Identification of Novel Somatic TP53 Mutations in Patients with High-Grade Serous Ovarian Cancer (HGSOC) Using Next-Generation Sequencing (NGS)
Somatic mutations in are a hallmark of high-grade serous ovarian cancer (HGSOC), although their prognostic and predictive value as markers is not well defined. Next-generation sequencing (NGS) can identify novel mutations with high sensitivity, that may be repurposed as potential druggable anti-canc...
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| Veröffentlicht in: | International journal of molecular sciences 2018-05, Vol.19 (5), p.1510 |
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| creator | Garziera, Marica Cecchin, Erika Canzonieri, Vincenzo Sorio, Roberto Giorda, Giorgio Scalone, Simona De Mattia, Elena Roncato, Rossana Gagno, Sara Poletto, Elena Romanato, Loredana Sartor, Franca Polesel, Jerry Toffoli, Giuseppe |
| description | Somatic mutations in
are a hallmark of high-grade serous ovarian cancer (HGSOC), although their prognostic and predictive value as markers is not well defined. Next-generation sequencing (NGS) can identify novel mutations with high sensitivity, that may be repurposed as potential druggable anti-cancer targets and aid in therapeutic decisions. Here, a commercial NGS cancer panel comprising 26 genes, including
, was used to identify new genetic markers of platinum resistance and patient prognosis in a retrospective set of patients diagnosed with epithelial ovarian cancer. Six novel
somatic mutations in untreated tumors from six distinct patients diagnosed with HGSOC were identified:
c.728_739delTGGGCGGCATGA (p.Met243_Met247del, in-frame insertion or deletion (INDEL);
c.795_809delGGGACGGAACAGCTT (p.Gly266_Phe270del, in-frame INDEL);
c.826_827GC>AT (p.Ala276Ile, missense);
c.1022insT (p.Arg342Profs*5, frameshift INDEL);
c.1180delT (p.Ter394Aspfs*28, frameshift INDEL); and
c.573insT (p.Gln192Serfs*17, frameshift INDEL). Novel
variants were validated by classical sequencing methods and their impact on protein expression in tumors explored by immunohistochemistry. Further insights into the potential functional effect of the mutations were obtained by different in silico approaches, bioinformatics tools, and structural modeling. This discovery of previously unreported
somatic mutations provides an opportunity to translate NGS technology into personalized medicine and identify new potential targets for therapeutic applications. |
| doi_str_mv | 10.3390/ijms19051510 |
| format | Article |
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are a hallmark of high-grade serous ovarian cancer (HGSOC), although their prognostic and predictive value as markers is not well defined. Next-generation sequencing (NGS) can identify novel mutations with high sensitivity, that may be repurposed as potential druggable anti-cancer targets and aid in therapeutic decisions. Here, a commercial NGS cancer panel comprising 26 genes, including
, was used to identify new genetic markers of platinum resistance and patient prognosis in a retrospective set of patients diagnosed with epithelial ovarian cancer. Six novel
somatic mutations in untreated tumors from six distinct patients diagnosed with HGSOC were identified:
c.728_739delTGGGCGGCATGA (p.Met243_Met247del, in-frame insertion or deletion (INDEL);
c.795_809delGGGACGGAACAGCTT (p.Gly266_Phe270del, in-frame INDEL);
c.826_827GC>AT (p.Ala276Ile, missense);
c.1022insT (p.Arg342Profs*5, frameshift INDEL);
c.1180delT (p.Ter394Aspfs*28, frameshift INDEL); and
c.573insT (p.Gln192Serfs*17, frameshift INDEL). Novel
variants were validated by classical sequencing methods and their impact on protein expression in tumors explored by immunohistochemistry. Further insights into the potential functional effect of the mutations were obtained by different in silico approaches, bioinformatics tools, and structural modeling. This discovery of previously unreported
somatic mutations provides an opportunity to translate NGS technology into personalized medicine and identify new potential targets for therapeutic applications.</description><identifier>ISSN: 1422-0067</identifier><identifier>ISSN: 1661-6596</identifier><identifier>EISSN: 1422-0067</identifier><identifier>DOI: 10.3390/ijms19051510</identifier><identifier>PMID: 29783665</identifier><language>eng</language><publisher>Switzerland: MDPI AG</publisher><subject>Aged ; Bioinformatics ; Case Report ; Female ; Frameshift Mutation ; Gene deletion ; Genetic markers ; Humans ; Immunohistochemistry ; INDEL Mutation ; Insertion ; Markers ; Middle Aged ; Mutation ; Neoplasms, Cystic, Mucinous, and Serous - genetics ; Neoplasms, Cystic, Mucinous, and Serous - pathology ; Ovarian cancer ; Ovarian Neoplasms - genetics ; Ovarian Neoplasms - pathology ; p53 Protein ; Patients ; Platinum ; Precision medicine ; Proteins ; Therapeutic applications ; Tumor Suppressor Protein p53 - chemistry ; Tumor Suppressor Protein p53 - genetics ; Tumor Suppressor Protein p53 - metabolism ; Tumors</subject><ispartof>International journal of molecular sciences, 2018-05, Vol.19 (5), p.1510</ispartof><rights>Copyright MDPI AG 2018</rights><rights>2018 by the authors. 2018</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c379t-903ae6caacf405abd9c3b0b0af131bffcfcafa0b0cf8f5fcdcdabfd23109ae803</citedby><cites>FETCH-LOGICAL-c379t-903ae6caacf405abd9c3b0b0af131bffcfcafa0b0cf8f5fcdcdabfd23109ae803</cites><orcidid>0000-0001-6902-210X ; 0000-0001-6010-0976 ; 0000-0001-9381-1520 ; 0000-0003-4948-8767 ; 0000-0002-4219-6182</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/PMC5983728/pdf/$$EPDF$$P50$$Gpubmedcentral$$Hfree_for_read</linktopdf><linktohtml>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC5983728/$$EHTML$$P50$$Gpubmedcentral$$Hfree_for_read</linktohtml><link.rule.ids>230,314,727,780,784,885,27924,27925,53791,53793</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/29783665$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Garziera, Marica</creatorcontrib><creatorcontrib>Cecchin, Erika</creatorcontrib><creatorcontrib>Canzonieri, Vincenzo</creatorcontrib><creatorcontrib>Sorio, Roberto</creatorcontrib><creatorcontrib>Giorda, Giorgio</creatorcontrib><creatorcontrib>Scalone, Simona</creatorcontrib><creatorcontrib>De Mattia, Elena</creatorcontrib><creatorcontrib>Roncato, Rossana</creatorcontrib><creatorcontrib>Gagno, Sara</creatorcontrib><creatorcontrib>Poletto, Elena</creatorcontrib><creatorcontrib>Romanato, Loredana</creatorcontrib><creatorcontrib>Sartor, Franca</creatorcontrib><creatorcontrib>Polesel, Jerry</creatorcontrib><creatorcontrib>Toffoli, Giuseppe</creatorcontrib><title>Identification of Novel Somatic TP53 Mutations in Patients with High-Grade Serous Ovarian Cancer (HGSOC) Using Next-Generation Sequencing (NGS)</title><title>International journal of molecular sciences</title><addtitle>Int J Mol Sci</addtitle><description>Somatic mutations in
are a hallmark of high-grade serous ovarian cancer (HGSOC), although their prognostic and predictive value as markers is not well defined. Next-generation sequencing (NGS) can identify novel mutations with high sensitivity, that may be repurposed as potential druggable anti-cancer targets and aid in therapeutic decisions. Here, a commercial NGS cancer panel comprising 26 genes, including
, was used to identify new genetic markers of platinum resistance and patient prognosis in a retrospective set of patients diagnosed with epithelial ovarian cancer. Six novel
somatic mutations in untreated tumors from six distinct patients diagnosed with HGSOC were identified:
c.728_739delTGGGCGGCATGA (p.Met243_Met247del, in-frame insertion or deletion (INDEL);
c.795_809delGGGACGGAACAGCTT (p.Gly266_Phe270del, in-frame INDEL);
c.826_827GC>AT (p.Ala276Ile, missense);
c.1022insT (p.Arg342Profs*5, frameshift INDEL);
c.1180delT (p.Ter394Aspfs*28, frameshift INDEL); and
c.573insT (p.Gln192Serfs*17, frameshift INDEL). Novel
variants were validated by classical sequencing methods and their impact on protein expression in tumors explored by immunohistochemistry. Further insights into the potential functional effect of the mutations were obtained by different in silico approaches, bioinformatics tools, and structural modeling. This discovery of previously unreported
somatic mutations provides an opportunity to translate NGS technology into personalized medicine and identify new potential targets for therapeutic applications.</description><subject>Aged</subject><subject>Bioinformatics</subject><subject>Case Report</subject><subject>Female</subject><subject>Frameshift Mutation</subject><subject>Gene deletion</subject><subject>Genetic markers</subject><subject>Humans</subject><subject>Immunohistochemistry</subject><subject>INDEL Mutation</subject><subject>Insertion</subject><subject>Markers</subject><subject>Middle Aged</subject><subject>Mutation</subject><subject>Neoplasms, Cystic, Mucinous, and Serous - genetics</subject><subject>Neoplasms, Cystic, Mucinous, and Serous - pathology</subject><subject>Ovarian cancer</subject><subject>Ovarian Neoplasms - genetics</subject><subject>Ovarian Neoplasms - pathology</subject><subject>p53 Protein</subject><subject>Patients</subject><subject>Platinum</subject><subject>Precision medicine</subject><subject>Proteins</subject><subject>Therapeutic applications</subject><subject>Tumor Suppressor Protein p53 - chemistry</subject><subject>Tumor Suppressor Protein p53 - genetics</subject><subject>Tumor Suppressor Protein p53 - metabolism</subject><subject>Tumors</subject><issn>1422-0067</issn><issn>1661-6596</issn><issn>1422-0067</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2018</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNpVUcFOGzEQtRAVUODGGVniEqRusdfxZn1BQlHZINEEaeFszXrtxFFig72btl_RX8Y0FIXTjOa9eW9GD6EzSr4zJsiVXa4jFYRTTskeOqLDPM8IKUb7O_0h-hrjkpCc5VwcoMNcjEpWFPwI_b1rteussQo66x32Bk_9Rq9w7ddpovDjA2f4Z9_9gyO2Dj-kNu1E_Mt2Czyx80VWBWg1rnXwfcSzDQQLDo_BKR3wYFLVs_ElforWzfFU_-6ySjsdtn61fum1U2_QYFrVlyfoi4FV1Kfv9Rg93f54HE-y-1l1N765zxQbiS4ThIEuFIAyQ8KhaYViDWkIGMpoY4wyCgykgTKl4Ua1qoXGtDmjRIAuCTtG11vd575Z61alhwKs5HOwawh_pAcrPyPOLuTcbyQXJRvlZRK4eBcIPr0QO7n0fXDpZpkTXgw5E5wl1rctSwUfY9Dmw4ES-Raf3I0v0c93r_og_8-LvQJnMJmA</recordid><startdate>20180518</startdate><enddate>20180518</enddate><creator>Garziera, Marica</creator><creator>Cecchin, Erika</creator><creator>Canzonieri, Vincenzo</creator><creator>Sorio, Roberto</creator><creator>Giorda, Giorgio</creator><creator>Scalone, Simona</creator><creator>De Mattia, Elena</creator><creator>Roncato, Rossana</creator><creator>Gagno, Sara</creator><creator>Poletto, Elena</creator><creator>Romanato, Loredana</creator><creator>Sartor, Franca</creator><creator>Polesel, Jerry</creator><creator>Toffoli, Giuseppe</creator><general>MDPI AG</general><general>MDPI</general><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>K9.</scope><scope>5PM</scope><orcidid>https://orcid.org/0000-0001-6902-210X</orcidid><orcidid>https://orcid.org/0000-0001-6010-0976</orcidid><orcidid>https://orcid.org/0000-0001-9381-1520</orcidid><orcidid>https://orcid.org/0000-0003-4948-8767</orcidid><orcidid>https://orcid.org/0000-0002-4219-6182</orcidid></search><sort><creationdate>20180518</creationdate><title>Identification of Novel Somatic TP53 Mutations in Patients with High-Grade Serous Ovarian Cancer (HGSOC) Using Next-Generation Sequencing (NGS)</title><author>Garziera, Marica ; Cecchin, Erika ; Canzonieri, Vincenzo ; Sorio, Roberto ; Giorda, Giorgio ; Scalone, Simona ; De Mattia, Elena ; Roncato, Rossana ; Gagno, Sara ; Poletto, Elena ; Romanato, Loredana ; Sartor, Franca ; Polesel, Jerry ; Toffoli, Giuseppe</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c379t-903ae6caacf405abd9c3b0b0af131bffcfcafa0b0cf8f5fcdcdabfd23109ae803</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2018</creationdate><topic>Aged</topic><topic>Bioinformatics</topic><topic>Case Report</topic><topic>Female</topic><topic>Frameshift Mutation</topic><topic>Gene deletion</topic><topic>Genetic markers</topic><topic>Humans</topic><topic>Immunohistochemistry</topic><topic>INDEL Mutation</topic><topic>Insertion</topic><topic>Markers</topic><topic>Middle Aged</topic><topic>Mutation</topic><topic>Neoplasms, Cystic, Mucinous, and Serous - genetics</topic><topic>Neoplasms, Cystic, Mucinous, and Serous - pathology</topic><topic>Ovarian cancer</topic><topic>Ovarian Neoplasms - genetics</topic><topic>Ovarian Neoplasms - pathology</topic><topic>p53 Protein</topic><topic>Patients</topic><topic>Platinum</topic><topic>Precision medicine</topic><topic>Proteins</topic><topic>Therapeutic applications</topic><topic>Tumor Suppressor Protein p53 - chemistry</topic><topic>Tumor Suppressor Protein p53 - genetics</topic><topic>Tumor Suppressor Protein p53 - metabolism</topic><topic>Tumors</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Garziera, Marica</creatorcontrib><creatorcontrib>Cecchin, Erika</creatorcontrib><creatorcontrib>Canzonieri, Vincenzo</creatorcontrib><creatorcontrib>Sorio, Roberto</creatorcontrib><creatorcontrib>Giorda, Giorgio</creatorcontrib><creatorcontrib>Scalone, Simona</creatorcontrib><creatorcontrib>De Mattia, Elena</creatorcontrib><creatorcontrib>Roncato, Rossana</creatorcontrib><creatorcontrib>Gagno, Sara</creatorcontrib><creatorcontrib>Poletto, Elena</creatorcontrib><creatorcontrib>Romanato, Loredana</creatorcontrib><creatorcontrib>Sartor, Franca</creatorcontrib><creatorcontrib>Polesel, Jerry</creatorcontrib><creatorcontrib>Toffoli, Giuseppe</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>ProQuest Health & Medical Complete (Alumni)</collection><collection>PubMed Central (Full Participant titles)</collection><jtitle>International journal of molecular sciences</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Garziera, Marica</au><au>Cecchin, Erika</au><au>Canzonieri, Vincenzo</au><au>Sorio, Roberto</au><au>Giorda, Giorgio</au><au>Scalone, Simona</au><au>De Mattia, Elena</au><au>Roncato, Rossana</au><au>Gagno, Sara</au><au>Poletto, Elena</au><au>Romanato, Loredana</au><au>Sartor, Franca</au><au>Polesel, Jerry</au><au>Toffoli, Giuseppe</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Identification of Novel Somatic TP53 Mutations in Patients with High-Grade Serous Ovarian Cancer (HGSOC) Using Next-Generation Sequencing (NGS)</atitle><jtitle>International journal of molecular sciences</jtitle><addtitle>Int J Mol Sci</addtitle><date>2018-05-18</date><risdate>2018</risdate><volume>19</volume><issue>5</issue><spage>1510</spage><pages>1510-</pages><issn>1422-0067</issn><issn>1661-6596</issn><eissn>1422-0067</eissn><abstract>Somatic mutations in
are a hallmark of high-grade serous ovarian cancer (HGSOC), although their prognostic and predictive value as markers is not well defined. Next-generation sequencing (NGS) can identify novel mutations with high sensitivity, that may be repurposed as potential druggable anti-cancer targets and aid in therapeutic decisions. Here, a commercial NGS cancer panel comprising 26 genes, including
, was used to identify new genetic markers of platinum resistance and patient prognosis in a retrospective set of patients diagnosed with epithelial ovarian cancer. Six novel
somatic mutations in untreated tumors from six distinct patients diagnosed with HGSOC were identified:
c.728_739delTGGGCGGCATGA (p.Met243_Met247del, in-frame insertion or deletion (INDEL);
c.795_809delGGGACGGAACAGCTT (p.Gly266_Phe270del, in-frame INDEL);
c.826_827GC>AT (p.Ala276Ile, missense);
c.1022insT (p.Arg342Profs*5, frameshift INDEL);
c.1180delT (p.Ter394Aspfs*28, frameshift INDEL); and
c.573insT (p.Gln192Serfs*17, frameshift INDEL). Novel
variants were validated by classical sequencing methods and their impact on protein expression in tumors explored by immunohistochemistry. Further insights into the potential functional effect of the mutations were obtained by different in silico approaches, bioinformatics tools, and structural modeling. This discovery of previously unreported
somatic mutations provides an opportunity to translate NGS technology into personalized medicine and identify new potential targets for therapeutic applications.</abstract><cop>Switzerland</cop><pub>MDPI AG</pub><pmid>29783665</pmid><doi>10.3390/ijms19051510</doi><orcidid>https://orcid.org/0000-0001-6902-210X</orcidid><orcidid>https://orcid.org/0000-0001-6010-0976</orcidid><orcidid>https://orcid.org/0000-0001-9381-1520</orcidid><orcidid>https://orcid.org/0000-0003-4948-8767</orcidid><orcidid>https://orcid.org/0000-0002-4219-6182</orcidid><oa>free_for_read</oa></addata></record> |
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| ispartof | International journal of molecular sciences, 2018-05, Vol.19 (5), p.1510 |
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| source | MEDLINE; MDPI - Multidisciplinary Digital Publishing Institute; EZB-FREE-00999 freely available EZB journals; PubMed Central |
| subjects | Aged Bioinformatics Case Report Female Frameshift Mutation Gene deletion Genetic markers Humans Immunohistochemistry INDEL Mutation Insertion Markers Middle Aged Mutation Neoplasms, Cystic, Mucinous, and Serous - genetics Neoplasms, Cystic, Mucinous, and Serous - pathology Ovarian cancer Ovarian Neoplasms - genetics Ovarian Neoplasms - pathology p53 Protein Patients Platinum Precision medicine Proteins Therapeutic applications Tumor Suppressor Protein p53 - chemistry Tumor Suppressor Protein p53 - genetics Tumor Suppressor Protein p53 - metabolism Tumors |
| title | Identification of Novel Somatic TP53 Mutations in Patients with High-Grade Serous Ovarian Cancer (HGSOC) Using Next-Generation Sequencing (NGS) |
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