Sequence Deletion ; Smad4 protein ; Smad4 Protein - genetics ; Stroma ; Survival ; Survival Rate ; Tumor Suppressor Protein p53 - genetics ; Tumors</subject><ispartof>British journal of cancer, 2017-08, Vol.117 (4), p.572-582</ispartof><rights>The Author(s) 2017</rights><rights>Copyright Nature Publishing Group Aug 8, 2017</rights><rights>Copyright © 2017 Cancer Research UK 2017 Cancer Research UK</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c516t-d328d99b16ef3cf7495ac4ea571438088ccfb042ea2003669897219ca2e6c27f3</citedby><cites>FETCH-LOGICAL-c516t-d328d99b16ef3cf7495ac4ea571438088ccfb042ea2003669897219ca2e6c27f3</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC5558689/pdf/$$EPDF$$P50$$Gpubmedcentral$$Hfree_for_read</linktopdf><linktohtml>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC5558689/$$EHTML$$P50$$Gpubmedcentral$$Hfree_for_read</linktohtml><link.rule.ids>230,314,723,776,780,881,27903,27904,41467,42536,51298,53770,53772</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/28720843$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Barrett, Michael T</creatorcontrib><creatorcontrib>Deiotte, Ray</creatorcontrib><creatorcontrib>Lenkiewicz, Elizabeth</creatorcontrib><creatorcontrib>Malasi, Smriti</creatorcontrib><creatorcontrib>Holley, Tara</creatorcontrib><creatorcontrib>Evers, Lisa</creatorcontrib><creatorcontrib>Posner, Richard G</creatorcontrib><creatorcontrib>Jones, Timothy</creatorcontrib><creatorcontrib>Han, Haiyong</creatorcontrib><creatorcontrib>Sausen, Mark</creatorcontrib><creatorcontrib>Velculescu, Victor E</creatorcontrib><creatorcontrib>Drebin, Jeffrey</creatorcontrib><creatorcontrib>O'Dwyer, Peter</creatorcontrib><creatorcontrib>Jameson, Gayle</creatorcontrib><creatorcontrib>Ramanathan, Ramesh K</creatorcontrib><creatorcontrib>Von Hoff, Daniel D</creatorcontrib><title>Clinical study of genomic drivers in pancreatic ductal adenocarcinoma</title><title>British journal of cancer</title><addtitle>Br J Cancer</addtitle><addtitle>Br J Cancer</addtitle><description>Background:
Pancreatic ductal adenocarcinoma (PDA) is a lethal cancer with complex genomes and dense fibrotic stroma. This study was designed to identify clinically relevant somatic aberrations in pancreatic cancer genomes of patients with primary and metastatic disease enrolled and treated in two clinical trials.
Methods:
Tumour nuclei were flow sorted prior to whole genome copy number variant (CNV) analysis. Targeted or whole exome sequencing was performed on most samples. We profiled biopsies from 68 patients enrolled in two Stand Up to Cancer (SU2C)-sponsored clinical trials. These included 38 resected chemoradiation naïve tumours (SU2C 20206-003) and metastases from 30 patients who progressed on prior therapies (SU2C 20206-001). Patient outcomes including progression-free survival (PFS) and overall survival (OS) were observed.
Results:
We defined: (a)
CDKN2A
homozygous deletions that included the adjacent
MTAP
gene, only its’ 3′ region, or excluded
MTAP
; (b)
SMAD4
homozygous deletions that included
ME2
; (c) a pancreas-specific MYC super-enhancer region; (d) DNA repair-deficient genomes; and (e) copy number aberrations present in PDA patients with long-term (⩾ 40 months) and short-term (⩽ 12 months) survival after surgical resection.
Conclusions:
We provide a clinically relevant framework for genomic drivers of PDA and for advancing novel treatments.</description><subject>631/208/2489/144/68</subject><subject>692/4028/67/1504/1713</subject><subject>Adenocarcinoma</subject><subject>Adult</subject><subject>Aged</subject><subject>Aged, 80 and over</subject><subject>Antineoplastic Combined Chemotherapy Protocols - therapeutic use</subject><subject>Base Sequence</subject><subject>Biomedical and Life Sciences</subject><subject>Biomedicine</subject><subject>Biopsy</subject><subject>Cancer</subject><subject>Cancer Research</subject><subject>Carcinoma, Pancreatic Ductal - drug therapy</subject><subject>Carcinoma, Pancreatic Ductal - genetics</subject><subject>Carcinoma, Pancreatic Ductal - secondary</subject><subject>Chemoradiotherapy</subject><subject>Clinical trials</subject><subject>Copy number</subject><subject>Cyclin-Dependent Kinase Inhibitor p18 - genetics</subject><subject>Disease-Free Survival</subject><subject>DNA Copy Number Variations</subject><subject>DNA Mutational Analysis</subject><subject>DNA repair</subject><subject>DNA Repair - genetics</subject><subject>Drug Resistance</subject><subject>Enhancer Elements, Genetic</subject><subject>Epidemiology</subject><subject>Exome</subject><subject>Female</subject><subject>Genes, myc</subject><subject>Genetics & Genomics</subject><subject>genetics-and-genomics</subject><subject>Genomes</subject><subject>Homozygote</subject><subject>Humans</subject><subject>Malate Dehydrogenase - genetics</subject><subject>Male</subject><subject>Metastases</subject><subject>Microtubule-Associated Proteins - genetics</subject><subject>Middle Aged</subject><subject>Molecular Medicine</subject><subject>Myc protein</subject><subject>Nuclei</subject><subject>Oncology</subject><subject>Pancreas</subject><subject>Pancreas - pathology</subject><subject>Pancreatic cancer</subject><subject>Pancreatic Neoplasms - drug therapy</subject><subject>Pancreatic Neoplasms - genetics</subject><subject>Pancreatic Neoplasms - pathology</subject><subject>Proto-Oncogene Proteins p21(ras) - genetics</subject><subject>Purine-Nucleoside Phosphorylase - genetics</subject><subject>Sequence Deletion</subject><subject>Smad4 protein</subject><subject>Smad4 Protein - genetics</subject><subject>Stroma</subject><subject>Survival</subject><subject>Survival Rate</subject><subject>Tumor Suppressor Protein p53 - genetics</subject><subject>Tumors</subject><issn>0007-0920</issn><issn>1532-1827</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2017</creationdate><recordtype>article</recordtype><sourceid>C6C</sourceid><sourceid>EIF</sourceid><sourceid>ABUWG</sourceid><sourceid>AFKRA</sourceid><sourceid>AZQEC</sourceid><sourceid>BENPR</sourceid><sourceid>CCPQU</sourceid><sourceid>DWQXO</sourceid><sourceid>GNUQQ</sourceid><recordid>eNptkU1LAzEQhoMotlZvnmXBiwe35mN3k1wEKfUDCl70HNLZbE3ZZmuyW-i_N0trUfEyw2Qe3pnJi9AlwWOCmbibL2FMMeExyCM0JDmjKRGUH6MhxpinWFI8QGchLGMpseCnaEAFp1hkbIimk9o6C7pOQtuV26SpkoVxzcpCUnq7MT4k1iVr7cAb3favHbSR1mWkQHuwEdbn6KTSdTAX-zxC74_Tt8lzOnt9epk8zFLISdGmJaOilHJOClMxqHgmcw2Z0TknGRNYCIBqjjNqNMWYFYUUklMiQVNTAOUVG6H7ne66m69MCca1Xtdq7e1K-61qtFW_O85-qEWzUXmei0LIKHCzF_DNZ2dCq1Y2gKlr7UzTBUXiZzHJKM4jev0HXTadd_G8nuKkIFKwSN3uKPBNCN5Uh2UIVr0_Kvqjen9i6Odf_TzgAH8bEoF0B4TYcgvjf0z9T_ALcZCaYg</recordid><startdate>20170808</startdate><enddate>20170808</enddate><creator>Barrett, Michael T</creator><creator>Deiotte, Ray</creator><creator>Lenkiewicz, Elizabeth</creator><creator>Malasi, Smriti</creator><creator>Holley, Tara</creator><creator>Evers, Lisa</creator><creator>Posner, Richard G</creator><creator>Jones, Timothy</creator><creator>Han, Haiyong</creator><creator>Sausen, Mark</creator><creator>Velculescu, Victor E</creator><creator>Drebin, Jeffrey</creator><creator>O'Dwyer, Peter</creator><creator>Jameson, Gayle</creator><creator>Ramanathan, Ramesh K</creator><creator>Von Hoff, Daniel D</creator><general>Nature Publishing Group UK</general><general>Nature Publishing Group</general><scope>C6C</scope><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>3V.</scope><scope>7RV</scope><scope>7TO</scope><scope>7U9</scope><scope>7X7</scope><scope>7XB</scope><scope>88E</scope><scope>8AO</scope><scope>8C1</scope><scope>8FE</scope><scope>8FH</scope><scope>8FI</scope><scope>8FJ</scope><scope>8FK</scope><scope>ABUWG</scope><scope>AFKRA</scope><scope>AN0</scope><scope>AZQEC</scope><scope>BBNVY</scope><scope>BENPR</scope><scope>BHPHI</scope><scope>CCPQU</scope><scope>DWQXO</scope><scope>FYUFA</scope><scope>GHDGH</scope><scope>GNUQQ</scope><scope>H94</scope><scope>HCIFZ</scope><scope>K9.</scope><scope>KB0</scope><scope>LK8</scope><scope>M0S</scope><scope>M1P</scope><scope>M7P</scope><scope>NAPCQ</scope><scope>PQEST</scope><scope>PQQKQ</scope><scope>PQUKI</scope><scope>PRINS</scope><scope>7X8</scope><scope>5PM</scope></search><sort><creationdate>20170808</creationdate><title>Clinical study of genomic drivers in pancreatic ductal adenocarcinoma</title><author>Barrett, Michael T ; Deiotte, Ray ; Lenkiewicz, Elizabeth ; Malasi, Smriti ; Holley, Tara ; Evers, Lisa ; Posner, Richard G ; Jones, Timothy ; Han, Haiyong ; Sausen, Mark ; Velculescu, Victor E ; Drebin, Jeffrey ; O'Dwyer, Peter ; Jameson, Gayle ; Ramanathan, Ramesh K ; Von Hoff, Daniel D</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c516t-d328d99b16ef3cf7495ac4ea571438088ccfb042ea2003669897219ca2e6c27f3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2017</creationdate><topic>631/208/2489/144/68</topic><topic>692/4028/67/1504/1713</topic><topic>Adenocarcinoma</topic><topic>Adult</topic><topic>Aged</topic><topic>Aged, 80 and over</topic><topic>Antineoplastic Combined Chemotherapy Protocols - therapeutic use</topic><topic>Base Sequence</topic><topic>Biomedical and Life Sciences</topic><topic>Biomedicine</topic><topic>Biopsy</topic><topic>Cancer</topic><topic>Cancer Research</topic><topic>Carcinoma, Pancreatic Ductal - drug therapy</topic><topic>Carcinoma, Pancreatic Ductal - genetics</topic><topic>Carcinoma, Pancreatic Ductal - secondary</topic><topic>Chemoradiotherapy</topic><topic>Clinical trials</topic><topic>Copy number</topic><topic>Cyclin-Dependent Kinase Inhibitor p18 - genetics</topic><topic>Disease-Free Survival</topic><topic>DNA Copy Number Variations</topic><topic>DNA Mutational Analysis</topic><topic>DNA repair</topic><topic>DNA Repair - genetics</topic><topic>Drug Resistance</topic><topic>Enhancer Elements, Genetic</topic><topic>Epidemiology</topic><topic>Exome</topic><topic>Female</topic><topic>Genes, myc</topic><topic>Genetics & Genomics</topic><topic>genetics-and-genomics</topic><topic>Genomes</topic><topic>Homozygote</topic><topic>Humans</topic><topic>Malate Dehydrogenase - genetics</topic><topic>Male</topic><topic>Metastases</topic><topic>Microtubule-Associated Proteins - genetics</topic><topic>Middle Aged</topic><topic>Molecular Medicine</topic><topic>Myc protein</topic><topic>Nuclei</topic><topic>Oncology</topic><topic>Pancreas</topic><topic>Pancreas - pathology</topic><topic>Pancreatic cancer</topic><topic>Pancreatic Neoplasms - drug therapy</topic><topic>Pancreatic Neoplasms - genetics</topic><topic>Pancreatic Neoplasms - pathology</topic><topic>Proto-Oncogene Proteins p21(ras) - genetics</topic><topic>Purine-Nucleoside Phosphorylase - genetics</topic><topic>Sequence Deletion</topic><topic>Smad4 protein</topic><topic>Smad4 Protein - genetics</topic><topic>Stroma</topic><topic>Survival</topic><topic>Survival Rate</topic><topic>Tumor Suppressor Protein p53 - genetics</topic><topic>Tumors</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Barrett, Michael T</creatorcontrib><creatorcontrib>Deiotte, Ray</creatorcontrib><creatorcontrib>Lenkiewicz, Elizabeth</creatorcontrib><creatorcontrib>Malasi, Smriti</creatorcontrib><creatorcontrib>Holley, Tara</creatorcontrib><creatorcontrib>Evers, Lisa</creatorcontrib><creatorcontrib>Posner, Richard G</creatorcontrib><creatorcontrib>Jones, Timothy</creatorcontrib><creatorcontrib>Han, Haiyong</creatorcontrib><creatorcontrib>Sausen, Mark</creatorcontrib><creatorcontrib>Velculescu, Victor E</creatorcontrib><creatorcontrib>Drebin, Jeffrey</creatorcontrib><creatorcontrib>O'Dwyer, Peter</creatorcontrib><creatorcontrib>Jameson, Gayle</creatorcontrib><creatorcontrib>Ramanathan, Ramesh K</creatorcontrib><creatorcontrib>Von Hoff, Daniel D</creatorcontrib><collection>Springer Open Access</collection><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>ProQuest Central (Corporate)</collection><collection>ProQuest Nursing and Allied Health Journals</collection><collection>Oncogenes and Growth Factors Abstracts</collection><collection>Virology and AIDS Abstracts</collection><collection>ProQuest Health and Medical</collection><collection>ProQuest Central (purchase pre-March 2016)</collection><collection>Medical Database (Alumni Edition)</collection><collection>ProQuest Pharma Collection</collection><collection>Public Health Database</collection><collection>ProQuest SciTech Collection</collection><collection>ProQuest Natural Science Collection</collection><collection>Hospital Premium Collection</collection><collection>Hospital Premium Collection (Alumni Edition)</collection><collection>ProQuest Central (Alumni) (purchase pre-March 2016)</collection><collection>ProQuest Central (Alumni Edition)</collection><collection>ProQuest Central UK/Ireland</collection><collection>British Nursing Database</collection><collection>ProQuest Central Essentials</collection><collection>Biological Science Collection</collection><collection>ProQuest Central</collection><collection>Natural Science Collection</collection><collection>ProQuest One Community College</collection><collection>ProQuest Central Korea</collection><collection>Health Research Premium Collection</collection><collection>Health Research Premium Collection (Alumni)</collection><collection>ProQuest Central Student</collection><collection>AIDS and Cancer Research Abstracts</collection><collection>SciTech Premium Collection</collection><collection>ProQuest Health & Medical Complete (Alumni)</collection><collection>Nursing & Allied Health Database (Alumni Edition)</collection><collection>ProQuest Biological Science Collection</collection><collection>Health & Medical Collection (Alumni Edition)</collection><collection>Medical Database</collection><collection>ProQuest Biological Science Journals</collection><collection>Nursing & Allied Health Premium</collection><collection>ProQuest One Academic Eastern Edition (DO NOT USE)</collection><collection>ProQuest One Academic</collection><collection>ProQuest One Academic UKI Edition</collection><collection>ProQuest Central China</collection><collection>MEDLINE - Academic</collection><collection>PubMed Central (Full Participant titles)</collection><jtitle>British journal of cancer</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Barrett, Michael T</au><au>Deiotte, Ray</au><au>Lenkiewicz, Elizabeth</au><au>Malasi, Smriti</au><au>Holley, Tara</au><au>Evers, Lisa</au><au>Posner, Richard G</au><au>Jones, Timothy</au><au>Han, Haiyong</au><au>Sausen, Mark</au><au>Velculescu, Victor E</au><au>Drebin, Jeffrey</au><au>O'Dwyer, Peter</au><au>Jameson, Gayle</au><au>Ramanathan, Ramesh K</au><au>Von Hoff, Daniel D</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Clinical study of genomic drivers in pancreatic ductal adenocarcinoma</atitle><jtitle>British journal of cancer</jtitle><stitle>Br J Cancer</stitle><addtitle>Br J Cancer</addtitle><date>2017-08-08</date><risdate>2017</risdate><volume>117</volume><issue>4</issue><spage>572</spage><epage>582</epage><pages>572-582</pages><issn>0007-0920</issn><eissn>1532-1827</eissn><abstract>Background:
Pancreatic ductal adenocarcinoma (PDA) is a lethal cancer with complex genomes and dense fibrotic stroma. This study was designed to identify clinically relevant somatic aberrations in pancreatic cancer genomes of patients with primary and metastatic disease enrolled and treated in two clinical trials.
Methods:
Tumour nuclei were flow sorted prior to whole genome copy number variant (CNV) analysis. Targeted or whole exome sequencing was performed on most samples. We profiled biopsies from 68 patients enrolled in two Stand Up to Cancer (SU2C)-sponsored clinical trials. These included 38 resected chemoradiation naïve tumours (SU2C 20206-003) and metastases from 30 patients who progressed on prior therapies (SU2C 20206-001). Patient outcomes including progression-free survival (PFS) and overall survival (OS) were observed.
Results:
We defined: (a)
CDKN2A
homozygous deletions that included the adjacent
MTAP
gene, only its’ 3′ region, or excluded
MTAP
; (b)
SMAD4
homozygous deletions that included
ME2
; (c) a pancreas-specific MYC super-enhancer region; (d) DNA repair-deficient genomes; and (e) copy number aberrations present in PDA patients with long-term (⩾ 40 months) and short-term (⩽ 12 months) survival after surgical resection.
Conclusions:
We provide a clinically relevant framework for genomic drivers of PDA and for advancing novel treatments.</abstract><cop>London</cop><pub>Nature Publishing Group UK</pub><pmid>28720843</pmid><doi>10.1038/bjc.2017.209</doi><tpages>11</tpages><oa>free_for_read</oa></addata></record> |
| fulltext | fulltext |
| identifier | ISSN: 0007-0920 |
| ispartof | British journal of cancer, 2017-08, Vol.117 (4), p.572-582 |
| issn | 0007-0920 1532-1827 |
| language | eng |
| recordid | cdi_pubmedcentral_primary_oai_pubmedcentral_nih_gov_5558689 |
| source | MEDLINE; Nature; Springer Nature - Complete Springer Journals; EZB-FREE-00999 freely available EZB journals; PubMed Central |
| subjects | 631/208/2489/144/68 692/4028/67/1504/1713 Adenocarcinoma Adult Aged Aged, 80 and over Antineoplastic Combined Chemotherapy Protocols - therapeutic use Base Sequence Biomedical and Life Sciences Biomedicine Biopsy Cancer Cancer Research Carcinoma, Pancreatic Ductal - drug therapy Carcinoma, Pancreatic Ductal - genetics Carcinoma, Pancreatic Ductal - secondary Chemoradiotherapy Clinical trials Copy number Cyclin-Dependent Kinase Inhibitor p18 - genetics Disease-Free Survival DNA Copy Number Variations DNA Mutational Analysis DNA repair DNA Repair - genetics Drug Resistance Enhancer Elements, Genetic Epidemiology Exome Female Genes, myc Genetics & Genomics genetics-and-genomics Genomes Homozygote Humans Malate Dehydrogenase - genetics Male Metastases Microtubule-Associated Proteins - genetics Middle Aged Molecular Medicine Myc protein Nuclei Oncology Pancreas Pancreas - pathology Pancreatic cancer Pancreatic Neoplasms - drug therapy Pancreatic Neoplasms - genetics Pancreatic Neoplasms - pathology Proto-Oncogene Proteins p21(ras) - genetics Purine-Nucleoside Phosphorylase - genetics Sequence Deletion Smad4 protein Smad4 Protein - genetics Stroma Survival Survival Rate Tumor Suppressor Protein p53 - genetics Tumors |
| title | Clinical study of genomic drivers in pancreatic ductal adenocarcinoma |
| url | https://sfx.bib-bvb.de/sfx_tum?ctx_ver=Z39.88-2004&ctx_enc=info:ofi/enc:UTF-8&ctx_tim=2025-01-22T21%3A09%3A26IST&url_ver=Z39.88-2004&url_ctx_fmt=infofi/fmt:kev:mtx:ctx&rfr_id=info:sid/primo.exlibrisgroup.com:primo3-Article-proquest_pubme&rft_val_fmt=info:ofi/fmt:kev:mtx:journal&rft.genre=article&rft.atitle=Clinical%20study%20of%20genomic%20drivers%20in%20pancreatic%20ductal%20adenocarcinoma&rft.jtitle=British%20journal%20of%20cancer&rft.au=Barrett,%20Michael%20T&rft.date=2017-08-08&rft.volume=117&rft.issue=4&rft.spage=572&rft.epage=582&rft.pages=572-582&rft.issn=0007-0920&rft.eissn=1532-1827&rft_id=info:doi/10.1038/bjc.2017.209&rft_dat=%3Cproquest_pubme%3E1920393205%3C/proquest_pubme%3E%3Curl%3E%3C/url%3E&disable_directlink=true&sfx.directlink=off&sfx.report_link=0&rft_id=info:oai/&rft_pqid=1927161983&rft_id=info:pmid/28720843&rfr_iscdi=true |