Genetic and Epigenetic Determinants of Aggressiveness in Cribriform Carcinoma of the Prostate
Among prostate cancers containing Gleason pattern 4, cribriform morphology is associated with unfavorable clinicopathologic factors, but its genetic features and association with long-term outcomes are incompletely understood. In this study, genetic, transcriptional, and epigenetic features of invas...
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| Veröffentlicht in: | Molecular cancer research 2019-02, Vol.17 (2), p.446-456 |
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| creator | Elfandy, Habiba Armenia, Joshua Pederzoli, Filippo Pullman, Eli Pertega-Gomes, Nelma Schultz, Nikolaus Viswanathan, Kartik Vosoughi, Aram Blattner, Mirjam Stopsack, Konrad H Zadra, Giorgia Penney, Kathryn L Mosquera, Juan Miguel Tyekucheva, Svitlana Mucci, Lorelei A Barbieri, Christopher Loda, Massimo |
| description | Among prostate cancers containing Gleason pattern 4, cribriform morphology is associated with unfavorable clinicopathologic factors, but its genetic features and association with long-term outcomes are incompletely understood. In this study, genetic, transcriptional, and epigenetic features of invasive cribriform carcinoma (ICC) tumors were compared with non-cribriform Gleason 4 (NC4) in The Cancer Genome Atlas (TCGA) cohort. ICC (
= 164) had distinctive molecular features when compared with NC4 (
= 102). These include: (i) increased somatic copy number variations (SCNV), specifically deletions at 6q, 8p and 10q, which encompassed
and
losses and gains at 3q; (ii) increased
and
; (iii) enrichment for
and
pathways by gene expression; and (iv) increased methylation of selected genes. In addition, when compared with the metastatic prostate cancer, ICC clustered more closely to metastatic prostate cancer than NC4. Validation in clinical cohorts and genomically annotated murine models confirmed the association with
(
= 38) and
(
= 818). The association of ICC with lethal disease was evaluated in the Health Professionals Follow-up Study (HPFS) and Physicians' Health Study (PHS) prospective prostate cancer cohorts (median follow-up, 13.4 years;
= 818). Patients with ICC were more likely to develop lethal cancer [HR, 1.62; 95% confidence interval (CI), 1.05-2.49], independent from Gleason score (GS). IMPLICATIONS: ICC has a distinct molecular phenotype that resembles metastatic prostate cancer and is associated with progression to lethal disease. |
| doi_str_mv | 10.1158/1541-7786.mcr-18-0440 |
| format | Article |
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= 164) had distinctive molecular features when compared with NC4 (
= 102). These include: (i) increased somatic copy number variations (SCNV), specifically deletions at 6q, 8p and 10q, which encompassed
and
losses and gains at 3q; (ii) increased
and
; (iii) enrichment for
and
pathways by gene expression; and (iv) increased methylation of selected genes. In addition, when compared with the metastatic prostate cancer, ICC clustered more closely to metastatic prostate cancer than NC4. Validation in clinical cohorts and genomically annotated murine models confirmed the association with
(
= 38) and
(
= 818). The association of ICC with lethal disease was evaluated in the Health Professionals Follow-up Study (HPFS) and Physicians' Health Study (PHS) prospective prostate cancer cohorts (median follow-up, 13.4 years;
= 818). Patients with ICC were more likely to develop lethal cancer [HR, 1.62; 95% confidence interval (CI), 1.05-2.49], independent from Gleason score (GS). IMPLICATIONS: ICC has a distinct molecular phenotype that resembles metastatic prostate cancer and is associated with progression to lethal disease.</description><identifier>ISSN: 1541-7786</identifier><identifier>ISSN: 1557-3125</identifier><identifier>EISSN: 1557-3125</identifier><identifier>DOI: 10.1158/1541-7786.mcr-18-0440</identifier><identifier>PMID: 30333152</identifier><language>eng</language><publisher>United States</publisher><subject>Adenocarcinoma - genetics ; Adenocarcinoma - pathology ; Animals ; Epigenomics - methods ; Humans ; Male ; Mice ; Prostatic Neoplasms - genetics ; Prostatic Neoplasms - pathology</subject><ispartof>Molecular cancer research, 2019-02, Vol.17 (2), p.446-456</ispartof><rights>2018 American Association for Cancer Research.</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c477t-9cb944240c283b15b88188429f81b6d3028b5681aec73a4273e0f3817a6f60f33</citedby><cites>FETCH-LOGICAL-c477t-9cb944240c283b15b88188429f81b6d3028b5681aec73a4273e0f3817a6f60f33</cites><orcidid>0000-0002-3119-6507 ; 0000-0002-0722-1311 ; 0000-0003-3873-7465 ; 0000-0002-0381-1947</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>230,314,780,784,885,3356,27924,27925</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/30333152$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Elfandy, Habiba</creatorcontrib><creatorcontrib>Armenia, Joshua</creatorcontrib><creatorcontrib>Pederzoli, Filippo</creatorcontrib><creatorcontrib>Pullman, Eli</creatorcontrib><creatorcontrib>Pertega-Gomes, Nelma</creatorcontrib><creatorcontrib>Schultz, Nikolaus</creatorcontrib><creatorcontrib>Viswanathan, Kartik</creatorcontrib><creatorcontrib>Vosoughi, Aram</creatorcontrib><creatorcontrib>Blattner, Mirjam</creatorcontrib><creatorcontrib>Stopsack, Konrad H</creatorcontrib><creatorcontrib>Zadra, Giorgia</creatorcontrib><creatorcontrib>Penney, Kathryn L</creatorcontrib><creatorcontrib>Mosquera, Juan Miguel</creatorcontrib><creatorcontrib>Tyekucheva, Svitlana</creatorcontrib><creatorcontrib>Mucci, Lorelei A</creatorcontrib><creatorcontrib>Barbieri, Christopher</creatorcontrib><creatorcontrib>Loda, Massimo</creatorcontrib><title>Genetic and Epigenetic Determinants of Aggressiveness in Cribriform Carcinoma of the Prostate</title><title>Molecular cancer research</title><addtitle>Mol Cancer Res</addtitle><description>Among prostate cancers containing Gleason pattern 4, cribriform morphology is associated with unfavorable clinicopathologic factors, but its genetic features and association with long-term outcomes are incompletely understood. In this study, genetic, transcriptional, and epigenetic features of invasive cribriform carcinoma (ICC) tumors were compared with non-cribriform Gleason 4 (NC4) in The Cancer Genome Atlas (TCGA) cohort. ICC (
= 164) had distinctive molecular features when compared with NC4 (
= 102). These include: (i) increased somatic copy number variations (SCNV), specifically deletions at 6q, 8p and 10q, which encompassed
and
losses and gains at 3q; (ii) increased
and
; (iii) enrichment for
and
pathways by gene expression; and (iv) increased methylation of selected genes. In addition, when compared with the metastatic prostate cancer, ICC clustered more closely to metastatic prostate cancer than NC4. Validation in clinical cohorts and genomically annotated murine models confirmed the association with
(
= 38) and
(
= 818). The association of ICC with lethal disease was evaluated in the Health Professionals Follow-up Study (HPFS) and Physicians' Health Study (PHS) prospective prostate cancer cohorts (median follow-up, 13.4 years;
= 818). Patients with ICC were more likely to develop lethal cancer [HR, 1.62; 95% confidence interval (CI), 1.05-2.49], independent from Gleason score (GS). IMPLICATIONS: ICC has a distinct molecular phenotype that resembles metastatic prostate cancer and is associated with progression to lethal disease.</description><subject>Adenocarcinoma - genetics</subject><subject>Adenocarcinoma - pathology</subject><subject>Animals</subject><subject>Epigenomics - methods</subject><subject>Humans</subject><subject>Male</subject><subject>Mice</subject><subject>Prostatic Neoplasms - genetics</subject><subject>Prostatic Neoplasms - pathology</subject><issn>1541-7786</issn><issn>1557-3125</issn><issn>1557-3125</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2019</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNpVUctOwzAQtBCI9yeAcuSS4vUjdi5IVXhKRSAER2Q5rtMaNU6x3Ur8PYlaEJx2Vzs7s7uD0BngEQCXl8AZ5ELIYtSakIPMMWN4Bx0C5yKnQPjukG8xB-goxg-MCQZR7KMDiimlwMkher-z3iZnMu2n2c3SzbbltU02tM5rn2LWNdl4Ngs2Rrfu-zFmzmdVcHVwTRfarNLBON-1ekCmuc2eQxeTTvYE7TV6Ee3pNh6jt9ub1-o-nzzdPVTjSW6YECkvTV0yRhg2RNIaeC0lSMlI2UioiynFRNa8kKCtEVQzIqjFDZUgdNEUfUaP0dWGd7mqWzs11qegF2oZXKvDl-q0U_873s3VrFurgvKy5KQnuNgShO5zZWNSrYvGLhba224VFQFCeFkAGbT4Bmr6I2Owza8MYDVYo4a3q-Ht6rF6USDVYE0_d_53x9-pHy_oN0A9i3U</recordid><startdate>20190201</startdate><enddate>20190201</enddate><creator>Elfandy, Habiba</creator><creator>Armenia, Joshua</creator><creator>Pederzoli, Filippo</creator><creator>Pullman, Eli</creator><creator>Pertega-Gomes, Nelma</creator><creator>Schultz, Nikolaus</creator><creator>Viswanathan, Kartik</creator><creator>Vosoughi, Aram</creator><creator>Blattner, Mirjam</creator><creator>Stopsack, Konrad H</creator><creator>Zadra, Giorgia</creator><creator>Penney, Kathryn L</creator><creator>Mosquera, Juan Miguel</creator><creator>Tyekucheva, Svitlana</creator><creator>Mucci, Lorelei A</creator><creator>Barbieri, Christopher</creator><creator>Loda, Massimo</creator><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>7X8</scope><scope>5PM</scope><orcidid>https://orcid.org/0000-0002-3119-6507</orcidid><orcidid>https://orcid.org/0000-0002-0722-1311</orcidid><orcidid>https://orcid.org/0000-0003-3873-7465</orcidid><orcidid>https://orcid.org/0000-0002-0381-1947</orcidid></search><sort><creationdate>20190201</creationdate><title>Genetic and Epigenetic Determinants of Aggressiveness in Cribriform Carcinoma of the Prostate</title><author>Elfandy, Habiba ; Armenia, Joshua ; Pederzoli, Filippo ; Pullman, Eli ; Pertega-Gomes, Nelma ; Schultz, Nikolaus ; Viswanathan, Kartik ; Vosoughi, Aram ; Blattner, Mirjam ; Stopsack, Konrad H ; Zadra, Giorgia ; Penney, Kathryn L ; Mosquera, Juan Miguel ; Tyekucheva, Svitlana ; Mucci, Lorelei A ; Barbieri, Christopher ; Loda, Massimo</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c477t-9cb944240c283b15b88188429f81b6d3028b5681aec73a4273e0f3817a6f60f33</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2019</creationdate><topic>Adenocarcinoma - genetics</topic><topic>Adenocarcinoma - pathology</topic><topic>Animals</topic><topic>Epigenomics - methods</topic><topic>Humans</topic><topic>Male</topic><topic>Mice</topic><topic>Prostatic Neoplasms - genetics</topic><topic>Prostatic Neoplasms - pathology</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Elfandy, Habiba</creatorcontrib><creatorcontrib>Armenia, Joshua</creatorcontrib><creatorcontrib>Pederzoli, Filippo</creatorcontrib><creatorcontrib>Pullman, Eli</creatorcontrib><creatorcontrib>Pertega-Gomes, Nelma</creatorcontrib><creatorcontrib>Schultz, Nikolaus</creatorcontrib><creatorcontrib>Viswanathan, Kartik</creatorcontrib><creatorcontrib>Vosoughi, Aram</creatorcontrib><creatorcontrib>Blattner, Mirjam</creatorcontrib><creatorcontrib>Stopsack, Konrad H</creatorcontrib><creatorcontrib>Zadra, Giorgia</creatorcontrib><creatorcontrib>Penney, Kathryn L</creatorcontrib><creatorcontrib>Mosquera, Juan Miguel</creatorcontrib><creatorcontrib>Tyekucheva, Svitlana</creatorcontrib><creatorcontrib>Mucci, Lorelei A</creatorcontrib><creatorcontrib>Barbieri, Christopher</creatorcontrib><creatorcontrib>Loda, Massimo</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>MEDLINE - Academic</collection><collection>PubMed Central (Full Participant titles)</collection><jtitle>Molecular cancer research</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Elfandy, Habiba</au><au>Armenia, Joshua</au><au>Pederzoli, Filippo</au><au>Pullman, Eli</au><au>Pertega-Gomes, Nelma</au><au>Schultz, Nikolaus</au><au>Viswanathan, Kartik</au><au>Vosoughi, Aram</au><au>Blattner, Mirjam</au><au>Stopsack, Konrad H</au><au>Zadra, Giorgia</au><au>Penney, Kathryn L</au><au>Mosquera, Juan Miguel</au><au>Tyekucheva, Svitlana</au><au>Mucci, Lorelei A</au><au>Barbieri, Christopher</au><au>Loda, Massimo</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Genetic and Epigenetic Determinants of Aggressiveness in Cribriform Carcinoma of the Prostate</atitle><jtitle>Molecular cancer research</jtitle><addtitle>Mol Cancer Res</addtitle><date>2019-02-01</date><risdate>2019</risdate><volume>17</volume><issue>2</issue><spage>446</spage><epage>456</epage><pages>446-456</pages><issn>1541-7786</issn><issn>1557-3125</issn><eissn>1557-3125</eissn><abstract>Among prostate cancers containing Gleason pattern 4, cribriform morphology is associated with unfavorable clinicopathologic factors, but its genetic features and association with long-term outcomes are incompletely understood. In this study, genetic, transcriptional, and epigenetic features of invasive cribriform carcinoma (ICC) tumors were compared with non-cribriform Gleason 4 (NC4) in The Cancer Genome Atlas (TCGA) cohort. ICC (
= 164) had distinctive molecular features when compared with NC4 (
= 102). These include: (i) increased somatic copy number variations (SCNV), specifically deletions at 6q, 8p and 10q, which encompassed
and
losses and gains at 3q; (ii) increased
and
; (iii) enrichment for
and
pathways by gene expression; and (iv) increased methylation of selected genes. In addition, when compared with the metastatic prostate cancer, ICC clustered more closely to metastatic prostate cancer than NC4. Validation in clinical cohorts and genomically annotated murine models confirmed the association with
(
= 38) and
(
= 818). The association of ICC with lethal disease was evaluated in the Health Professionals Follow-up Study (HPFS) and Physicians' Health Study (PHS) prospective prostate cancer cohorts (median follow-up, 13.4 years;
= 818). Patients with ICC were more likely to develop lethal cancer [HR, 1.62; 95% confidence interval (CI), 1.05-2.49], independent from Gleason score (GS). IMPLICATIONS: ICC has a distinct molecular phenotype that resembles metastatic prostate cancer and is associated with progression to lethal disease.</abstract><cop>United States</cop><pmid>30333152</pmid><doi>10.1158/1541-7786.mcr-18-0440</doi><tpages>11</tpages><orcidid>https://orcid.org/0000-0002-3119-6507</orcidid><orcidid>https://orcid.org/0000-0002-0722-1311</orcidid><orcidid>https://orcid.org/0000-0003-3873-7465</orcidid><orcidid>https://orcid.org/0000-0002-0381-1947</orcidid><oa>free_for_read</oa></addata></record> |
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| ispartof | Molecular cancer research, 2019-02, Vol.17 (2), p.446-456 |
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| source | MEDLINE; American Association for Cancer Research; EZB-FREE-00999 freely available EZB journals; Free Full-Text Journals in Chemistry |
| subjects | Adenocarcinoma - genetics Adenocarcinoma - pathology Animals Epigenomics - methods Humans Male Mice Prostatic Neoplasms - genetics Prostatic Neoplasms - pathology |
| title | Genetic and Epigenetic Determinants of Aggressiveness in Cribriform Carcinoma of the Prostate |
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