CHD1 loss negatively influences metastasis-free survival in R0-resected prostate cancer patients and promotes spontaneous metastasis in vivo
The outcome of prostate cancer (PCa) patients is highly variable and depends on whether or not distant metastases occur. Multiple chromosomal deletions have been linked to early tumor marker PSA recurrence (biochemical relapse, BCR) after radical prostatectomy (RP), but their potential role for dist...
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| Veröffentlicht in: | Cancer gene therapy 2022-01, Vol.29 (1), p.49-61 |
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| creator | Oh-Hohenhorst, Su Jung Tilki, Derya Ahlers, Ann-Kristin Suling, Anna Hahn, Oliver Tennstedt, Pierre Matuszcak, Christiane Maar, Hanna Labitzky, Vera Hanika, Sandra Starzonek, Sarah Baumgart, Simon Johnsen, Steven A. Kluth, Martina Sirma, Hüseyin Simon, Ronald Sauter, Guido Huland, Hartwig Schumacher, Udo Lange, Tobias |
| description | The outcome of prostate cancer (PCa) patients is highly variable and depends on whether or not distant metastases occur. Multiple chromosomal deletions have been linked to early tumor marker PSA recurrence (biochemical relapse, BCR) after radical prostatectomy (RP), but their potential role for distant metastasis formation is largely unknown. Here, we specifically analyzed whether deletion of the tumor suppressor CHD1 (5q21) influences the post-surgical risk of distant metastasis and whether CHD1 loss directly contributes to metastasis formation in vivo. By considering >6800 patients we found that the CHD1 deletion negatively influences metastasis-free survival in R0 patients (HR: 2.32; 95% CI: 1.61, 3.33;
p
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| doi_str_mv | 10.1038/s41417-020-00288-z |
| format | Article |
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p
< 0.001) independent of preoperative PSA, pT stage, pN status, Gleason Score, and BCR. Moreover, CHD1 deletion predicts shortened BCR-free survival in pT2 patients and cancer-specific survival in all patients. In vivo, CHD1 loss increases spontaneous pulmonary metastasis formation in two distinct PCa models coupled with a higher number of multicellular colonies as compared to single-cell metastases. Transcriptome analyses revealed down-regulation of the PCa-specific metastasis suppressor and TGFβ signaling regulator PMEPA1 after CHD1 depletion in both tested PCa models. CHD1 loss increases the risk of postoperative metastasis in R0-resected PCa patients and promotes spontaneous metastasis formation in vivo.</description><identifier>ISSN: 0929-1903</identifier><identifier>EISSN: 1476-5500</identifier><identifier>DOI: 10.1038/s41417-020-00288-z</identifier><identifier>PMID: 33414516</identifier><language>eng</language><publisher>New York: Nature Publishing Group US</publisher><subject>13 ; 13/51 ; 13/89 ; 14 ; 14/32 ; 45 ; 45/91 ; 631/67/322 ; 631/67/589/466 ; 64 ; 64/60 ; Biomedical and Life Sciences ; Biomedicine ; Disease-Free Survival ; DNA Helicases - genetics ; DNA-Binding Proteins - genetics ; Gene Expression ; Gene Therapy ; Genes, Tumor Suppressor ; Humans ; Male ; Membrane Proteins ; Metastases ; Metastasis ; Neoplasm Grading ; Neoplasm Recurrence, Local ; Prostate cancer ; Prostate-Specific Antigen ; Prostatectomy ; Prostatic Neoplasms - genetics ; Prostatic Neoplasms - pathology ; Prostatic Neoplasms - surgery ; Transcriptomes ; Tumor markers ; Tumor suppressor genes ; Tumors</subject><ispartof>Cancer gene therapy, 2022-01, Vol.29 (1), p.49-61</ispartof><rights>The Author(s) 2021</rights><rights>2021. The Author(s).</rights><rights>The Author(s) 2021. This work is published under http://creativecommons.org/licenses/by/4.0/ (the “License”). Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c474t-7fb50ab255f7ae43b92f144bd9d6cf6dc73c45c96051227a8e254a1f2d8330533</citedby><cites>FETCH-LOGICAL-c474t-7fb50ab255f7ae43b92f144bd9d6cf6dc73c45c96051227a8e254a1f2d8330533</cites><orcidid>0000-0001-6632-337X ; 0000-0003-1198-5805</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://link.springer.com/content/pdf/10.1038/s41417-020-00288-z$$EPDF$$P50$$Gspringer$$Hfree_for_read</linktopdf><linktohtml>$$Uhttps://link.springer.com/10.1038/s41417-020-00288-z$$EHTML$$P50$$Gspringer$$Hfree_for_read</linktohtml><link.rule.ids>230,314,776,780,881,27903,27904,41467,42536,51297</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/33414516$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Oh-Hohenhorst, Su Jung</creatorcontrib><creatorcontrib>Tilki, Derya</creatorcontrib><creatorcontrib>Ahlers, Ann-Kristin</creatorcontrib><creatorcontrib>Suling, Anna</creatorcontrib><creatorcontrib>Hahn, Oliver</creatorcontrib><creatorcontrib>Tennstedt, Pierre</creatorcontrib><creatorcontrib>Matuszcak, Christiane</creatorcontrib><creatorcontrib>Maar, Hanna</creatorcontrib><creatorcontrib>Labitzky, Vera</creatorcontrib><creatorcontrib>Hanika, Sandra</creatorcontrib><creatorcontrib>Starzonek, Sarah</creatorcontrib><creatorcontrib>Baumgart, Simon</creatorcontrib><creatorcontrib>Johnsen, Steven A.</creatorcontrib><creatorcontrib>Kluth, Martina</creatorcontrib><creatorcontrib>Sirma, Hüseyin</creatorcontrib><creatorcontrib>Simon, Ronald</creatorcontrib><creatorcontrib>Sauter, Guido</creatorcontrib><creatorcontrib>Huland, Hartwig</creatorcontrib><creatorcontrib>Schumacher, Udo</creatorcontrib><creatorcontrib>Lange, Tobias</creatorcontrib><title>CHD1 loss negatively influences metastasis-free survival in R0-resected prostate cancer patients and promotes spontaneous metastasis in vivo</title><title>Cancer gene therapy</title><addtitle>Cancer Gene Ther</addtitle><addtitle>Cancer Gene Ther</addtitle><description>The outcome of prostate cancer (PCa) patients is highly variable and depends on whether or not distant metastases occur. Multiple chromosomal deletions have been linked to early tumor marker PSA recurrence (biochemical relapse, BCR) after radical prostatectomy (RP), but their potential role for distant metastasis formation is largely unknown. Here, we specifically analyzed whether deletion of the tumor suppressor CHD1 (5q21) influences the post-surgical risk of distant metastasis and whether CHD1 loss directly contributes to metastasis formation in vivo. By considering >6800 patients we found that the CHD1 deletion negatively influences metastasis-free survival in R0 patients (HR: 2.32; 95% CI: 1.61, 3.33;
p
< 0.001) independent of preoperative PSA, pT stage, pN status, Gleason Score, and BCR. Moreover, CHD1 deletion predicts shortened BCR-free survival in pT2 patients and cancer-specific survival in all patients. In vivo, CHD1 loss increases spontaneous pulmonary metastasis formation in two distinct PCa models coupled with a higher number of multicellular colonies as compared to single-cell metastases. Transcriptome analyses revealed down-regulation of the PCa-specific metastasis suppressor and TGFβ signaling regulator PMEPA1 after CHD1 depletion in both tested PCa models. CHD1 loss increases the risk of postoperative metastasis in R0-resected PCa patients and promotes spontaneous metastasis formation in vivo.</description><subject>13</subject><subject>13/51</subject><subject>13/89</subject><subject>14</subject><subject>14/32</subject><subject>45</subject><subject>45/91</subject><subject>631/67/322</subject><subject>631/67/589/466</subject><subject>64</subject><subject>64/60</subject><subject>Biomedical and Life Sciences</subject><subject>Biomedicine</subject><subject>Disease-Free Survival</subject><subject>DNA Helicases - genetics</subject><subject>DNA-Binding Proteins - genetics</subject><subject>Gene Expression</subject><subject>Gene Therapy</subject><subject>Genes, Tumor Suppressor</subject><subject>Humans</subject><subject>Male</subject><subject>Membrane Proteins</subject><subject>Metastases</subject><subject>Metastasis</subject><subject>Neoplasm Grading</subject><subject>Neoplasm Recurrence, Local</subject><subject>Prostate cancer</subject><subject>Prostate-Specific Antigen</subject><subject>Prostatectomy</subject><subject>Prostatic Neoplasms - 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Academic</collection><collection>PubMed Central (Full Participant titles)</collection><jtitle>Cancer gene therapy</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Oh-Hohenhorst, Su Jung</au><au>Tilki, Derya</au><au>Ahlers, Ann-Kristin</au><au>Suling, Anna</au><au>Hahn, Oliver</au><au>Tennstedt, Pierre</au><au>Matuszcak, Christiane</au><au>Maar, Hanna</au><au>Labitzky, Vera</au><au>Hanika, Sandra</au><au>Starzonek, Sarah</au><au>Baumgart, Simon</au><au>Johnsen, Steven A.</au><au>Kluth, Martina</au><au>Sirma, Hüseyin</au><au>Simon, Ronald</au><au>Sauter, Guido</au><au>Huland, Hartwig</au><au>Schumacher, Udo</au><au>Lange, Tobias</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>CHD1 loss negatively influences metastasis-free survival in R0-resected prostate cancer patients and promotes spontaneous metastasis in vivo</atitle><jtitle>Cancer gene therapy</jtitle><stitle>Cancer Gene Ther</stitle><addtitle>Cancer Gene Ther</addtitle><date>2022-01-01</date><risdate>2022</risdate><volume>29</volume><issue>1</issue><spage>49</spage><epage>61</epage><pages>49-61</pages><issn>0929-1903</issn><eissn>1476-5500</eissn><abstract>The outcome of prostate cancer (PCa) patients is highly variable and depends on whether or not distant metastases occur. Multiple chromosomal deletions have been linked to early tumor marker PSA recurrence (biochemical relapse, BCR) after radical prostatectomy (RP), but their potential role for distant metastasis formation is largely unknown. Here, we specifically analyzed whether deletion of the tumor suppressor CHD1 (5q21) influences the post-surgical risk of distant metastasis and whether CHD1 loss directly contributes to metastasis formation in vivo. By considering >6800 patients we found that the CHD1 deletion negatively influences metastasis-free survival in R0 patients (HR: 2.32; 95% CI: 1.61, 3.33;
p
< 0.001) independent of preoperative PSA, pT stage, pN status, Gleason Score, and BCR. Moreover, CHD1 deletion predicts shortened BCR-free survival in pT2 patients and cancer-specific survival in all patients. In vivo, CHD1 loss increases spontaneous pulmonary metastasis formation in two distinct PCa models coupled with a higher number of multicellular colonies as compared to single-cell metastases. Transcriptome analyses revealed down-regulation of the PCa-specific metastasis suppressor and TGFβ signaling regulator PMEPA1 after CHD1 depletion in both tested PCa models. CHD1 loss increases the risk of postoperative metastasis in R0-resected PCa patients and promotes spontaneous metastasis formation in vivo.</abstract><cop>New York</cop><pub>Nature Publishing Group US</pub><pmid>33414516</pmid><doi>10.1038/s41417-020-00288-z</doi><tpages>13</tpages><orcidid>https://orcid.org/0000-0001-6632-337X</orcidid><orcidid>https://orcid.org/0000-0003-1198-5805</orcidid><oa>free_for_read</oa></addata></record> |
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| ispartof | Cancer gene therapy, 2022-01, Vol.29 (1), p.49-61 |
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| subjects | 13 13/51 13/89 14 14/32 45 45/91 631/67/322 631/67/589/466 64 64/60 Biomedical and Life Sciences Biomedicine Disease-Free Survival DNA Helicases - genetics DNA-Binding Proteins - genetics Gene Expression Gene Therapy Genes, Tumor Suppressor Humans Male Membrane Proteins Metastases Metastasis Neoplasm Grading Neoplasm Recurrence, Local Prostate cancer Prostate-Specific Antigen Prostatectomy Prostatic Neoplasms - genetics Prostatic Neoplasms - pathology Prostatic Neoplasms - surgery Transcriptomes Tumor markers Tumor suppressor genes Tumors |
| title | CHD1 loss negatively influences metastasis-free survival in R0-resected prostate cancer patients and promotes spontaneous metastasis in vivo |
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