Genetic and epigenetic profiling indicates the proximal tubule origin of renal cancers in end‐stage renal disease
End‐stage renal disease (ESRD) patients on dialysis therapy have a higher incidence of renal cell carcinomas (RCCs), which consist of 2 major histopathological types: clear‐cell RCCs (ESRD‐ccRCCs) and acquired cystic disease (ACD)‐associated RCCs. However, their genetic and epigenetic alterations ar...
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| Veröffentlicht in: | Cancer science 2020-11, Vol.111 (11), p.4276-4287 |
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| creator | Ishihara, Hiroki Yamashita, Satoshi Liu, Yu‐Yu Hattori, Naoko El‐Omar, Omar Ikeda, Takashi Fukuda, Hironori Yoshida, Kazuhiko Takagi, Toshio Taneda, Sekiko Kondo, Tsunenori Nagashima, Yoji Tanabe, Kazunari Ushijima, Toshikazu |
| description | End‐stage renal disease (ESRD) patients on dialysis therapy have a higher incidence of renal cell carcinomas (RCCs), which consist of 2 major histopathological types: clear‐cell RCCs (ESRD‐ccRCCs) and acquired cystic disease (ACD)‐associated RCCs. However, their genetic and epigenetic alterations are still poorly understood. Here, we investigated somatic mutations, copy number alterations (CNAs), and DNA methylation profiles in 9 ESRD‐ccRCCs and 7 ACD‐associated RCCs to identify their molecular alterations and cellular origins. Targeted sequencing of 409 cancer‐related genes, including VHL, PBRM1, SETD2, BAP1, KDM5C, MET, KMT2C (MLL3), and TP53, showed ESRD‐ccRCCs harbored frequent VHL mutations, while ACD‐associated RCCs did not. CNA analysis showed that ESRD‐ccRCCs had a frequent loss of chromosome 3p while ACD‐associated RCCs had a gain of chromosome 16. Beadarray methylation analysis showed that ESRD‐ccRCCs had methylation profiles similar to those of sporadic ccRCCs, while ACD‐associated RCCs had profiles similar to those of papillary RCCs. Expression analysis of genes whose expression levels are characteristic to individual segments of a nephron showed that ESRD‐ccRCCs and ACD‐associated RCCs had high expression of proximal tubule cell marker genes, while chromophobe RCCs had high expression of distal tubule cell/collecting duct cell marker genes. In conclusion, ESRD‐ccRCCs and ACD‐associated RCCs had mutation and methylation profiles similar to those of sporadic ccRCCs and papillary RCCs, respectively, and these 2 histopathological types of RCCs were indicated to have originated from proximal tubule cells of the nephron.
We revealed that 2 major histopathological types of renal cell carcinomas (RCCs) that arise in end‐stage renal disease (ESRD), namely clear‐cell RCCs (ESRD‐ccRCCs) and acquired cystic disease (ACD)‐associated RCCs, had mutation and methylation profiles similar to those of sporadic ccRCCs and papillary RCCs, respectively. This finding indicates that these 2 histopathological types of RCCs arising in ESRD originated from proximal tubule cells of a nephron. |
| doi_str_mv | 10.1111/cas.14633 |
| format | Article |
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We revealed that 2 major histopathological types of renal cell carcinomas (RCCs) that arise in end‐stage renal disease (ESRD), namely clear‐cell RCCs (ESRD‐ccRCCs) and acquired cystic disease (ACD)‐associated RCCs, had mutation and methylation profiles similar to those of sporadic ccRCCs and papillary RCCs, respectively. This finding indicates that these 2 histopathological types of RCCs arising in ESRD originated from proximal tubule cells of a nephron.</description><identifier>ISSN: 1347-9032</identifier><identifier>EISSN: 1349-7006</identifier><identifier>DOI: 10.1111/cas.14633</identifier><identifier>PMID: 32860304</identifier><language>eng</language><publisher>HOBOKEN: Wiley</publisher><subject>ACD‐RCC ; Adult ; Aged ; Cancer ; Carcinoma, Renal Cell - etiology ; Carcinoma, Renal Cell - pathology ; Chromosome 16 ; Chromosome 3 ; Chromosomes ; Clear cell-type renal cell carcinoma ; Collecting duct ; Copy number ; Deoxyribonucleic acid ; Diabetes ; Dialysis ; DNA ; DNA Copy Number Variations ; DNA methylation ; Epigenesis, Genetic ; Epigenetics ; Epigenome ; Female ; Gene expression ; Gene Expression Profiling ; Genetic Predisposition to Disease ; Genomes ; Genomics ; Genotype ; Hemodialysis ; Humans ; Immunohistochemistry ; kidney cancer ; Kidney diseases ; Kidney Failure, Chronic - complications ; Kidney Failure, Chronic - genetics ; Kidney Neoplasms - etiology ; Kidney Neoplasms - pathology ; Kidney Tubules, Proximal - metabolism ; Kidney Tubules, Proximal - pathology ; Life Sciences & Biomedicine ; Male ; Middle Aged ; Mutation ; Oncology ; Original ; p53 Protein ; Peritoneal dialysis ; renal cell carcinoma ; Science & Technology ; Transcriptome ; VHL protein ; Women</subject><ispartof>Cancer science, 2020-11, Vol.111 (11), p.4276-4287</ispartof><rights>2020 The Authors. published by John Wiley & Sons Australia, Ltd on behalf of Japanese Cancer Association</rights><rights>2020 The Authors. Cancer Science published by John Wiley & Sons Australia, Ltd on behalf of Japanese Cancer Association.</rights><rights>2020. This work is published under http://creativecommons.org/licenses/by-nc/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>true</woscitedreferencessubscribed><woscitedreferencescount>11</woscitedreferencescount><woscitedreferencesoriginalsourcerecordid>wos000570294800001</woscitedreferencesoriginalsourcerecordid><citedby>FETCH-LOGICAL-c5333-f87ea7c0eb5e344745b5765adb5c80dbb069fd27b8e81b147ce3f3b4d66f34513</citedby><cites>FETCH-LOGICAL-c5333-f87ea7c0eb5e344745b5765adb5c80dbb069fd27b8e81b147ce3f3b4d66f34513</cites><orcidid>0000-0003-3405-7817 ; 0000-0002-5146-656X ; 0000-0002-4814-8616 ; 0000-0002-8609-5797 ; 0000-0002-0901-4869</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/PMC7648048/pdf/$$EPDF$$P50$$Gpubmedcentral$$Hfree_for_read</linktopdf><linktohtml>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC7648048/$$EHTML$$P50$$Gpubmedcentral$$Hfree_for_read</linktohtml><link.rule.ids>230,315,728,781,785,865,886,1418,2115,11566,27928,27929,45578,45579,46056,46480,53795,53797</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/32860304$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Ishihara, Hiroki</creatorcontrib><creatorcontrib>Yamashita, Satoshi</creatorcontrib><creatorcontrib>Liu, Yu‐Yu</creatorcontrib><creatorcontrib>Hattori, Naoko</creatorcontrib><creatorcontrib>El‐Omar, Omar</creatorcontrib><creatorcontrib>Ikeda, Takashi</creatorcontrib><creatorcontrib>Fukuda, Hironori</creatorcontrib><creatorcontrib>Yoshida, Kazuhiko</creatorcontrib><creatorcontrib>Takagi, Toshio</creatorcontrib><creatorcontrib>Taneda, Sekiko</creatorcontrib><creatorcontrib>Kondo, Tsunenori</creatorcontrib><creatorcontrib>Nagashima, Yoji</creatorcontrib><creatorcontrib>Tanabe, Kazunari</creatorcontrib><creatorcontrib>Ushijima, Toshikazu</creatorcontrib><title>Genetic and epigenetic profiling indicates the proximal tubule origin of renal cancers in end‐stage renal disease</title><title>Cancer science</title><addtitle>CANCER SCI</addtitle><addtitle>Cancer Sci</addtitle><description>End‐stage renal disease (ESRD) patients on dialysis therapy have a higher incidence of renal cell carcinomas (RCCs), which consist of 2 major histopathological types: clear‐cell RCCs (ESRD‐ccRCCs) and acquired cystic disease (ACD)‐associated RCCs. However, their genetic and epigenetic alterations are still poorly understood. Here, we investigated somatic mutations, copy number alterations (CNAs), and DNA methylation profiles in 9 ESRD‐ccRCCs and 7 ACD‐associated RCCs to identify their molecular alterations and cellular origins. Targeted sequencing of 409 cancer‐related genes, including VHL, PBRM1, SETD2, BAP1, KDM5C, MET, KMT2C (MLL3), and TP53, showed ESRD‐ccRCCs harbored frequent VHL mutations, while ACD‐associated RCCs did not. CNA analysis showed that ESRD‐ccRCCs had a frequent loss of chromosome 3p while ACD‐associated RCCs had a gain of chromosome 16. Beadarray methylation analysis showed that ESRD‐ccRCCs had methylation profiles similar to those of sporadic ccRCCs, while ACD‐associated RCCs had profiles similar to those of papillary RCCs. Expression analysis of genes whose expression levels are characteristic to individual segments of a nephron showed that ESRD‐ccRCCs and ACD‐associated RCCs had high expression of proximal tubule cell marker genes, while chromophobe RCCs had high expression of distal tubule cell/collecting duct cell marker genes. In conclusion, ESRD‐ccRCCs and ACD‐associated RCCs had mutation and methylation profiles similar to those of sporadic ccRCCs and papillary RCCs, respectively, and these 2 histopathological types of RCCs were indicated to have originated from proximal tubule cells of the nephron.
We revealed that 2 major histopathological types of renal cell carcinomas (RCCs) that arise in end‐stage renal disease (ESRD), namely clear‐cell RCCs (ESRD‐ccRCCs) and acquired cystic disease (ACD)‐associated RCCs, had mutation and methylation profiles similar to those of sporadic ccRCCs and papillary RCCs, respectively. This finding indicates that these 2 histopathological types of RCCs arising in ESRD originated from proximal tubule cells of a nephron.</description><subject>ACD‐RCC</subject><subject>Adult</subject><subject>Aged</subject><subject>Cancer</subject><subject>Carcinoma, Renal Cell - etiology</subject><subject>Carcinoma, Renal Cell - pathology</subject><subject>Chromosome 16</subject><subject>Chromosome 3</subject><subject>Chromosomes</subject><subject>Clear cell-type renal cell carcinoma</subject><subject>Collecting duct</subject><subject>Copy number</subject><subject>Deoxyribonucleic acid</subject><subject>Diabetes</subject><subject>Dialysis</subject><subject>DNA</subject><subject>DNA Copy Number Variations</subject><subject>DNA methylation</subject><subject>Epigenesis, Genetic</subject><subject>Epigenetics</subject><subject>Epigenome</subject><subject>Female</subject><subject>Gene expression</subject><subject>Gene Expression Profiling</subject><subject>Genetic Predisposition to Disease</subject><subject>Genomes</subject><subject>Genomics</subject><subject>Genotype</subject><subject>Hemodialysis</subject><subject>Humans</subject><subject>Immunohistochemistry</subject><subject>kidney cancer</subject><subject>Kidney diseases</subject><subject>Kidney Failure, Chronic - complications</subject><subject>Kidney Failure, Chronic - genetics</subject><subject>Kidney Neoplasms - etiology</subject><subject>Kidney Neoplasms - pathology</subject><subject>Kidney Tubules, Proximal - metabolism</subject><subject>Kidney Tubules, Proximal - pathology</subject><subject>Life Sciences & Biomedicine</subject><subject>Male</subject><subject>Middle Aged</subject><subject>Mutation</subject><subject>Oncology</subject><subject>Original</subject><subject>p53 Protein</subject><subject>Peritoneal dialysis</subject><subject>renal cell carcinoma</subject><subject>Science & Technology</subject><subject>Transcriptome</subject><subject>VHL protein</subject><subject>Women</subject><issn>1347-9032</issn><issn>1349-7006</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2020</creationdate><recordtype>article</recordtype><sourceid>24P</sourceid><sourceid>WIN</sourceid><sourceid>AOWDO</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>eNqNkc9u1DAQxiMEoqVw4AVQJC4glNaO_-aCVEVQkCpxAM6W7UxSV1l7sR2gNx6BZ-RJ8HbDCpCQ8MX2zG9G38xXVY8xOsXlnFmdTjHlhNypjjGhXSMQ4ndv36LpEGmPqgcpXSNEOO3o_eqItJIjguhxlS7AQ3a21n6oYeum9buNYXSz81Pt_OCszpDqfAW7-Fe30XOdF7PMUIfoJufrMNYRfAlb7S3EVKpq8MOPb99T1hOsycEl0AkeVvdGPSd4tN4n1cfXrz70b5rLdxdv-_PLxjJCSDNKAVpYBIYBoVRQZpjgTA-GWYkGYxDvxqEVRoLEBlNhgYzE0IHzkVCGyUn1ct93u5gNDBZ8jnpW21gGiDcqaKf-zHh3pabwWQlOJaKyNHi2Nojh0wIpq41LFuZZewhLUi0lkktUll3Qp3-h12GJZegdxWSLJUasUM_3lI0hpQjjQQxGamelKlaqWysL--R39Qfyl3cFkHvgC5gwJuugrP6AFVVMoLajO30I9y7r7ILvw-JzKX3x_6WFPltpN8PNvyWr_vz9XvtPxZvLyQ</recordid><startdate>202011</startdate><enddate>202011</enddate><creator>Ishihara, Hiroki</creator><creator>Yamashita, Satoshi</creator><creator>Liu, Yu‐Yu</creator><creator>Hattori, Naoko</creator><creator>El‐Omar, Omar</creator><creator>Ikeda, Takashi</creator><creator>Fukuda, Hironori</creator><creator>Yoshida, Kazuhiko</creator><creator>Takagi, Toshio</creator><creator>Taneda, Sekiko</creator><creator>Kondo, Tsunenori</creator><creator>Nagashima, Yoji</creator><creator>Tanabe, Kazunari</creator><creator>Ushijima, Toshikazu</creator><general>Wiley</general><general>John Wiley & Sons, Inc</general><general>John Wiley and Sons Inc</general><scope>24P</scope><scope>WIN</scope><scope>AOWDO</scope><scope>BLEPL</scope><scope>DTL</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>8FE</scope><scope>8FH</scope><scope>ABUWG</scope><scope>AFKRA</scope><scope>AZQEC</scope><scope>BBNVY</scope><scope>BENPR</scope><scope>BHPHI</scope><scope>CCPQU</scope><scope>DWQXO</scope><scope>GNUQQ</scope><scope>HCIFZ</scope><scope>LK8</scope><scope>M7P</scope><scope>PIMPY</scope><scope>PQEST</scope><scope>PQQKQ</scope><scope>PQUKI</scope><scope>PRINS</scope><scope>7X8</scope><scope>5PM</scope><orcidid>https://orcid.org/0000-0003-3405-7817</orcidid><orcidid>https://orcid.org/0000-0002-5146-656X</orcidid><orcidid>https://orcid.org/0000-0002-4814-8616</orcidid><orcidid>https://orcid.org/0000-0002-8609-5797</orcidid><orcidid>https://orcid.org/0000-0002-0901-4869</orcidid></search><sort><creationdate>202011</creationdate><title>Genetic and epigenetic profiling indicates the proximal tubule origin of renal cancers in end‐stage renal disease</title><author>Ishihara, Hiroki ; Yamashita, Satoshi ; Liu, Yu‐Yu ; Hattori, Naoko ; El‐Omar, Omar ; Ikeda, Takashi ; Fukuda, Hironori ; Yoshida, Kazuhiko ; Takagi, Toshio ; Taneda, Sekiko ; Kondo, Tsunenori ; Nagashima, Yoji ; Tanabe, Kazunari ; Ushijima, Toshikazu</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c5333-f87ea7c0eb5e344745b5765adb5c80dbb069fd27b8e81b147ce3f3b4d66f34513</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2020</creationdate><topic>ACD‐RCC</topic><topic>Adult</topic><topic>Aged</topic><topic>Cancer</topic><topic>Carcinoma, Renal Cell - etiology</topic><topic>Carcinoma, Renal Cell - pathology</topic><topic>Chromosome 16</topic><topic>Chromosome 3</topic><topic>Chromosomes</topic><topic>Clear cell-type renal cell carcinoma</topic><topic>Collecting duct</topic><topic>Copy number</topic><topic>Deoxyribonucleic acid</topic><topic>Diabetes</topic><topic>Dialysis</topic><topic>DNA</topic><topic>DNA Copy Number Variations</topic><topic>DNA methylation</topic><topic>Epigenesis, Genetic</topic><topic>Epigenetics</topic><topic>Epigenome</topic><topic>Female</topic><topic>Gene expression</topic><topic>Gene Expression Profiling</topic><topic>Genetic Predisposition to Disease</topic><topic>Genomes</topic><topic>Genomics</topic><topic>Genotype</topic><topic>Hemodialysis</topic><topic>Humans</topic><topic>Immunohistochemistry</topic><topic>kidney cancer</topic><topic>Kidney diseases</topic><topic>Kidney Failure, Chronic - complications</topic><topic>Kidney Failure, Chronic - genetics</topic><topic>Kidney Neoplasms - etiology</topic><topic>Kidney Neoplasms - 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Academic</collection><collection>PubMed Central (Full Participant titles)</collection><jtitle>Cancer science</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Ishihara, Hiroki</au><au>Yamashita, Satoshi</au><au>Liu, Yu‐Yu</au><au>Hattori, Naoko</au><au>El‐Omar, Omar</au><au>Ikeda, Takashi</au><au>Fukuda, Hironori</au><au>Yoshida, Kazuhiko</au><au>Takagi, Toshio</au><au>Taneda, Sekiko</au><au>Kondo, Tsunenori</au><au>Nagashima, Yoji</au><au>Tanabe, Kazunari</au><au>Ushijima, Toshikazu</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Genetic and epigenetic profiling indicates the proximal tubule origin of renal cancers in end‐stage renal disease</atitle><jtitle>Cancer science</jtitle><stitle>CANCER SCI</stitle><addtitle>Cancer Sci</addtitle><date>2020-11</date><risdate>2020</risdate><volume>111</volume><issue>11</issue><spage>4276</spage><epage>4287</epage><pages>4276-4287</pages><issn>1347-9032</issn><eissn>1349-7006</eissn><abstract>End‐stage renal disease (ESRD) patients on dialysis therapy have a higher incidence of renal cell carcinomas (RCCs), which consist of 2 major histopathological types: clear‐cell RCCs (ESRD‐ccRCCs) and acquired cystic disease (ACD)‐associated RCCs. However, their genetic and epigenetic alterations are still poorly understood. Here, we investigated somatic mutations, copy number alterations (CNAs), and DNA methylation profiles in 9 ESRD‐ccRCCs and 7 ACD‐associated RCCs to identify their molecular alterations and cellular origins. Targeted sequencing of 409 cancer‐related genes, including VHL, PBRM1, SETD2, BAP1, KDM5C, MET, KMT2C (MLL3), and TP53, showed ESRD‐ccRCCs harbored frequent VHL mutations, while ACD‐associated RCCs did not. CNA analysis showed that ESRD‐ccRCCs had a frequent loss of chromosome 3p while ACD‐associated RCCs had a gain of chromosome 16. Beadarray methylation analysis showed that ESRD‐ccRCCs had methylation profiles similar to those of sporadic ccRCCs, while ACD‐associated RCCs had profiles similar to those of papillary RCCs. Expression analysis of genes whose expression levels are characteristic to individual segments of a nephron showed that ESRD‐ccRCCs and ACD‐associated RCCs had high expression of proximal tubule cell marker genes, while chromophobe RCCs had high expression of distal tubule cell/collecting duct cell marker genes. In conclusion, ESRD‐ccRCCs and ACD‐associated RCCs had mutation and methylation profiles similar to those of sporadic ccRCCs and papillary RCCs, respectively, and these 2 histopathological types of RCCs were indicated to have originated from proximal tubule cells of the nephron.
We revealed that 2 major histopathological types of renal cell carcinomas (RCCs) that arise in end‐stage renal disease (ESRD), namely clear‐cell RCCs (ESRD‐ccRCCs) and acquired cystic disease (ACD)‐associated RCCs, had mutation and methylation profiles similar to those of sporadic ccRCCs and papillary RCCs, respectively. This finding indicates that these 2 histopathological types of RCCs arising in ESRD originated from proximal tubule cells of a nephron.</abstract><cop>HOBOKEN</cop><pub>Wiley</pub><pmid>32860304</pmid><doi>10.1111/cas.14633</doi><tpages>12</tpages><orcidid>https://orcid.org/0000-0003-3405-7817</orcidid><orcidid>https://orcid.org/0000-0002-5146-656X</orcidid><orcidid>https://orcid.org/0000-0002-4814-8616</orcidid><orcidid>https://orcid.org/0000-0002-8609-5797</orcidid><orcidid>https://orcid.org/0000-0002-0901-4869</orcidid><oa>free_for_read</oa></addata></record> |
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| language | eng |
| recordid | cdi_pubmed_primary_32860304 |
| source | MEDLINE; DOAJ Directory of Open Access Journals; Access via Wiley Online Library; Wiley Online Library (Open Access Collection); PubMed Central |
| subjects | ACD‐RCC Adult Aged Cancer Carcinoma, Renal Cell - etiology Carcinoma, Renal Cell - pathology Chromosome 16 Chromosome 3 Chromosomes Clear cell-type renal cell carcinoma Collecting duct Copy number Deoxyribonucleic acid Diabetes Dialysis DNA DNA Copy Number Variations DNA methylation Epigenesis, Genetic Epigenetics Epigenome Female Gene expression Gene Expression Profiling Genetic Predisposition to Disease Genomes Genomics Genotype Hemodialysis Humans Immunohistochemistry kidney cancer Kidney diseases Kidney Failure, Chronic - complications Kidney Failure, Chronic - genetics Kidney Neoplasms - etiology Kidney Neoplasms - pathology Kidney Tubules, Proximal - metabolism Kidney Tubules, Proximal - pathology Life Sciences & Biomedicine Male Middle Aged Mutation Oncology Original p53 Protein Peritoneal dialysis renal cell carcinoma Science & Technology Transcriptome VHL protein Women |
| title | Genetic and epigenetic profiling indicates the proximal tubule origin of renal cancers in end‐stage renal disease |
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