Optimizing the identification of risk‐relevant mutations by multigene panel testing in selected hereditary breast/ovarian cancer families
The introduction of multigene panel testing for hereditary breast/ovarian cancer screening has greatly improved efficiency, speed, and costs. However, its clinical utility is still debated, mostly due to the lack of conclusive evidences on the impact of newly discovered genetic variants on cancer ri...
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| Veröffentlicht in: | Cancer medicine (Malden, MA) MA), 2018-01, Vol.7 (1), p.46-55 |
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| creator | Coppa, Anna Nicolussi, Arianna D'Inzeo, Sonia Capalbo, Carlo Belardinilli, Francesca Colicchia, Valeria Petroni, Marialaura Zani, Massimo Ferraro, Sergio Rinaldi, Christian Buffone, Amelia Bartolazzi, Armando Screpanti, Isabella Ottini, Laura Giannini, Giuseppe |
| description | The introduction of multigene panel testing for hereditary breast/ovarian cancer screening has greatly improved efficiency, speed, and costs. However, its clinical utility is still debated, mostly due to the lack of conclusive evidences on the impact of newly discovered genetic variants on cancer risk and lack of evidence‐based guidelines for the clinical management of their carriers. In this pilot study, we aimed to test whether a systematic and multiparametric characterization of newly discovered mutations could enhance the clinical utility of multigene panel sequencing. Out of a pool of 367 breast/ovarian cancer families Sanger‐sequenced for BRCA1 and BRCA2 gene mutations, we selected a cohort of 20 BRCA1/2‐negative families to be subjected to the BROCA‐Cancer Risk Panel massive parallel sequencing. As a strategy for the systematic characterization of newly discovered genetic variants, we collected blood and cancer tissue samples and established lymphoblastoid cell lines from all available individuals in these families, to perform segregation analysis, loss‐of‐heterozygosity and further molecular studies. We identified loss‐of‐function mutations in 6 out 20 high‐risk families, 5 of which occurred on BRCA1, CHEK2 and ATM and are esteemed to be risk‐relevant. In contrast, a novel RAD50 truncating mutation is most likely unrelated to breast cancer. Our data suggest that integrating multigene panel testing with a pre‐organized, multiparametric characterization of newly discovered genetic variants improves the identification of risk‐relevant alleles impacting on the clinical management of their carriers.
Multigene panel sequencing for the diagnosis of hereditary breast/ovarian cancer syndromes is raising concerns due to the absence of univocal interpretation of the cancer risk conferred by non‐BRCA1/2 mutations. Integrating these technologies with a systematic and multiparametric characterization of newly discovered genetic variants improves the identification of risk‐relevant alleles enhancing their clinical utility. |
| doi_str_mv | 10.1002/cam4.1251 |
| format | Article |
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Multigene panel sequencing for the diagnosis of hereditary breast/ovarian cancer syndromes is raising concerns due to the absence of univocal interpretation of the cancer risk conferred by non‐BRCA1/2 mutations. Integrating these technologies with a systematic and multiparametric characterization of newly discovered genetic variants improves the identification of risk‐relevant alleles enhancing their clinical utility.</description><identifier>ISSN: 2045-7634</identifier><identifier>EISSN: 2045-7634</identifier><identifier>DOI: 10.1002/cam4.1251</identifier><identifier>PMID: 29271107</identifier><language>eng</language><publisher>United States: John Wiley & Sons, Inc</publisher><subject>Acid Anhydride Hydrolases ; Adult ; Ataxia Telangiectasia Mutated Proteins - genetics ; ATM ; BRCA1 protein ; BRCA1 Protein - genetics ; BRCA2 protein ; BRCA2 Protein - genetics ; BRCAPro5 ; Breast cancer ; Cancer screening ; Checkpoint Kinase 2 - genetics ; CHEK2 ; Clinical Cancer Research ; Cohort Studies ; DNA Mutational Analysis - methods ; DNA Repair Enzymes - genetics ; DNA-Binding Proteins - genetics ; Female ; Genetic diversity ; Genetic Predisposition to Disease ; Genetic Testing - methods ; Hereditary Breast and Ovarian Cancer Syndrome - genetics ; hereditary breast cancer ; Heterozygosity ; High-Throughput Nucleotide Sequencing - methods ; Humans ; Loss of Function Mutation ; Lymphoblastoid cell lines ; Medical screening ; Middle Aged ; Mutation ; NGS ; Original Research ; Ovarian cancer ; Pilot Projects</subject><ispartof>Cancer medicine (Malden, MA), 2018-01, Vol.7 (1), p.46-55</ispartof><rights>2017 The Authors. published by John Wiley & Sons Ltd.</rights><rights>2017 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.</rights><rights>2018. 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-c5091-dbff3f3801d25462e97dbae9c6f5a8865769f44d9da487e51950b73bb7f1395a3</citedby><cites>FETCH-LOGICAL-c5091-dbff3f3801d25462e97dbae9c6f5a8865769f44d9da487e51950b73bb7f1395a3</cites><orcidid>0000-0003-0299-4056</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/PMC5773970/pdf/$$EPDF$$P50$$Gpubmedcentral$$Hfree_for_read</linktopdf><linktohtml>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC5773970/$$EHTML$$P50$$Gpubmedcentral$$Hfree_for_read</linktohtml><link.rule.ids>230,314,723,776,780,860,881,1411,11541,27901,27902,45550,45551,46027,46451,53766,53768</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/29271107$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Coppa, Anna</creatorcontrib><creatorcontrib>Nicolussi, Arianna</creatorcontrib><creatorcontrib>D'Inzeo, Sonia</creatorcontrib><creatorcontrib>Capalbo, Carlo</creatorcontrib><creatorcontrib>Belardinilli, Francesca</creatorcontrib><creatorcontrib>Colicchia, Valeria</creatorcontrib><creatorcontrib>Petroni, Marialaura</creatorcontrib><creatorcontrib>Zani, Massimo</creatorcontrib><creatorcontrib>Ferraro, Sergio</creatorcontrib><creatorcontrib>Rinaldi, Christian</creatorcontrib><creatorcontrib>Buffone, Amelia</creatorcontrib><creatorcontrib>Bartolazzi, Armando</creatorcontrib><creatorcontrib>Screpanti, Isabella</creatorcontrib><creatorcontrib>Ottini, Laura</creatorcontrib><creatorcontrib>Giannini, Giuseppe</creatorcontrib><title>Optimizing the identification of risk‐relevant mutations by multigene panel testing in selected hereditary breast/ovarian cancer families</title><title>Cancer medicine (Malden, MA)</title><addtitle>Cancer Med</addtitle><description>The introduction of multigene panel testing for hereditary breast/ovarian cancer screening has greatly improved efficiency, speed, and costs. However, its clinical utility is still debated, mostly due to the lack of conclusive evidences on the impact of newly discovered genetic variants on cancer risk and lack of evidence‐based guidelines for the clinical management of their carriers. In this pilot study, we aimed to test whether a systematic and multiparametric characterization of newly discovered mutations could enhance the clinical utility of multigene panel sequencing. Out of a pool of 367 breast/ovarian cancer families Sanger‐sequenced for BRCA1 and BRCA2 gene mutations, we selected a cohort of 20 BRCA1/2‐negative families to be subjected to the BROCA‐Cancer Risk Panel massive parallel sequencing. As a strategy for the systematic characterization of newly discovered genetic variants, we collected blood and cancer tissue samples and established lymphoblastoid cell lines from all available individuals in these families, to perform segregation analysis, loss‐of‐heterozygosity and further molecular studies. We identified loss‐of‐function mutations in 6 out 20 high‐risk families, 5 of which occurred on BRCA1, CHEK2 and ATM and are esteemed to be risk‐relevant. In contrast, a novel RAD50 truncating mutation is most likely unrelated to breast cancer. Our data suggest that integrating multigene panel testing with a pre‐organized, multiparametric characterization of newly discovered genetic variants improves the identification of risk‐relevant alleles impacting on the clinical management of their carriers.
Multigene panel sequencing for the diagnosis of hereditary breast/ovarian cancer syndromes is raising concerns due to the absence of univocal interpretation of the cancer risk conferred by non‐BRCA1/2 mutations. Integrating these technologies with a systematic and multiparametric characterization of newly discovered genetic variants improves the identification of risk‐relevant alleles enhancing their clinical utility.</description><subject>Acid Anhydride Hydrolases</subject><subject>Adult</subject><subject>Ataxia Telangiectasia Mutated Proteins - genetics</subject><subject>ATM</subject><subject>BRCA1 protein</subject><subject>BRCA1 Protein - genetics</subject><subject>BRCA2 protein</subject><subject>BRCA2 Protein - genetics</subject><subject>BRCAPro5</subject><subject>Breast cancer</subject><subject>Cancer screening</subject><subject>Checkpoint Kinase 2 - genetics</subject><subject>CHEK2</subject><subject>Clinical Cancer Research</subject><subject>Cohort Studies</subject><subject>DNA Mutational Analysis - methods</subject><subject>DNA Repair Enzymes - genetics</subject><subject>DNA-Binding Proteins - genetics</subject><subject>Female</subject><subject>Genetic diversity</subject><subject>Genetic Predisposition to Disease</subject><subject>Genetic Testing - methods</subject><subject>Hereditary Breast and Ovarian Cancer Syndrome - genetics</subject><subject>hereditary breast cancer</subject><subject>Heterozygosity</subject><subject>High-Throughput Nucleotide Sequencing - methods</subject><subject>Humans</subject><subject>Loss of Function Mutation</subject><subject>Lymphoblastoid cell lines</subject><subject>Medical screening</subject><subject>Middle Aged</subject><subject>Mutation</subject><subject>NGS</subject><subject>Original Research</subject><subject>Ovarian cancer</subject><subject>Pilot Projects</subject><issn>2045-7634</issn><issn>2045-7634</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2018</creationdate><recordtype>article</recordtype><sourceid>24P</sourceid><sourceid>EIF</sourceid><sourceid>BENPR</sourceid><recordid>eNp1kc9u1DAQhyMEolXpgRdAlrjAYbt2EsfxBala8U8q6gXOlmOPd6ckzmI7i5YT9176jDwJTrdUBQlfbMufP83MryieM3rGKC2XRg_1GSs5e1Qcl7TmC9FU9eMH56PiNMYrmpegZSPY0-KolKVgjIrj4vpym3DAH-jXJG2AoAWf0KHRCUdPRkcCxq-_ft4E6GGnfSLDlG7fIun2-dInXIMHstUeepIgplmFnsT8wSSwZAMBLCYd9qQLoGNajjsdUHtitDcQiNMD9gjxWfHE6T7C6d1-Unx59_bz6sPi4vL9x9X5xcJwKtnCds5VrmopsyWvmxKksJ0GaRrHdds2XDTS1bWVVtetAM4kp52ouk44Vkmuq5PizcG7nboBrMkdB92rbcAhF6lGjervF48btR53igtRSUGz4NWdIIzfptyyGjAa6Ps8g3GKikkhZZNn32b05T_o1TgFn9vLVNu2QrJqFr4-UCaMMQZw98UwquaU1ZyymlPO7IuH1d-TfzLNwPIAfMce9v83qdX5p_pW-RvcorXb</recordid><startdate>201801</startdate><enddate>201801</enddate><creator>Coppa, Anna</creator><creator>Nicolussi, Arianna</creator><creator>D'Inzeo, Sonia</creator><creator>Capalbo, Carlo</creator><creator>Belardinilli, Francesca</creator><creator>Colicchia, Valeria</creator><creator>Petroni, Marialaura</creator><creator>Zani, Massimo</creator><creator>Ferraro, Sergio</creator><creator>Rinaldi, Christian</creator><creator>Buffone, Amelia</creator><creator>Bartolazzi, Armando</creator><creator>Screpanti, Isabella</creator><creator>Ottini, Laura</creator><creator>Giannini, Giuseppe</creator><general>John Wiley & Sons, Inc</general><general>John Wiley and Sons Inc</general><scope>24P</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>3V.</scope><scope>7X7</scope><scope>7XB</scope><scope>8FE</scope><scope>8FH</scope><scope>8FI</scope><scope>8FJ</scope><scope>8FK</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>FYUFA</scope><scope>GHDGH</scope><scope>GNUQQ</scope><scope>HCIFZ</scope><scope>K9.</scope><scope>LK8</scope><scope>M0S</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/0000-0003-0299-4056</orcidid></search><sort><creationdate>201801</creationdate><title>Optimizing the identification of risk‐relevant mutations by multigene panel testing in selected hereditary breast/ovarian cancer families</title><author>Coppa, Anna ; Nicolussi, Arianna ; D'Inzeo, Sonia ; Capalbo, Carlo ; Belardinilli, Francesca ; Colicchia, Valeria ; Petroni, Marialaura ; Zani, Massimo ; Ferraro, Sergio ; Rinaldi, Christian ; Buffone, Amelia ; Bartolazzi, Armando ; Screpanti, Isabella ; Ottini, Laura ; Giannini, Giuseppe</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c5091-dbff3f3801d25462e97dbae9c6f5a8865769f44d9da487e51950b73bb7f1395a3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2018</creationdate><topic>Acid Anhydride Hydrolases</topic><topic>Adult</topic><topic>Ataxia Telangiectasia Mutated Proteins - 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Academic</collection><collection>PubMed Central (Full Participant titles)</collection><jtitle>Cancer medicine (Malden, MA)</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Coppa, Anna</au><au>Nicolussi, Arianna</au><au>D'Inzeo, Sonia</au><au>Capalbo, Carlo</au><au>Belardinilli, Francesca</au><au>Colicchia, Valeria</au><au>Petroni, Marialaura</au><au>Zani, Massimo</au><au>Ferraro, Sergio</au><au>Rinaldi, Christian</au><au>Buffone, Amelia</au><au>Bartolazzi, Armando</au><au>Screpanti, Isabella</au><au>Ottini, Laura</au><au>Giannini, Giuseppe</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Optimizing the identification of risk‐relevant mutations by multigene panel testing in selected hereditary breast/ovarian cancer families</atitle><jtitle>Cancer medicine (Malden, MA)</jtitle><addtitle>Cancer Med</addtitle><date>2018-01</date><risdate>2018</risdate><volume>7</volume><issue>1</issue><spage>46</spage><epage>55</epage><pages>46-55</pages><issn>2045-7634</issn><eissn>2045-7634</eissn><abstract>The introduction of multigene panel testing for hereditary breast/ovarian cancer screening has greatly improved efficiency, speed, and costs. However, its clinical utility is still debated, mostly due to the lack of conclusive evidences on the impact of newly discovered genetic variants on cancer risk and lack of evidence‐based guidelines for the clinical management of their carriers. In this pilot study, we aimed to test whether a systematic and multiparametric characterization of newly discovered mutations could enhance the clinical utility of multigene panel sequencing. Out of a pool of 367 breast/ovarian cancer families Sanger‐sequenced for BRCA1 and BRCA2 gene mutations, we selected a cohort of 20 BRCA1/2‐negative families to be subjected to the BROCA‐Cancer Risk Panel massive parallel sequencing. As a strategy for the systematic characterization of newly discovered genetic variants, we collected blood and cancer tissue samples and established lymphoblastoid cell lines from all available individuals in these families, to perform segregation analysis, loss‐of‐heterozygosity and further molecular studies. We identified loss‐of‐function mutations in 6 out 20 high‐risk families, 5 of which occurred on BRCA1, CHEK2 and ATM and are esteemed to be risk‐relevant. In contrast, a novel RAD50 truncating mutation is most likely unrelated to breast cancer. Our data suggest that integrating multigene panel testing with a pre‐organized, multiparametric characterization of newly discovered genetic variants improves the identification of risk‐relevant alleles impacting on the clinical management of their carriers.
Multigene panel sequencing for the diagnosis of hereditary breast/ovarian cancer syndromes is raising concerns due to the absence of univocal interpretation of the cancer risk conferred by non‐BRCA1/2 mutations. Integrating these technologies with a systematic and multiparametric characterization of newly discovered genetic variants improves the identification of risk‐relevant alleles enhancing their clinical utility.</abstract><cop>United States</cop><pub>John Wiley & Sons, Inc</pub><pmid>29271107</pmid><doi>10.1002/cam4.1251</doi><tpages>10</tpages><orcidid>https://orcid.org/0000-0003-0299-4056</orcidid><oa>free_for_read</oa></addata></record> |
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| ispartof | Cancer medicine (Malden, MA), 2018-01, Vol.7 (1), p.46-55 |
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| source | MEDLINE; Wiley Online Library Open Access; DOAJ Directory of Open Access Journals; Wiley Online Library Journals Frontfile Complete; Elektronische Zeitschriftenbibliothek - Frei zugängliche E-Journals; PubMed Central |
| subjects | Acid Anhydride Hydrolases Adult Ataxia Telangiectasia Mutated Proteins - genetics ATM BRCA1 protein BRCA1 Protein - genetics BRCA2 protein BRCA2 Protein - genetics BRCAPro5 Breast cancer Cancer screening Checkpoint Kinase 2 - genetics CHEK2 Clinical Cancer Research Cohort Studies DNA Mutational Analysis - methods DNA Repair Enzymes - genetics DNA-Binding Proteins - genetics Female Genetic diversity Genetic Predisposition to Disease Genetic Testing - methods Hereditary Breast and Ovarian Cancer Syndrome - genetics hereditary breast cancer Heterozygosity High-Throughput Nucleotide Sequencing - methods Humans Loss of Function Mutation Lymphoblastoid cell lines Medical screening Middle Aged Mutation NGS Original Research Ovarian cancer Pilot Projects |
| title | Optimizing the identification of risk‐relevant mutations by multigene panel testing in selected hereditary breast/ovarian cancer families |
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