Analysis of Paired Primary-Metastatic Hormone-Receptor Positive Breast Tumors (HRPBC) Uncovers Potential Novel Drivers of Hormonal Resistance
We sought to identify genetic variants associated with disease relapse and failure to hormonal treatment in hormone-receptor positive breast cancer (HRPBC). We analyzed a series of HRPBC with distant relapse, by sequencing pairs (n = 11) of tumors (primary and metastases) at >800X. Comparative ge...
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| creator | Manso, Luis Mourón, Silvana Tress, Michael Gómez-López, Gonzalo Morente, Manuel Ciruelos, Eva Rubio-Camarillo, Miriam Rodriguez-Peralto, Jose Luis Pujana, Miguel A Pisano, David G Quintela-Fandino, Miguel |
| description | We sought to identify genetic variants associated with disease relapse and failure to hormonal treatment in hormone-receptor positive breast cancer (HRPBC). We analyzed a series of HRPBC with distant relapse, by sequencing pairs (n = 11) of tumors (primary and metastases) at >800X. Comparative genomic hybridization was performed as well. Top hits, based on the frequency of alteration and severity of the changes, were tested in the TCGA series. Genes determining the most parsimonious prognostic signature were studied for their functional role in vitro, by performing cell growth assays in hormonal-deprivation conditions, a setting that mimics treatment with aromatase inhibitors. Severe alterations were recurrently found in 18 genes in the pairs. However, only MYC, DNAH5, CSFR1, EPHA7, ARID1B, and KMT2C preserved an independent prognosis impact and/or showed a significantly different incidence of alterations between relapsed and non-relapsed cases in the TCGA series. The signature composed of MYC, KMT2C, and EPHA7 best discriminated the clinical course, (overall survival 90,7 vs. 144,5 months; p = 0.0001). Having an alteration in any of the genes of the signature implied a hazard ratio of death of 3.25 (p |
| doi_str_mv | 10.1371/journal.pone.0155840 |
| format | Article |
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We analyzed a series of HRPBC with distant relapse, by sequencing pairs (n = 11) of tumors (primary and metastases) at >800X. Comparative genomic hybridization was performed as well. Top hits, based on the frequency of alteration and severity of the changes, were tested in the TCGA series. Genes determining the most parsimonious prognostic signature were studied for their functional role in vitro, by performing cell growth assays in hormonal-deprivation conditions, a setting that mimics treatment with aromatase inhibitors. Severe alterations were recurrently found in 18 genes in the pairs. However, only MYC, DNAH5, CSFR1, EPHA7, ARID1B, and KMT2C preserved an independent prognosis impact and/or showed a significantly different incidence of alterations between relapsed and non-relapsed cases in the TCGA series. The signature composed of MYC, KMT2C, and EPHA7 best discriminated the clinical course, (overall survival 90,7 vs. 144,5 months; p = 0.0001). Having an alteration in any of the genes of the signature implied a hazard ratio of death of 3.25 (p<0.0001), and early relapse during the adjuvant hormonal treatment. The presence of the D348N mutation in KMT2C and/or the T666I mutation in the kinase domain of EPHA7 conferred hormonal resistance in vitro. Novel inactivating mutations in KMT2C and EPHA7, which confer hormonal resistance, are linked to adverse clinical course in HRPBC.</description><identifier>ISSN: 1932-6203</identifier><identifier>EISSN: 1932-6203</identifier><identifier>DOI: 10.1371/journal.pone.0155840</identifier><identifier>PMID: 27195705</identifier><language>eng</language><publisher>United States: Public Library of Science</publisher><subject>Alterations ; Analysis ; Antineoplastic Agents, Hormonal - therapeutic use ; Aromatase ; Aromatase Inhibitors - pharmacology ; Bioinformatics ; Biology and Life Sciences ; Biomedical research ; Breast - pathology ; Breast cancer ; Breast Neoplasms - genetics ; Breast Neoplasms - pathology ; Cancer metastasis ; Cell cycle ; Cloning ; Comparative Genomic Hybridization ; Deoxyribonucleic acid ; Deprivation ; Development and progression ; DNA ; DNA methylation ; Drug Resistance, Neoplasm - genetics ; Failure analysis ; Female ; Gene Expression Profiling ; Gene Expression Regulation, Neoplastic ; Genes ; Genetic aspects ; Genetic diversity ; Genetic variance ; Genetic Variation ; Hormones ; Hormones - metabolism ; Humans ; Hybridization ; Medical research ; Medical treatment ; Medicine and Health Sciences ; Metastases ; Metastasis ; Mutation ; Myc protein ; Neoplasm Recurrence, Local - genetics ; Neoplasm Recurrence, Local - pathology ; Oligonucleotide Array Sequence Analysis ; Physiological aspects ; Prognosis ; Receptors, Estrogen - metabolism ; Recurrence ; Research and Analysis Methods ; Retrospective Studies ; Review boards ; Risk ; Sequence Analysis, DNA ; Sequences ; Studies ; Tamoxifen - pharmacology ; Treatment Outcome ; Tumors</subject><ispartof>PloS one, 2016-05, Vol.11 (5), p.e0155840-e0155840</ispartof><rights>COPYRIGHT 2016 Public Library of Science</rights><rights>2016 Manso et al. This is an open access article distributed under the terms of the Creative Commons Attribution License: http://creativecommons.org/licenses/by/4.0/ (the “License”), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.</rights><rights>2016 Manso et al 2016 Manso et al</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c593t-d49dac8db459feb1aa6b26266142b44420fd56465fdb42edf1a72b2eba3cc8c63</citedby><cites>FETCH-LOGICAL-c593t-d49dac8db459feb1aa6b26266142b44420fd56465fdb42edf1a72b2eba3cc8c63</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC4873174/pdf/$$EPDF$$P50$$Gpubmedcentral$$Hfree_for_read</linktopdf><linktohtml>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC4873174/$$EHTML$$P50$$Gpubmedcentral$$Hfree_for_read</linktohtml><link.rule.ids>230,314,727,780,784,864,885,2102,2928,23866,27924,27925,53791,53793,79600,79601</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/27195705$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><contributor>Agoulnik, Irina U</contributor><creatorcontrib>Manso, Luis</creatorcontrib><creatorcontrib>Mourón, Silvana</creatorcontrib><creatorcontrib>Tress, Michael</creatorcontrib><creatorcontrib>Gómez-López, Gonzalo</creatorcontrib><creatorcontrib>Morente, Manuel</creatorcontrib><creatorcontrib>Ciruelos, Eva</creatorcontrib><creatorcontrib>Rubio-Camarillo, Miriam</creatorcontrib><creatorcontrib>Rodriguez-Peralto, Jose Luis</creatorcontrib><creatorcontrib>Pujana, Miguel A</creatorcontrib><creatorcontrib>Pisano, David G</creatorcontrib><creatorcontrib>Quintela-Fandino, Miguel</creatorcontrib><title>Analysis of Paired Primary-Metastatic Hormone-Receptor Positive Breast Tumors (HRPBC) Uncovers Potential Novel Drivers of Hormonal Resistance</title><title>PloS one</title><addtitle>PLoS One</addtitle><description>We sought to identify genetic variants associated with disease relapse and failure to hormonal treatment in hormone-receptor positive breast cancer (HRPBC). We analyzed a series of HRPBC with distant relapse, by sequencing pairs (n = 11) of tumors (primary and metastases) at >800X. Comparative genomic hybridization was performed as well. Top hits, based on the frequency of alteration and severity of the changes, were tested in the TCGA series. Genes determining the most parsimonious prognostic signature were studied for their functional role in vitro, by performing cell growth assays in hormonal-deprivation conditions, a setting that mimics treatment with aromatase inhibitors. Severe alterations were recurrently found in 18 genes in the pairs. However, only MYC, DNAH5, CSFR1, EPHA7, ARID1B, and KMT2C preserved an independent prognosis impact and/or showed a significantly different incidence of alterations between relapsed and non-relapsed cases in the TCGA series. The signature composed of MYC, KMT2C, and EPHA7 best discriminated the clinical course, (overall survival 90,7 vs. 144,5 months; p = 0.0001). Having an alteration in any of the genes of the signature implied a hazard ratio of death of 3.25 (p<0.0001), and early relapse during the adjuvant hormonal treatment. The presence of the D348N mutation in KMT2C and/or the T666I mutation in the kinase domain of EPHA7 conferred hormonal resistance in vitro. Novel inactivating mutations in KMT2C and EPHA7, which confer hormonal resistance, are linked to adverse clinical course in HRPBC.</description><subject>Alterations</subject><subject>Analysis</subject><subject>Antineoplastic Agents, Hormonal - therapeutic use</subject><subject>Aromatase</subject><subject>Aromatase Inhibitors - pharmacology</subject><subject>Bioinformatics</subject><subject>Biology and Life Sciences</subject><subject>Biomedical research</subject><subject>Breast - pathology</subject><subject>Breast cancer</subject><subject>Breast Neoplasms - genetics</subject><subject>Breast Neoplasms - pathology</subject><subject>Cancer metastasis</subject><subject>Cell cycle</subject><subject>Cloning</subject><subject>Comparative Genomic Hybridization</subject><subject>Deoxyribonucleic acid</subject><subject>Deprivation</subject><subject>Development and progression</subject><subject>DNA</subject><subject>DNA methylation</subject><subject>Drug Resistance, Neoplasm - genetics</subject><subject>Failure analysis</subject><subject>Female</subject><subject>Gene Expression Profiling</subject><subject>Gene Expression Regulation, Neoplastic</subject><subject>Genes</subject><subject>Genetic aspects</subject><subject>Genetic diversity</subject><subject>Genetic variance</subject><subject>Genetic Variation</subject><subject>Hormones</subject><subject>Hormones - 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Academic</collection><collection>PubMed Central (Full Participant titles)</collection><collection>DOAJ Directory of Open Access Journals</collection><jtitle>PloS one</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Manso, Luis</au><au>Mourón, Silvana</au><au>Tress, Michael</au><au>Gómez-López, Gonzalo</au><au>Morente, Manuel</au><au>Ciruelos, Eva</au><au>Rubio-Camarillo, Miriam</au><au>Rodriguez-Peralto, Jose Luis</au><au>Pujana, Miguel A</au><au>Pisano, David G</au><au>Quintela-Fandino, Miguel</au><au>Agoulnik, Irina U</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Analysis of Paired Primary-Metastatic Hormone-Receptor Positive Breast Tumors (HRPBC) Uncovers Potential Novel Drivers of Hormonal Resistance</atitle><jtitle>PloS one</jtitle><addtitle>PLoS One</addtitle><date>2016-05-19</date><risdate>2016</risdate><volume>11</volume><issue>5</issue><spage>e0155840</spage><epage>e0155840</epage><pages>e0155840-e0155840</pages><issn>1932-6203</issn><eissn>1932-6203</eissn><abstract>We sought to identify genetic variants associated with disease relapse and failure to hormonal treatment in hormone-receptor positive breast cancer (HRPBC). We analyzed a series of HRPBC with distant relapse, by sequencing pairs (n = 11) of tumors (primary and metastases) at >800X. Comparative genomic hybridization was performed as well. Top hits, based on the frequency of alteration and severity of the changes, were tested in the TCGA series. Genes determining the most parsimonious prognostic signature were studied for their functional role in vitro, by performing cell growth assays in hormonal-deprivation conditions, a setting that mimics treatment with aromatase inhibitors. Severe alterations were recurrently found in 18 genes in the pairs. However, only MYC, DNAH5, CSFR1, EPHA7, ARID1B, and KMT2C preserved an independent prognosis impact and/or showed a significantly different incidence of alterations between relapsed and non-relapsed cases in the TCGA series. The signature composed of MYC, KMT2C, and EPHA7 best discriminated the clinical course, (overall survival 90,7 vs. 144,5 months; p = 0.0001). Having an alteration in any of the genes of the signature implied a hazard ratio of death of 3.25 (p<0.0001), and early relapse during the adjuvant hormonal treatment. The presence of the D348N mutation in KMT2C and/or the T666I mutation in the kinase domain of EPHA7 conferred hormonal resistance in vitro. Novel inactivating mutations in KMT2C and EPHA7, which confer hormonal resistance, are linked to adverse clinical course in HRPBC.</abstract><cop>United States</cop><pub>Public Library of Science</pub><pmid>27195705</pmid><doi>10.1371/journal.pone.0155840</doi><oa>free_for_read</oa></addata></record> |
| fulltext | fulltext |
| identifier | ISSN: 1932-6203 |
| ispartof | PloS one, 2016-05, Vol.11 (5), p.e0155840-e0155840 |
| issn | 1932-6203 1932-6203 |
| language | eng |
| recordid | cdi_plos_journals_1790065417 |
| source | MEDLINE; DOAJ Directory of Open Access Journals; Public Library of Science (PLoS) Journals Open Access; EZB-FREE-00999 freely available EZB journals; PubMed Central; Free Full-Text Journals in Chemistry |
| subjects | Alterations Analysis Antineoplastic Agents, Hormonal - therapeutic use Aromatase Aromatase Inhibitors - pharmacology Bioinformatics Biology and Life Sciences Biomedical research Breast - pathology Breast cancer Breast Neoplasms - genetics Breast Neoplasms - pathology Cancer metastasis Cell cycle Cloning Comparative Genomic Hybridization Deoxyribonucleic acid Deprivation Development and progression DNA DNA methylation Drug Resistance, Neoplasm - genetics Failure analysis Female Gene Expression Profiling Gene Expression Regulation, Neoplastic Genes Genetic aspects Genetic diversity Genetic variance Genetic Variation Hormones Hormones - metabolism Humans Hybridization Medical research Medical treatment Medicine and Health Sciences Metastases Metastasis Mutation Myc protein Neoplasm Recurrence, Local - genetics Neoplasm Recurrence, Local - pathology Oligonucleotide Array Sequence Analysis Physiological aspects Prognosis Receptors, Estrogen - metabolism Recurrence Research and Analysis Methods Retrospective Studies Review boards Risk Sequence Analysis, DNA Sequences Studies Tamoxifen - pharmacology Treatment Outcome Tumors |
| title | Analysis of Paired Primary-Metastatic Hormone-Receptor Positive Breast Tumors (HRPBC) Uncovers Potential Novel Drivers of Hormonal Resistance |
| url | https://sfx.bib-bvb.de/sfx_tum?ctx_ver=Z39.88-2004&ctx_enc=info:ofi/enc:UTF-8&ctx_tim=2025-01-01T01%3A59%3A49IST&url_ver=Z39.88-2004&url_ctx_fmt=infofi/fmt:kev:mtx:ctx&rfr_id=info:sid/primo.exlibrisgroup.com:primo3-Article-gale_plos_&rft_val_fmt=info:ofi/fmt:kev:mtx:journal&rft.genre=article&rft.atitle=Analysis%20of%20Paired%20Primary-Metastatic%20Hormone-Receptor%20Positive%20Breast%20Tumors%20(HRPBC)%20Uncovers%20Potential%20Novel%20Drivers%20of%20Hormonal%20Resistance&rft.jtitle=PloS%20one&rft.au=Manso,%20Luis&rft.date=2016-05-19&rft.volume=11&rft.issue=5&rft.spage=e0155840&rft.epage=e0155840&rft.pages=e0155840-e0155840&rft.issn=1932-6203&rft.eissn=1932-6203&rft_id=info:doi/10.1371/journal.pone.0155840&rft_dat=%3Cgale_plos_%3EA453360174%3C/gale_plos_%3E%3Curl%3E%3C/url%3E&disable_directlink=true&sfx.directlink=off&sfx.report_link=0&rft_id=info:oai/&rft_pqid=1790065417&rft_id=info:pmid/27195705&rft_galeid=A453360174&rft_doaj_id=oai_doaj_org_article_3a333d3a2fd64d30952d0bd985d00a96&rfr_iscdi=true |