Ploidy and Large-Scale Genomic Instability Consistently Identify Basal-like Breast Carcinomas with BRCA1/2 Inactivation
BRCA1 inactivation is a frequent event in basal-like breast carcinomas (BLC). However, BRCA1 can be inactivated by multiple mechanisms and determining its status is not a trivial issue. As an alternate approach, we profiled 65 BLC cases using single-nucleotide polymorphism arrays to define a signatu...
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| Veröffentlicht in: | Cancer research (Chicago, Ill.) Ill.), 2012-11, Vol.72 (21), p.5454-5462 |
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| creator | POPOVA, Tatiana MANIE, Elodie HOUDAYE, Claude SASTRE-GARAU, Xavier VINCENT-SALOMON, Anne STOPPA-LYONNET, Dominique STERN, Marc-Henri RIEUNIER, Guillaume CAUX-MONCOUTIER, Virginie TIRAPO, Carole DUBOIS, Thierry DELATTRE, Olivier SIGAL-ZAFRANI, Brigitte BOLLET, Marc LONGY, Michel |
| description | BRCA1 inactivation is a frequent event in basal-like breast carcinomas (BLC). However, BRCA1 can be inactivated by multiple mechanisms and determining its status is not a trivial issue. As an alternate approach, we profiled 65 BLC cases using single-nucleotide polymorphism arrays to define a signature of BRCA1-associated genomic instability. Large-scale state transitions (LST), defined as chromosomal break between adjacent regions of at least 10 Mb, were found to be a robust indicator of BRCA1 status in this setting. Two major ploidy-specific cutoffs in LST distributions were sufficient to distinguish highly rearranged BLCs with 85% of proven BRCA1-inactivated cases from less rearranged BLCs devoid of proven BRCA1-inactivated cases. The genomic signature we defined was validated in a second independent series of 55 primary BLC cases and 17 BLC-derived tumor cell lines. High numbers of LSTs resembling BRCA1-inactivated BLC were observed in 4 primary BLC cases and 2 BLC cell lines that harbored BRCA2 mutations. Overall, the genomic signature we defined predicted BRCA1/2 inactivation in BLCs with 100% sensitivity and 90% specificity (97% accuracy). This assay may ease the challenge of selecting patients for genetic testing or recruitment to clinical trials of novel emerging therapies that target DNA repair deficiencies in cancer. |
| doi_str_mv | 10.1158/0008-5472.CAN-12-1470 |
| format | Article |
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However, BRCA1 can be inactivated by multiple mechanisms and determining its status is not a trivial issue. As an alternate approach, we profiled 65 BLC cases using single-nucleotide polymorphism arrays to define a signature of BRCA1-associated genomic instability. Large-scale state transitions (LST), defined as chromosomal break between adjacent regions of at least 10 Mb, were found to be a robust indicator of BRCA1 status in this setting. Two major ploidy-specific cutoffs in LST distributions were sufficient to distinguish highly rearranged BLCs with 85% of proven BRCA1-inactivated cases from less rearranged BLCs devoid of proven BRCA1-inactivated cases. The genomic signature we defined was validated in a second independent series of 55 primary BLC cases and 17 BLC-derived tumor cell lines. High numbers of LSTs resembling BRCA1-inactivated BLC were observed in 4 primary BLC cases and 2 BLC cell lines that harbored BRCA2 mutations. Overall, the genomic signature we defined predicted BRCA1/2 inactivation in BLCs with 100% sensitivity and 90% specificity (97% accuracy). This assay may ease the challenge of selecting patients for genetic testing or recruitment to clinical trials of novel emerging therapies that target DNA repair deficiencies in cancer.</description><identifier>ISSN: 0008-5472</identifier><identifier>EISSN: 1538-7445</identifier><identifier>DOI: 10.1158/0008-5472.CAN-12-1470</identifier><identifier>PMID: 22933060</identifier><identifier>CODEN: CNREA8</identifier><language>eng</language><publisher>Philadelphia, PA: American Association for Cancer Research</publisher><subject>Adenocarcinoma - genetics ; Adenocarcinoma - pathology ; Antineoplastic agents ; Biological and medical sciences ; Breast Neoplasms - genetics ; Breast Neoplasms - pathology ; Carcinoma, Ductal, Breast - genetics ; Carcinoma, Ductal, Breast - pathology ; Female ; Fluorescent Antibody Technique ; Genes, BRCA1 ; Genes, BRCA2 ; Genetic Testing - methods ; Genomic Instability ; Gynecology. Andrology. Obstetrics ; Humans ; Mammary gland diseases ; Medical sciences ; Pharmacology. Drug treatments ; Ploidies ; Polymerase Chain Reaction ; Polymorphism, Single Nucleotide ; Sensitivity and Specificity ; Tumors</subject><ispartof>Cancer research (Chicago, Ill.), 2012-11, Vol.72 (21), p.5454-5462</ispartof><rights>2015 INIST-CNRS</rights><rights>2012 AACR.</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c523t-cc90f72f07ff7878fdb145e69af5dd582877141764c5cd7a6eb9b88a1008df103</citedby><cites>FETCH-LOGICAL-c523t-cc90f72f07ff7878fdb145e69af5dd582877141764c5cd7a6eb9b88a1008df103</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>314,776,780,3343,27901,27902</link.rule.ids><backlink>$$Uhttp://pascal-francis.inist.fr/vibad/index.php?action=getRecordDetail&idt=26598001$$DView record in Pascal Francis$$Hfree_for_read</backlink><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/22933060$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>POPOVA, Tatiana</creatorcontrib><creatorcontrib>MANIE, Elodie</creatorcontrib><creatorcontrib>HOUDAYE, Claude</creatorcontrib><creatorcontrib>SASTRE-GARAU, Xavier</creatorcontrib><creatorcontrib>VINCENT-SALOMON, Anne</creatorcontrib><creatorcontrib>STOPPA-LYONNET, Dominique</creatorcontrib><creatorcontrib>STERN, Marc-Henri</creatorcontrib><creatorcontrib>RIEUNIER, Guillaume</creatorcontrib><creatorcontrib>CAUX-MONCOUTIER, Virginie</creatorcontrib><creatorcontrib>TIRAPO, Carole</creatorcontrib><creatorcontrib>DUBOIS, Thierry</creatorcontrib><creatorcontrib>DELATTRE, Olivier</creatorcontrib><creatorcontrib>SIGAL-ZAFRANI, Brigitte</creatorcontrib><creatorcontrib>BOLLET, Marc</creatorcontrib><creatorcontrib>LONGY, Michel</creatorcontrib><title>Ploidy and Large-Scale Genomic Instability Consistently Identify Basal-like Breast Carcinomas with BRCA1/2 Inactivation</title><title>Cancer research (Chicago, Ill.)</title><addtitle>Cancer Res</addtitle><description>BRCA1 inactivation is a frequent event in basal-like breast carcinomas (BLC). However, BRCA1 can be inactivated by multiple mechanisms and determining its status is not a trivial issue. As an alternate approach, we profiled 65 BLC cases using single-nucleotide polymorphism arrays to define a signature of BRCA1-associated genomic instability. Large-scale state transitions (LST), defined as chromosomal break between adjacent regions of at least 10 Mb, were found to be a robust indicator of BRCA1 status in this setting. Two major ploidy-specific cutoffs in LST distributions were sufficient to distinguish highly rearranged BLCs with 85% of proven BRCA1-inactivated cases from less rearranged BLCs devoid of proven BRCA1-inactivated cases. The genomic signature we defined was validated in a second independent series of 55 primary BLC cases and 17 BLC-derived tumor cell lines. High numbers of LSTs resembling BRCA1-inactivated BLC were observed in 4 primary BLC cases and 2 BLC cell lines that harbored BRCA2 mutations. Overall, the genomic signature we defined predicted BRCA1/2 inactivation in BLCs with 100% sensitivity and 90% specificity (97% accuracy). This assay may ease the challenge of selecting patients for genetic testing or recruitment to clinical trials of novel emerging therapies that target DNA repair deficiencies in cancer.</description><subject>Adenocarcinoma - genetics</subject><subject>Adenocarcinoma - pathology</subject><subject>Antineoplastic agents</subject><subject>Biological and medical sciences</subject><subject>Breast Neoplasms - genetics</subject><subject>Breast Neoplasms - pathology</subject><subject>Carcinoma, Ductal, Breast - genetics</subject><subject>Carcinoma, Ductal, Breast - pathology</subject><subject>Female</subject><subject>Fluorescent Antibody Technique</subject><subject>Genes, BRCA1</subject><subject>Genes, BRCA2</subject><subject>Genetic Testing - methods</subject><subject>Genomic Instability</subject><subject>Gynecology. Andrology. Obstetrics</subject><subject>Humans</subject><subject>Mammary gland diseases</subject><subject>Medical sciences</subject><subject>Pharmacology. Drug treatments</subject><subject>Ploidies</subject><subject>Polymerase Chain Reaction</subject><subject>Polymorphism, Single Nucleotide</subject><subject>Sensitivity and Specificity</subject><subject>Tumors</subject><issn>0008-5472</issn><issn>1538-7445</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2012</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNqFkc1u1DAURi1ERYfCI4C8QWLj1nbs2FnORKUdaUSrAmvrxj9gyCQl9lDl7XHUaVmyurrS-T7L9yD0jtFzxqS-oJRqIoXi5-36M2GcMKHoC7RistJECSFfotUzc4pep_SzrJJR-Qqdct5UFa3pCj3c9mN0M4bB4R1M3z35YqH3-MoP4z5avB1Shi72Mc-4HYcUU_ZD7me8dWXGMOMNJOhJH395vJk8pIxbmGwscUj4IeYfeHPXrtkFL11gc_wDOY7DG3QSoE_-7XGeoW-fLr-212R3c7Vt1ztiJa8ysbahQfFAVQhKKx1cx4T0dQNBOic110oxwVQtrLROQe27ptMaWPm5C4xWZ-jjY-_9NP4--JTNPibr-x4GPx6SYbKutRBCyf-jjNf1UtwUVD6idhpTmnww91PcwzQbRs2ixyynN8vpTdFjGDeLnpJ7f3zi0O29e049-SjAhyMAqXgIEww2pn9cLRtNKav-AnYzl68</recordid><startdate>20121101</startdate><enddate>20121101</enddate><creator>POPOVA, Tatiana</creator><creator>MANIE, Elodie</creator><creator>HOUDAYE, Claude</creator><creator>SASTRE-GARAU, Xavier</creator><creator>VINCENT-SALOMON, Anne</creator><creator>STOPPA-LYONNET, Dominique</creator><creator>STERN, Marc-Henri</creator><creator>RIEUNIER, Guillaume</creator><creator>CAUX-MONCOUTIER, Virginie</creator><creator>TIRAPO, Carole</creator><creator>DUBOIS, Thierry</creator><creator>DELATTRE, Olivier</creator><creator>SIGAL-ZAFRANI, Brigitte</creator><creator>BOLLET, Marc</creator><creator>LONGY, Michel</creator><general>American Association for Cancer Research</general><scope>IQODW</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>8FD</scope><scope>FR3</scope><scope>P64</scope><scope>RC3</scope></search><sort><creationdate>20121101</creationdate><title>Ploidy and Large-Scale Genomic Instability Consistently Identify Basal-like Breast Carcinomas with BRCA1/2 Inactivation</title><author>POPOVA, Tatiana ; MANIE, Elodie ; HOUDAYE, Claude ; SASTRE-GARAU, Xavier ; VINCENT-SALOMON, Anne ; STOPPA-LYONNET, Dominique ; STERN, Marc-Henri ; RIEUNIER, Guillaume ; CAUX-MONCOUTIER, Virginie ; TIRAPO, Carole ; DUBOIS, Thierry ; DELATTRE, Olivier ; SIGAL-ZAFRANI, Brigitte ; BOLLET, Marc ; LONGY, Michel</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c523t-cc90f72f07ff7878fdb145e69af5dd582877141764c5cd7a6eb9b88a1008df103</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2012</creationdate><topic>Adenocarcinoma - genetics</topic><topic>Adenocarcinoma - pathology</topic><topic>Antineoplastic agents</topic><topic>Biological and medical sciences</topic><topic>Breast Neoplasms - genetics</topic><topic>Breast Neoplasms - pathology</topic><topic>Carcinoma, Ductal, Breast - genetics</topic><topic>Carcinoma, Ductal, Breast - pathology</topic><topic>Female</topic><topic>Fluorescent Antibody Technique</topic><topic>Genes, BRCA1</topic><topic>Genes, BRCA2</topic><topic>Genetic Testing - methods</topic><topic>Genomic Instability</topic><topic>Gynecology. Andrology. Obstetrics</topic><topic>Humans</topic><topic>Mammary gland diseases</topic><topic>Medical sciences</topic><topic>Pharmacology. Drug treatments</topic><topic>Ploidies</topic><topic>Polymerase Chain Reaction</topic><topic>Polymorphism, Single Nucleotide</topic><topic>Sensitivity and Specificity</topic><topic>Tumors</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>POPOVA, Tatiana</creatorcontrib><creatorcontrib>MANIE, Elodie</creatorcontrib><creatorcontrib>HOUDAYE, Claude</creatorcontrib><creatorcontrib>SASTRE-GARAU, Xavier</creatorcontrib><creatorcontrib>VINCENT-SALOMON, Anne</creatorcontrib><creatorcontrib>STOPPA-LYONNET, Dominique</creatorcontrib><creatorcontrib>STERN, Marc-Henri</creatorcontrib><creatorcontrib>RIEUNIER, Guillaume</creatorcontrib><creatorcontrib>CAUX-MONCOUTIER, Virginie</creatorcontrib><creatorcontrib>TIRAPO, Carole</creatorcontrib><creatorcontrib>DUBOIS, Thierry</creatorcontrib><creatorcontrib>DELATTRE, Olivier</creatorcontrib><creatorcontrib>SIGAL-ZAFRANI, Brigitte</creatorcontrib><creatorcontrib>BOLLET, Marc</creatorcontrib><creatorcontrib>LONGY, Michel</creatorcontrib><collection>Pascal-Francis</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>Technology Research Database</collection><collection>Engineering Research Database</collection><collection>Biotechnology and BioEngineering Abstracts</collection><collection>Genetics Abstracts</collection><jtitle>Cancer research (Chicago, Ill.)</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>POPOVA, Tatiana</au><au>MANIE, Elodie</au><au>HOUDAYE, Claude</au><au>SASTRE-GARAU, Xavier</au><au>VINCENT-SALOMON, Anne</au><au>STOPPA-LYONNET, Dominique</au><au>STERN, Marc-Henri</au><au>RIEUNIER, Guillaume</au><au>CAUX-MONCOUTIER, Virginie</au><au>TIRAPO, Carole</au><au>DUBOIS, Thierry</au><au>DELATTRE, Olivier</au><au>SIGAL-ZAFRANI, Brigitte</au><au>BOLLET, Marc</au><au>LONGY, Michel</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Ploidy and Large-Scale Genomic Instability Consistently Identify Basal-like Breast Carcinomas with BRCA1/2 Inactivation</atitle><jtitle>Cancer research (Chicago, Ill.)</jtitle><addtitle>Cancer Res</addtitle><date>2012-11-01</date><risdate>2012</risdate><volume>72</volume><issue>21</issue><spage>5454</spage><epage>5462</epage><pages>5454-5462</pages><issn>0008-5472</issn><eissn>1538-7445</eissn><coden>CNREA8</coden><abstract>BRCA1 inactivation is a frequent event in basal-like breast carcinomas (BLC). However, BRCA1 can be inactivated by multiple mechanisms and determining its status is not a trivial issue. As an alternate approach, we profiled 65 BLC cases using single-nucleotide polymorphism arrays to define a signature of BRCA1-associated genomic instability. Large-scale state transitions (LST), defined as chromosomal break between adjacent regions of at least 10 Mb, were found to be a robust indicator of BRCA1 status in this setting. Two major ploidy-specific cutoffs in LST distributions were sufficient to distinguish highly rearranged BLCs with 85% of proven BRCA1-inactivated cases from less rearranged BLCs devoid of proven BRCA1-inactivated cases. The genomic signature we defined was validated in a second independent series of 55 primary BLC cases and 17 BLC-derived tumor cell lines. High numbers of LSTs resembling BRCA1-inactivated BLC were observed in 4 primary BLC cases and 2 BLC cell lines that harbored BRCA2 mutations. Overall, the genomic signature we defined predicted BRCA1/2 inactivation in BLCs with 100% sensitivity and 90% specificity (97% accuracy). This assay may ease the challenge of selecting patients for genetic testing or recruitment to clinical trials of novel emerging therapies that target DNA repair deficiencies in cancer.</abstract><cop>Philadelphia, PA</cop><pub>American Association for Cancer Research</pub><pmid>22933060</pmid><doi>10.1158/0008-5472.CAN-12-1470</doi><tpages>9</tpages><oa>free_for_read</oa></addata></record> |
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| source | MEDLINE; American Association for Cancer Research; Elektronische Zeitschriftenbibliothek - Frei zugängliche E-Journals |
| subjects | Adenocarcinoma - genetics Adenocarcinoma - pathology Antineoplastic agents Biological and medical sciences Breast Neoplasms - genetics Breast Neoplasms - pathology Carcinoma, Ductal, Breast - genetics Carcinoma, Ductal, Breast - pathology Female Fluorescent Antibody Technique Genes, BRCA1 Genes, BRCA2 Genetic Testing - methods Genomic Instability Gynecology. Andrology. Obstetrics Humans Mammary gland diseases Medical sciences Pharmacology. Drug treatments Ploidies Polymerase Chain Reaction Polymorphism, Single Nucleotide Sensitivity and Specificity Tumors |
| title | Ploidy and Large-Scale Genomic Instability Consistently Identify Basal-like Breast Carcinomas with BRCA1/2 Inactivation |
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