Genome-wide plasma DNA methylation features of metastatic prostate cancer
Tumor DNA circulates in the plasma of cancer patients admixed with DNA from noncancerous cells. The genomic landscape of plasma DNA has been characterized in metastatic castration-resistant prostate cancer (mCRPC) but the plasma methylome has not been extensively explored. Here, we performed next-ge...
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| Veröffentlicht in: | The Journal of clinical investigation 2020-04, Vol.130 (4), p.1991-2000 |
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| container_title | The Journal of clinical investigation |
| container_volume | 130 |
| creator | Wu, Anjui Cremaschi, Paolo Wetterskog, Daniel Conteduca, Vincenza Franceschini, Gian Marco Kleftogiannis, Dimitrios Jayaram, Anuradha Sandhu, Shahneen Wong, Stephen Q Benelli, Matteo Salvi, Samanta Gurioli, Giorgia Feber, Andrew Pereira, Mariana Buongermino Wingate, Anna Maria Gonzalez-Billalebeitia, Enrique De Giorgi, Ugo Demichelis, Francesca Lise, Stefano Attard, Gerhardt |
| description | Tumor DNA circulates in the plasma of cancer patients admixed with DNA from noncancerous cells. The genomic landscape of plasma DNA has been characterized in metastatic castration-resistant prostate cancer (mCRPC) but the plasma methylome has not been extensively explored. Here, we performed next-generation sequencing (NGS) on plasma DNA with and without bisulfite treatment from mCRPC patients receiving either abiraterone or enzalutamide in the pre- or post-chemotherapy setting. Principal component analysis on the mCRPC plasma methylome indicated that the main contributor to methylation variance (principal component one, or PC1) was strongly correlated with genomically determined tumor fraction (r = -0.96; P < 10-8) and characterized by hypermethylation of targets of the polycomb repressor complex 2 components. Further deconvolution of the PC1 top-correlated segments revealed that these segments are comprised of methylation patterns specific to either prostate cancer or prostate normal epithelium. To extract information specific to an individual's cancer, we then focused on an orthogonal methylation signature, which revealed enrichment for androgen receptor binding sequences and hypomethylation of these segments associated with AR copy number gain. Individuals harboring this methylation pattern had a more aggressive clinical course. Plasma methylome analysis can accurately quantitate tumor fraction and identify distinct biologically relevant mCRPC phenotypes. |
| doi_str_mv | 10.1172/JCI130887 |
| format | Article |
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The genomic landscape of plasma DNA has been characterized in metastatic castration-resistant prostate cancer (mCRPC) but the plasma methylome has not been extensively explored. Here, we performed next-generation sequencing (NGS) on plasma DNA with and without bisulfite treatment from mCRPC patients receiving either abiraterone or enzalutamide in the pre- or post-chemotherapy setting. Principal component analysis on the mCRPC plasma methylome indicated that the main contributor to methylation variance (principal component one, or PC1) was strongly correlated with genomically determined tumor fraction (r = -0.96; P < 10-8) and characterized by hypermethylation of targets of the polycomb repressor complex 2 components. Further deconvolution of the PC1 top-correlated segments revealed that these segments are comprised of methylation patterns specific to either prostate cancer or prostate normal epithelium. To extract information specific to an individual's cancer, we then focused on an orthogonal methylation signature, which revealed enrichment for androgen receptor binding sequences and hypomethylation of these segments associated with AR copy number gain. Individuals harboring this methylation pattern had a more aggressive clinical course. Plasma methylome analysis can accurately quantitate tumor fraction and identify distinct biologically relevant mCRPC phenotypes.</description><identifier>ISSN: 0021-9738</identifier><identifier>EISSN: 1558-8238</identifier><identifier>DOI: 10.1172/JCI130887</identifier><identifier>PMID: 32149736</identifier><language>eng</language><publisher>United States: American Society for Clinical Investigation</publisher><subject>Abiraterone ; Adult ; Aged ; Aged, 80 and over ; Analysis ; Androgen receptors ; Androgens ; Biomarkers ; Biomedical research ; Bisulfite ; Blood ; Cancer genetics ; Cancer metastasis ; Cancer patients ; Cancer treatment ; Care and treatment ; Castration ; Chemotherapy ; Circulating Tumor DNA - blood ; Circulating Tumor DNA - genetics ; Copy number ; Deoxyribonucleic acid ; DNA ; DNA Methylation ; DNA sequencing ; Enzalutamide ; Epigenesis, Genetic ; Epithelium ; Gene Expression Regulation, Neoplastic ; Genome-Wide Association Study ; Genomes ; Genomics ; Humans ; Information processing ; Male ; Metastases ; Metastasis ; Methylation ; Middle Aged ; Mutation ; Neoplasm Metastasis ; Next-generation sequencing ; Patients ; Phenotypes ; Polycomb group proteins ; Prostate cancer ; Prostatic Neoplasms - blood ; Prostatic Neoplasms - genetics ; Prostatic Neoplasms - pathology ; Ratios ; Setting (Literature) ; Sulfites ; Tumors</subject><ispartof>The Journal of clinical investigation, 2020-04, Vol.130 (4), p.1991-2000</ispartof><rights>COPYRIGHT 2020 American Society for Clinical Investigation</rights><rights>Copyright American Society for Clinical Investigation Apr 2020</rights><rights>2020 Wu et al. 2020 Wu et al.</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c647t-2c776b96a2bb881dde894ae03dbfbdf2c3df9365bda463a07806bfaa0119ce333</citedby><cites>FETCH-LOGICAL-c647t-2c776b96a2bb881dde894ae03dbfbdf2c3df9365bda463a07806bfaa0119ce333</cites><orcidid>0000-0002-9584-3021 ; 0000-0002-8266-8631 ; 0000-0001-5349-4188 ; 0000-0002-6921-714X ; 0000-0002-7391-3535 ; 0000-0003-1227-356X ; 0000-0003-1086-821X ; 0000-0003-4472-6893 ; 0000-0003-3450-949X</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC7108919/pdf/$$EPDF$$P50$$Gpubmedcentral$$Hfree_for_read</linktopdf><linktohtml>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC7108919/$$EHTML$$P50$$Gpubmedcentral$$Hfree_for_read</linktohtml><link.rule.ids>230,314,727,780,784,885,27922,27923,53789,53791</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/32149736$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Wu, Anjui</creatorcontrib><creatorcontrib>Cremaschi, Paolo</creatorcontrib><creatorcontrib>Wetterskog, Daniel</creatorcontrib><creatorcontrib>Conteduca, Vincenza</creatorcontrib><creatorcontrib>Franceschini, Gian Marco</creatorcontrib><creatorcontrib>Kleftogiannis, Dimitrios</creatorcontrib><creatorcontrib>Jayaram, Anuradha</creatorcontrib><creatorcontrib>Sandhu, Shahneen</creatorcontrib><creatorcontrib>Wong, Stephen Q</creatorcontrib><creatorcontrib>Benelli, Matteo</creatorcontrib><creatorcontrib>Salvi, Samanta</creatorcontrib><creatorcontrib>Gurioli, Giorgia</creatorcontrib><creatorcontrib>Feber, Andrew</creatorcontrib><creatorcontrib>Pereira, Mariana Buongermino</creatorcontrib><creatorcontrib>Wingate, Anna Maria</creatorcontrib><creatorcontrib>Gonzalez-Billalebeitia, Enrique</creatorcontrib><creatorcontrib>De Giorgi, Ugo</creatorcontrib><creatorcontrib>Demichelis, Francesca</creatorcontrib><creatorcontrib>Lise, Stefano</creatorcontrib><creatorcontrib>Attard, Gerhardt</creatorcontrib><title>Genome-wide plasma DNA methylation features of metastatic prostate cancer</title><title>The Journal of clinical investigation</title><addtitle>J Clin Invest</addtitle><description>Tumor DNA circulates in the plasma of cancer patients admixed with DNA from noncancerous cells. The genomic landscape of plasma DNA has been characterized in metastatic castration-resistant prostate cancer (mCRPC) but the plasma methylome has not been extensively explored. Here, we performed next-generation sequencing (NGS) on plasma DNA with and without bisulfite treatment from mCRPC patients receiving either abiraterone or enzalutamide in the pre- or post-chemotherapy setting. Principal component analysis on the mCRPC plasma methylome indicated that the main contributor to methylation variance (principal component one, or PC1) was strongly correlated with genomically determined tumor fraction (r = -0.96; P < 10-8) and characterized by hypermethylation of targets of the polycomb repressor complex 2 components. Further deconvolution of the PC1 top-correlated segments revealed that these segments are comprised of methylation patterns specific to either prostate cancer or prostate normal epithelium. To extract information specific to an individual's cancer, we then focused on an orthogonal methylation signature, which revealed enrichment for androgen receptor binding sequences and hypomethylation of these segments associated with AR copy number gain. Individuals harboring this methylation pattern had a more aggressive clinical course. Plasma methylome analysis can accurately quantitate tumor fraction and identify distinct biologically relevant mCRPC phenotypes.</description><subject>Abiraterone</subject><subject>Adult</subject><subject>Aged</subject><subject>Aged, 80 and over</subject><subject>Analysis</subject><subject>Androgen receptors</subject><subject>Androgens</subject><subject>Biomarkers</subject><subject>Biomedical research</subject><subject>Bisulfite</subject><subject>Blood</subject><subject>Cancer genetics</subject><subject>Cancer metastasis</subject><subject>Cancer patients</subject><subject>Cancer treatment</subject><subject>Care and treatment</subject><subject>Castration</subject><subject>Chemotherapy</subject><subject>Circulating Tumor DNA - blood</subject><subject>Circulating Tumor DNA - genetics</subject><subject>Copy number</subject><subject>Deoxyribonucleic acid</subject><subject>DNA</subject><subject>DNA Methylation</subject><subject>DNA sequencing</subject><subject>Enzalutamide</subject><subject>Epigenesis, Genetic</subject><subject>Epithelium</subject><subject>Gene Expression Regulation, Neoplastic</subject><subject>Genome-Wide Association Study</subject><subject>Genomes</subject><subject>Genomics</subject><subject>Humans</subject><subject>Information processing</subject><subject>Male</subject><subject>Metastases</subject><subject>Metastasis</subject><subject>Methylation</subject><subject>Middle Aged</subject><subject>Mutation</subject><subject>Neoplasm Metastasis</subject><subject>Next-generation sequencing</subject><subject>Patients</subject><subject>Phenotypes</subject><subject>Polycomb group proteins</subject><subject>Prostate cancer</subject><subject>Prostatic Neoplasms - blood</subject><subject>Prostatic Neoplasms - genetics</subject><subject>Prostatic Neoplasms - pathology</subject><subject>Ratios</subject><subject>Setting (Literature)</subject><subject>Sulfites</subject><subject>Tumors</subject><issn>0021-9738</issn><issn>1558-8238</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2020</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><sourceid>ABUWG</sourceid><sourceid>AFKRA</sourceid><sourceid>AZQEC</sourceid><sourceid>BEC</sourceid><sourceid>BENPR</sourceid><sourceid>CCPQU</sourceid><sourceid>DWQXO</sourceid><sourceid>GNUQQ</sourceid><recordid>eNqNkl2L1DAUhoMo7rh64R-QgiB60TUfbZPeCMOo68jigl-34TQ9menSJmOTqvvvTXEdd2QuJBcJb57zJofzEvKY0TPGJH_5frVmgiol75AFK0uVKy7UXbKglLO8lkKdkAchXFHKiqIs7pMTwVmR9GpB1ufo_ID5j67FbNdDGCB7_WGZDRi31z3EzrvMIsRpxJB5O-sQYtJNthv9fMLMgDM4PiT3LPQBH93sp-TL2zefV-_yi8vz9Wp5kZuqkDHnRsqqqSvgTaMUa1tUdQFIRdvYprXciNbWoiqbFopKAJWKVo0FoIzVBoUQp-TVb9_d1AzYGnRxhF7vxm6A8Vp76PThjeu2euO_a8moqlmdDJ7fGIz-24Qh6qELBvseHPopaC5kWdKSlyqhT_9Br_w0utReopQUohKK_qU20KPunPXpXTOb6mXFWeqPMZao_Ai1QYfpk96h7ZJ8wJ8d4dNqcejM0YIXBwWJifgzbmAKQa8_ffx_9vLrIfvsFrtF6OM2-H6asxGOmpqUjDCi3Q-FUT0HVe-Dmtgnt6e4J_8kU_wCkv7e0A</recordid><startdate>20200401</startdate><enddate>20200401</enddate><creator>Wu, Anjui</creator><creator>Cremaschi, Paolo</creator><creator>Wetterskog, Daniel</creator><creator>Conteduca, Vincenza</creator><creator>Franceschini, Gian Marco</creator><creator>Kleftogiannis, Dimitrios</creator><creator>Jayaram, Anuradha</creator><creator>Sandhu, Shahneen</creator><creator>Wong, Stephen Q</creator><creator>Benelli, Matteo</creator><creator>Salvi, Samanta</creator><creator>Gurioli, Giorgia</creator><creator>Feber, Andrew</creator><creator>Pereira, Mariana Buongermino</creator><creator>Wingate, Anna Maria</creator><creator>Gonzalez-Billalebeitia, Enrique</creator><creator>De Giorgi, Ugo</creator><creator>Demichelis, Francesca</creator><creator>Lise, Stefano</creator><creator>Attard, Gerhardt</creator><general>American Society for Clinical Investigation</general><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>IOV</scope><scope>ISR</scope><scope>3V.</scope><scope>7RV</scope><scope>7X7</scope><scope>7XB</scope><scope>88A</scope><scope>88E</scope><scope>8AO</scope><scope>8FE</scope><scope>8FH</scope><scope>8FI</scope><scope>8FJ</scope><scope>8FK</scope><scope>ABUWG</scope><scope>AFKRA</scope><scope>AZQEC</scope><scope>BBNVY</scope><scope>BEC</scope><scope>BENPR</scope><scope>BHPHI</scope><scope>CCPQU</scope><scope>DWQXO</scope><scope>FYUFA</scope><scope>GHDGH</scope><scope>GNUQQ</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>S0X</scope><scope>7X8</scope><scope>5PM</scope><orcidid>https://orcid.org/0000-0002-9584-3021</orcidid><orcidid>https://orcid.org/0000-0002-8266-8631</orcidid><orcidid>https://orcid.org/0000-0001-5349-4188</orcidid><orcidid>https://orcid.org/0000-0002-6921-714X</orcidid><orcidid>https://orcid.org/0000-0002-7391-3535</orcidid><orcidid>https://orcid.org/0000-0003-1227-356X</orcidid><orcidid>https://orcid.org/0000-0003-1086-821X</orcidid><orcidid>https://orcid.org/0000-0003-4472-6893</orcidid><orcidid>https://orcid.org/0000-0003-3450-949X</orcidid></search><sort><creationdate>20200401</creationdate><title>Genome-wide plasma DNA methylation features of metastatic prostate cancer</title><author>Wu, Anjui ; Cremaschi, Paolo ; Wetterskog, Daniel ; Conteduca, Vincenza ; Franceschini, Gian Marco ; Kleftogiannis, Dimitrios ; Jayaram, Anuradha ; Sandhu, Shahneen ; Wong, Stephen Q ; Benelli, Matteo ; Salvi, Samanta ; Gurioli, Giorgia ; Feber, Andrew ; Pereira, Mariana Buongermino ; Wingate, Anna Maria ; Gonzalez-Billalebeitia, Enrique ; De Giorgi, Ugo ; Demichelis, Francesca ; Lise, Stefano ; Attard, Gerhardt</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c647t-2c776b96a2bb881dde894ae03dbfbdf2c3df9365bda463a07806bfaa0119ce333</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2020</creationdate><topic>Abiraterone</topic><topic>Adult</topic><topic>Aged</topic><topic>Aged, 80 and over</topic><topic>Analysis</topic><topic>Androgen receptors</topic><topic>Androgens</topic><topic>Biomarkers</topic><topic>Biomedical research</topic><topic>Bisulfite</topic><topic>Blood</topic><topic>Cancer genetics</topic><topic>Cancer metastasis</topic><topic>Cancer patients</topic><topic>Cancer treatment</topic><topic>Care and treatment</topic><topic>Castration</topic><topic>Chemotherapy</topic><topic>Circulating Tumor DNA - 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Academic</collection><collection>PubMed Central (Full Participant titles)</collection><jtitle>The Journal of clinical investigation</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Wu, Anjui</au><au>Cremaschi, Paolo</au><au>Wetterskog, Daniel</au><au>Conteduca, Vincenza</au><au>Franceschini, Gian Marco</au><au>Kleftogiannis, Dimitrios</au><au>Jayaram, Anuradha</au><au>Sandhu, Shahneen</au><au>Wong, Stephen Q</au><au>Benelli, Matteo</au><au>Salvi, Samanta</au><au>Gurioli, Giorgia</au><au>Feber, Andrew</au><au>Pereira, Mariana Buongermino</au><au>Wingate, Anna Maria</au><au>Gonzalez-Billalebeitia, Enrique</au><au>De Giorgi, Ugo</au><au>Demichelis, Francesca</au><au>Lise, Stefano</au><au>Attard, Gerhardt</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Genome-wide plasma DNA methylation features of metastatic prostate cancer</atitle><jtitle>The Journal of clinical investigation</jtitle><addtitle>J Clin Invest</addtitle><date>2020-04-01</date><risdate>2020</risdate><volume>130</volume><issue>4</issue><spage>1991</spage><epage>2000</epage><pages>1991-2000</pages><issn>0021-9738</issn><eissn>1558-8238</eissn><abstract>Tumor DNA circulates in the plasma of cancer patients admixed with DNA from noncancerous cells. The genomic landscape of plasma DNA has been characterized in metastatic castration-resistant prostate cancer (mCRPC) but the plasma methylome has not been extensively explored. Here, we performed next-generation sequencing (NGS) on plasma DNA with and without bisulfite treatment from mCRPC patients receiving either abiraterone or enzalutamide in the pre- or post-chemotherapy setting. Principal component analysis on the mCRPC plasma methylome indicated that the main contributor to methylation variance (principal component one, or PC1) was strongly correlated with genomically determined tumor fraction (r = -0.96; P < 10-8) and characterized by hypermethylation of targets of the polycomb repressor complex 2 components. Further deconvolution of the PC1 top-correlated segments revealed that these segments are comprised of methylation patterns specific to either prostate cancer or prostate normal epithelium. To extract information specific to an individual's cancer, we then focused on an orthogonal methylation signature, which revealed enrichment for androgen receptor binding sequences and hypomethylation of these segments associated with AR copy number gain. Individuals harboring this methylation pattern had a more aggressive clinical course. Plasma methylome analysis can accurately quantitate tumor fraction and identify distinct biologically relevant mCRPC phenotypes.</abstract><cop>United States</cop><pub>American Society for Clinical Investigation</pub><pmid>32149736</pmid><doi>10.1172/JCI130887</doi><tpages>10</tpages><orcidid>https://orcid.org/0000-0002-9584-3021</orcidid><orcidid>https://orcid.org/0000-0002-8266-8631</orcidid><orcidid>https://orcid.org/0000-0001-5349-4188</orcidid><orcidid>https://orcid.org/0000-0002-6921-714X</orcidid><orcidid>https://orcid.org/0000-0002-7391-3535</orcidid><orcidid>https://orcid.org/0000-0003-1227-356X</orcidid><orcidid>https://orcid.org/0000-0003-1086-821X</orcidid><orcidid>https://orcid.org/0000-0003-4472-6893</orcidid><orcidid>https://orcid.org/0000-0003-3450-949X</orcidid><oa>free_for_read</oa></addata></record> |
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| ispartof | The Journal of clinical investigation, 2020-04, Vol.130 (4), p.1991-2000 |
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| language | eng |
| recordid | cdi_pubmedcentral_primary_oai_pubmedcentral_nih_gov_7108919 |
| source | MEDLINE; EZB-FREE-00999 freely available EZB journals; PubMed Central; Alma/SFX Local Collection |
| subjects | Abiraterone Adult Aged Aged, 80 and over Analysis Androgen receptors Androgens Biomarkers Biomedical research Bisulfite Blood Cancer genetics Cancer metastasis Cancer patients Cancer treatment Care and treatment Castration Chemotherapy Circulating Tumor DNA - blood Circulating Tumor DNA - genetics Copy number Deoxyribonucleic acid DNA DNA Methylation DNA sequencing Enzalutamide Epigenesis, Genetic Epithelium Gene Expression Regulation, Neoplastic Genome-Wide Association Study Genomes Genomics Humans Information processing Male Metastases Metastasis Methylation Middle Aged Mutation Neoplasm Metastasis Next-generation sequencing Patients Phenotypes Polycomb group proteins Prostate cancer Prostatic Neoplasms - blood Prostatic Neoplasms - genetics Prostatic Neoplasms - pathology Ratios Setting (Literature) Sulfites Tumors |
| title | Genome-wide plasma DNA methylation features of metastatic prostate cancer |
| url | https://sfx.bib-bvb.de/sfx_tum?ctx_ver=Z39.88-2004&ctx_enc=info:ofi/enc:UTF-8&ctx_tim=2025-01-09T23%3A46%3A09IST&url_ver=Z39.88-2004&url_ctx_fmt=infofi/fmt:kev:mtx:ctx&rfr_id=info:sid/primo.exlibrisgroup.com:primo3-Article-gale_pubme&rft_val_fmt=info:ofi/fmt:kev:mtx:journal&rft.genre=article&rft.atitle=Genome-wide%20plasma%20DNA%20methylation%20features%20of%20metastatic%20prostate%20cancer&rft.jtitle=The%20Journal%20of%20clinical%20investigation&rft.au=Wu,%20Anjui&rft.date=2020-04-01&rft.volume=130&rft.issue=4&rft.spage=1991&rft.epage=2000&rft.pages=1991-2000&rft.issn=0021-9738&rft.eissn=1558-8238&rft_id=info:doi/10.1172/JCI130887&rft_dat=%3Cgale_pubme%3EA621894111%3C/gale_pubme%3E%3Curl%3E%3C/url%3E&disable_directlink=true&sfx.directlink=off&sfx.report_link=0&rft_id=info:oai/&rft_pqid=2387336380&rft_id=info:pmid/32149736&rft_galeid=A621894111&rfr_iscdi=true |