Genetic and molecular subtype heterogeneity in newly diagnosed early- and advanced-stage endometrial cancer
To characterize and compare the molecular subtypes and profiles of prospectively-accrued newly-diagnosed early- and advanced-stage endometrial cancers (ECs). EC patients consented to an IRB-approved protocol of massively parallel sequencing of 410–468 cancer-related genes; 175 ECs of 7 histologic ty...
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| Veröffentlicht in: | Gynecologic oncology 2021-05, Vol.161 (2), p.535-544 |
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| creator | Da Cruz Paula, Arnaud DeLair, Deborah F. Ferrando, Lorenzo Fix, Daniel J. Soslow, Robert A. Park, Kay J. Chiang, Sarah Reis-Filho, Jorge S. Zehir, Ahmet Donoghue, Mark T.A. Wu, Michelle Brown, David N. Murali, Rajmohan Friedman, Claire F. Zamarin, Dmitriy Makker, Vicky Mueller, Jennifer J. Leitao, Mario M. Abu-Rustum, Nadeem R. Aghajanian, Carol Weigelt, Britta |
| description | To characterize and compare the molecular subtypes and profiles of prospectively-accrued newly-diagnosed early- and advanced-stage endometrial cancers (ECs).
EC patients consented to an IRB-approved protocol of massively parallel sequencing of 410–468 cancer-related genes; 175 ECs of 7 histologic types (n = 135 FIGO stages I/II, n = 40 FIGO stages III/IV) were included. Previously reported sequencing data from 99 additional advanced-stage ECs were retrieved for comparisons.
Irrespective of histologic type, all 175 ECs could be stratified into the molecular subtypes, with 75 (43%) being of p53 wild-type, 49 (28%) MMR-deficient, 39 (22%) p53 abnormal and 12 (7%) of POLE molecular subtypes. Subtype distribution, mutational and copy number profiles varied according to histologic type. In endometrioid ECs, genetic alterations varied according to histologic grade. Potential therapeutic targets, including high tumor mutational burden, ERBB2 amplification and PIK3CA hotspot mutations, were found across histologic types in 63% (n = 110) of all ECs. Compared to their early-stage counterparts, advanced-stage endometrioid ECs had a significantly higher fraction of genome altered (median 0.1% vs 12%, p 0.05) and PIK3CA mutations (46% vs 27%, p > 0.05). Whole-genome doubling was found in advanced- but not early-stage carcinosarcomas and clear cell carcinomas.
Our findings demonstrate the molecular heterogeneity within and across histologic types of EC and the increased genomic complexity of advanced-stage ECs. Molecular subtypes are present across EC histologic types and may help stratify EC patients for prognostic and therapeutic purposes.
•Molecular subtype distribution varies according to histologic types of EC.•Advanced-stage endometrioid ECs show increased genomic instability.•ERBB2 amplification is more common in advanced- than early-stage serous ECs.•Whole-genome doubling is found in advanced- but not early-stage carcinosarcomas and clear cell carcinomas.•Potential therapeutic targets were identified in >60% of ECs. |
| doi_str_mv | 10.1016/j.ygyno.2021.02.015 |
| format | Article |
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EC patients consented to an IRB-approved protocol of massively parallel sequencing of 410–468 cancer-related genes; 175 ECs of 7 histologic types (n = 135 FIGO stages I/II, n = 40 FIGO stages III/IV) were included. Previously reported sequencing data from 99 additional advanced-stage ECs were retrieved for comparisons.
Irrespective of histologic type, all 175 ECs could be stratified into the molecular subtypes, with 75 (43%) being of p53 wild-type, 49 (28%) MMR-deficient, 39 (22%) p53 abnormal and 12 (7%) of POLE molecular subtypes. Subtype distribution, mutational and copy number profiles varied according to histologic type. In endometrioid ECs, genetic alterations varied according to histologic grade. Potential therapeutic targets, including high tumor mutational burden, ERBB2 amplification and PIK3CA hotspot mutations, were found across histologic types in 63% (n = 110) of all ECs. Compared to their early-stage counterparts, advanced-stage endometrioid ECs had a significantly higher fraction of genome altered (median 0.1% vs 12%, p < 0.001) and ARID1B mutations (0% vs 11%, p = 0.01), and advanced-stage serous ECs harbored more frequent ERBB2 amplification (18% vs 8%, p > 0.05) and PIK3CA mutations (46% vs 27%, p > 0.05). Whole-genome doubling was found in advanced- but not early-stage carcinosarcomas and clear cell carcinomas.
Our findings demonstrate the molecular heterogeneity within and across histologic types of EC and the increased genomic complexity of advanced-stage ECs. Molecular subtypes are present across EC histologic types and may help stratify EC patients for prognostic and therapeutic purposes.
•Molecular subtype distribution varies according to histologic types of EC.•Advanced-stage endometrioid ECs show increased genomic instability.•ERBB2 amplification is more common in advanced- than early-stage serous ECs.•Whole-genome doubling is found in advanced- but not early-stage carcinosarcomas and clear cell carcinomas.•Potential therapeutic targets were identified in >60% of ECs.</description><identifier>ISSN: 0090-8258</identifier><identifier>EISSN: 1095-6859</identifier><identifier>DOI: 10.1016/j.ygyno.2021.02.015</identifier><identifier>PMID: 33622519</identifier><language>eng</language><publisher>SAN DIEGO: Elsevier Inc</publisher><subject>Adult ; Aged ; Aged, 80 and over ; Carcinoma, Endometrioid - genetics ; Carcinoma, Endometrioid - pathology ; Endometrial cancer ; Endometrial Neoplasms - genetics ; Endometrial Neoplasms - pathology ; Female ; Gene Amplification ; Gene Duplication ; Genes, erbB-2 ; Genome, Human ; Genomic Instability ; Humans ; Life Sciences & Biomedicine ; Massively parallel sequencing ; Middle Aged ; Molecular subtypes ; Neoplasm Staging ; Obstetrics & Gynecology ; Oncology ; Receptor, ErbB-2 - genetics ; Science & Technology ; Whole-genome duplication</subject><ispartof>Gynecologic oncology, 2021-05, Vol.161 (2), p.535-544</ispartof><rights>2021 Elsevier Inc.</rights><rights>Copyright © 2021 Elsevier Inc. All rights reserved.</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>true</woscitedreferencessubscribed><woscitedreferencescount>20</woscitedreferencescount><woscitedreferencesoriginalsourcerecordid>wos000644070000036</woscitedreferencesoriginalsourcerecordid><citedby>FETCH-LOGICAL-c459t-afe11f7a53b287b63783f1273f15861de460e9033b239d90f1a048272c1a0db03</citedby><cites>FETCH-LOGICAL-c459t-afe11f7a53b287b63783f1273f15861de460e9033b239d90f1a048272c1a0db03</cites><orcidid>0000-0002-4025-7930 ; 0000-0002-0094-0161</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktohtml>$$Uhttps://dx.doi.org/10.1016/j.ygyno.2021.02.015$$EHTML$$P50$$Gelsevier$$H</linktohtml><link.rule.ids>230,315,781,785,886,3551,27929,27930,39263,46000</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/33622519$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Da Cruz Paula, Arnaud</creatorcontrib><creatorcontrib>DeLair, Deborah F.</creatorcontrib><creatorcontrib>Ferrando, Lorenzo</creatorcontrib><creatorcontrib>Fix, Daniel J.</creatorcontrib><creatorcontrib>Soslow, Robert A.</creatorcontrib><creatorcontrib>Park, Kay J.</creatorcontrib><creatorcontrib>Chiang, Sarah</creatorcontrib><creatorcontrib>Reis-Filho, Jorge S.</creatorcontrib><creatorcontrib>Zehir, Ahmet</creatorcontrib><creatorcontrib>Donoghue, Mark T.A.</creatorcontrib><creatorcontrib>Wu, Michelle</creatorcontrib><creatorcontrib>Brown, David N.</creatorcontrib><creatorcontrib>Murali, Rajmohan</creatorcontrib><creatorcontrib>Friedman, Claire F.</creatorcontrib><creatorcontrib>Zamarin, Dmitriy</creatorcontrib><creatorcontrib>Makker, Vicky</creatorcontrib><creatorcontrib>Mueller, Jennifer J.</creatorcontrib><creatorcontrib>Leitao, Mario M.</creatorcontrib><creatorcontrib>Abu-Rustum, Nadeem R.</creatorcontrib><creatorcontrib>Aghajanian, Carol</creatorcontrib><creatorcontrib>Weigelt, Britta</creatorcontrib><title>Genetic and molecular subtype heterogeneity in newly diagnosed early- and advanced-stage endometrial cancer</title><title>Gynecologic oncology</title><addtitle>GYNECOL ONCOL</addtitle><addtitle>Gynecol Oncol</addtitle><description>To characterize and compare the molecular subtypes and profiles of prospectively-accrued newly-diagnosed early- and advanced-stage endometrial cancers (ECs).
EC patients consented to an IRB-approved protocol of massively parallel sequencing of 410–468 cancer-related genes; 175 ECs of 7 histologic types (n = 135 FIGO stages I/II, n = 40 FIGO stages III/IV) were included. Previously reported sequencing data from 99 additional advanced-stage ECs were retrieved for comparisons.
Irrespective of histologic type, all 175 ECs could be stratified into the molecular subtypes, with 75 (43%) being of p53 wild-type, 49 (28%) MMR-deficient, 39 (22%) p53 abnormal and 12 (7%) of POLE molecular subtypes. Subtype distribution, mutational and copy number profiles varied according to histologic type. In endometrioid ECs, genetic alterations varied according to histologic grade. Potential therapeutic targets, including high tumor mutational burden, ERBB2 amplification and PIK3CA hotspot mutations, were found across histologic types in 63% (n = 110) of all ECs. Compared to their early-stage counterparts, advanced-stage endometrioid ECs had a significantly higher fraction of genome altered (median 0.1% vs 12%, p < 0.001) and ARID1B mutations (0% vs 11%, p = 0.01), and advanced-stage serous ECs harbored more frequent ERBB2 amplification (18% vs 8%, p > 0.05) and PIK3CA mutations (46% vs 27%, p > 0.05). Whole-genome doubling was found in advanced- but not early-stage carcinosarcomas and clear cell carcinomas.
Our findings demonstrate the molecular heterogeneity within and across histologic types of EC and the increased genomic complexity of advanced-stage ECs. Molecular subtypes are present across EC histologic types and may help stratify EC patients for prognostic and therapeutic purposes.
•Molecular subtype distribution varies according to histologic types of EC.•Advanced-stage endometrioid ECs show increased genomic instability.•ERBB2 amplification is more common in advanced- than early-stage serous ECs.•Whole-genome doubling is found in advanced- but not early-stage carcinosarcomas and clear cell carcinomas.•Potential therapeutic targets were identified in >60% of ECs.</description><subject>Adult</subject><subject>Aged</subject><subject>Aged, 80 and over</subject><subject>Carcinoma, Endometrioid - genetics</subject><subject>Carcinoma, Endometrioid - pathology</subject><subject>Endometrial cancer</subject><subject>Endometrial Neoplasms - genetics</subject><subject>Endometrial Neoplasms - pathology</subject><subject>Female</subject><subject>Gene Amplification</subject><subject>Gene Duplication</subject><subject>Genes, erbB-2</subject><subject>Genome, Human</subject><subject>Genomic Instability</subject><subject>Humans</subject><subject>Life Sciences & Biomedicine</subject><subject>Massively parallel sequencing</subject><subject>Middle Aged</subject><subject>Molecular subtypes</subject><subject>Neoplasm Staging</subject><subject>Obstetrics & Gynecology</subject><subject>Oncology</subject><subject>Receptor, ErbB-2 - genetics</subject><subject>Science & Technology</subject><subject>Whole-genome duplication</subject><issn>0090-8258</issn><issn>1095-6859</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2021</creationdate><recordtype>article</recordtype><sourceid>HGBXW</sourceid><sourceid>EIF</sourceid><recordid>eNqNkV2L1DAUhoso7rj6CwTppSCtJ0nTjwsFGXQVFrzR65Amp92MbTIm6Sz992Z2xkFvxFwkgfO8Jx9Plr0kUBIg9dtduY6rdSUFSkqgJRD-KNsQ6HhRt7x7nG0AOihaytur7FkIOwBgQOjT7IqxmlJOuk324wYtRqNyaXU-uwnVMkmfh6WP6x7zO4zo3ZgYE9fc2Nzi_bTm2sjRuoA6R-mntXhIS32QVqEuQpQj5mi1mzF6I6dcHQv-efZkkFPAF-f1Ovv-6eO37efi9uvNl-2H20JVvIuFHJCQoZGc9bRt-po1LRsIbdLE25porGrADlgqs053MBAJVUsbqtJG98Cus_envvuln1ErtNHLSey9maVfhZNG_F2x5k6M7iBaaDlwlhq8Pjfw7ueCIYrZBIXTJC26JQhadSz9JackoeyEKu9C8DhcjiEgjprETjxoEkdNAqhImlLq1Z83vGR-e0lAewLusXdDUAbTB16wJLKuKmjgOFi9NVFG4-zWLTam6Jv_jyb63YnGJORg0ItzQhuPKgrtzD9f8gs8U8e-</recordid><startdate>20210501</startdate><enddate>20210501</enddate><creator>Da Cruz Paula, Arnaud</creator><creator>DeLair, Deborah F.</creator><creator>Ferrando, Lorenzo</creator><creator>Fix, Daniel J.</creator><creator>Soslow, Robert A.</creator><creator>Park, Kay J.</creator><creator>Chiang, Sarah</creator><creator>Reis-Filho, Jorge S.</creator><creator>Zehir, Ahmet</creator><creator>Donoghue, Mark T.A.</creator><creator>Wu, Michelle</creator><creator>Brown, David N.</creator><creator>Murali, Rajmohan</creator><creator>Friedman, Claire F.</creator><creator>Zamarin, Dmitriy</creator><creator>Makker, Vicky</creator><creator>Mueller, Jennifer J.</creator><creator>Leitao, Mario M.</creator><creator>Abu-Rustum, Nadeem R.</creator><creator>Aghajanian, Carol</creator><creator>Weigelt, Britta</creator><general>Elsevier Inc</general><general>Elsevier</general><scope>BLEPL</scope><scope>DTL</scope><scope>HGBXW</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>7X8</scope><scope>5PM</scope><orcidid>https://orcid.org/0000-0002-4025-7930</orcidid><orcidid>https://orcid.org/0000-0002-0094-0161</orcidid></search><sort><creationdate>20210501</creationdate><title>Genetic and molecular subtype heterogeneity in newly diagnosed early- and advanced-stage endometrial cancer</title><author>Da Cruz Paula, Arnaud ; DeLair, Deborah F. ; Ferrando, Lorenzo ; Fix, Daniel J. ; Soslow, Robert A. ; Park, Kay J. ; Chiang, Sarah ; Reis-Filho, Jorge S. ; Zehir, Ahmet ; Donoghue, Mark T.A. ; Wu, Michelle ; Brown, David N. ; Murali, Rajmohan ; Friedman, Claire F. ; Zamarin, Dmitriy ; Makker, Vicky ; Mueller, Jennifer J. ; Leitao, Mario M. ; Abu-Rustum, Nadeem R. ; Aghajanian, Carol ; Weigelt, Britta</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c459t-afe11f7a53b287b63783f1273f15861de460e9033b239d90f1a048272c1a0db03</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2021</creationdate><topic>Adult</topic><topic>Aged</topic><topic>Aged, 80 and over</topic><topic>Carcinoma, Endometrioid - genetics</topic><topic>Carcinoma, Endometrioid - pathology</topic><topic>Endometrial cancer</topic><topic>Endometrial Neoplasms - genetics</topic><topic>Endometrial Neoplasms - pathology</topic><topic>Female</topic><topic>Gene Amplification</topic><topic>Gene Duplication</topic><topic>Genes, erbB-2</topic><topic>Genome, Human</topic><topic>Genomic Instability</topic><topic>Humans</topic><topic>Life Sciences & Biomedicine</topic><topic>Massively parallel sequencing</topic><topic>Middle Aged</topic><topic>Molecular subtypes</topic><topic>Neoplasm Staging</topic><topic>Obstetrics & Gynecology</topic><topic>Oncology</topic><topic>Receptor, ErbB-2 - genetics</topic><topic>Science & Technology</topic><topic>Whole-genome duplication</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Da Cruz Paula, Arnaud</creatorcontrib><creatorcontrib>DeLair, Deborah F.</creatorcontrib><creatorcontrib>Ferrando, Lorenzo</creatorcontrib><creatorcontrib>Fix, Daniel J.</creatorcontrib><creatorcontrib>Soslow, Robert A.</creatorcontrib><creatorcontrib>Park, Kay J.</creatorcontrib><creatorcontrib>Chiang, Sarah</creatorcontrib><creatorcontrib>Reis-Filho, Jorge S.</creatorcontrib><creatorcontrib>Zehir, Ahmet</creatorcontrib><creatorcontrib>Donoghue, Mark T.A.</creatorcontrib><creatorcontrib>Wu, Michelle</creatorcontrib><creatorcontrib>Brown, David N.</creatorcontrib><creatorcontrib>Murali, Rajmohan</creatorcontrib><creatorcontrib>Friedman, Claire F.</creatorcontrib><creatorcontrib>Zamarin, Dmitriy</creatorcontrib><creatorcontrib>Makker, Vicky</creatorcontrib><creatorcontrib>Mueller, Jennifer J.</creatorcontrib><creatorcontrib>Leitao, Mario M.</creatorcontrib><creatorcontrib>Abu-Rustum, Nadeem R.</creatorcontrib><creatorcontrib>Aghajanian, Carol</creatorcontrib><creatorcontrib>Weigelt, Britta</creatorcontrib><collection>Web of Science Core Collection</collection><collection>Science Citation Index Expanded</collection><collection>Web of Science - Science Citation Index Expanded - 2021</collection><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>Gynecologic oncology</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Da Cruz Paula, Arnaud</au><au>DeLair, Deborah F.</au><au>Ferrando, Lorenzo</au><au>Fix, Daniel J.</au><au>Soslow, Robert A.</au><au>Park, Kay J.</au><au>Chiang, Sarah</au><au>Reis-Filho, Jorge S.</au><au>Zehir, Ahmet</au><au>Donoghue, Mark T.A.</au><au>Wu, Michelle</au><au>Brown, David N.</au><au>Murali, Rajmohan</au><au>Friedman, Claire F.</au><au>Zamarin, Dmitriy</au><au>Makker, Vicky</au><au>Mueller, Jennifer J.</au><au>Leitao, Mario M.</au><au>Abu-Rustum, Nadeem R.</au><au>Aghajanian, Carol</au><au>Weigelt, Britta</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Genetic and molecular subtype heterogeneity in newly diagnosed early- and advanced-stage endometrial cancer</atitle><jtitle>Gynecologic oncology</jtitle><stitle>GYNECOL ONCOL</stitle><addtitle>Gynecol Oncol</addtitle><date>2021-05-01</date><risdate>2021</risdate><volume>161</volume><issue>2</issue><spage>535</spage><epage>544</epage><pages>535-544</pages><issn>0090-8258</issn><eissn>1095-6859</eissn><abstract>To characterize and compare the molecular subtypes and profiles of prospectively-accrued newly-diagnosed early- and advanced-stage endometrial cancers (ECs).
EC patients consented to an IRB-approved protocol of massively parallel sequencing of 410–468 cancer-related genes; 175 ECs of 7 histologic types (n = 135 FIGO stages I/II, n = 40 FIGO stages III/IV) were included. Previously reported sequencing data from 99 additional advanced-stage ECs were retrieved for comparisons.
Irrespective of histologic type, all 175 ECs could be stratified into the molecular subtypes, with 75 (43%) being of p53 wild-type, 49 (28%) MMR-deficient, 39 (22%) p53 abnormal and 12 (7%) of POLE molecular subtypes. Subtype distribution, mutational and copy number profiles varied according to histologic type. In endometrioid ECs, genetic alterations varied according to histologic grade. Potential therapeutic targets, including high tumor mutational burden, ERBB2 amplification and PIK3CA hotspot mutations, were found across histologic types in 63% (n = 110) of all ECs. Compared to their early-stage counterparts, advanced-stage endometrioid ECs had a significantly higher fraction of genome altered (median 0.1% vs 12%, p < 0.001) and ARID1B mutations (0% vs 11%, p = 0.01), and advanced-stage serous ECs harbored more frequent ERBB2 amplification (18% vs 8%, p > 0.05) and PIK3CA mutations (46% vs 27%, p > 0.05). Whole-genome doubling was found in advanced- but not early-stage carcinosarcomas and clear cell carcinomas.
Our findings demonstrate the molecular heterogeneity within and across histologic types of EC and the increased genomic complexity of advanced-stage ECs. Molecular subtypes are present across EC histologic types and may help stratify EC patients for prognostic and therapeutic purposes.
•Molecular subtype distribution varies according to histologic types of EC.•Advanced-stage endometrioid ECs show increased genomic instability.•ERBB2 amplification is more common in advanced- than early-stage serous ECs.•Whole-genome doubling is found in advanced- but not early-stage carcinosarcomas and clear cell carcinomas.•Potential therapeutic targets were identified in >60% of ECs.</abstract><cop>SAN DIEGO</cop><pub>Elsevier Inc</pub><pmid>33622519</pmid><doi>10.1016/j.ygyno.2021.02.015</doi><tpages>10</tpages><orcidid>https://orcid.org/0000-0002-4025-7930</orcidid><orcidid>https://orcid.org/0000-0002-0094-0161</orcidid><oa>free_for_read</oa></addata></record> |
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| subjects | Adult Aged Aged, 80 and over Carcinoma, Endometrioid - genetics Carcinoma, Endometrioid - pathology Endometrial cancer Endometrial Neoplasms - genetics Endometrial Neoplasms - pathology Female Gene Amplification Gene Duplication Genes, erbB-2 Genome, Human Genomic Instability Humans Life Sciences & Biomedicine Massively parallel sequencing Middle Aged Molecular subtypes Neoplasm Staging Obstetrics & Gynecology Oncology Receptor, ErbB-2 - genetics Science & Technology Whole-genome duplication |
| title | Genetic and molecular subtype heterogeneity in newly diagnosed early- and advanced-stage endometrial cancer |
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