High frequency of allelic loss at the BRCA1 locus in ovarian cancers: clinicopathologic and molecular associations
BRCA1 dysfunction may occur by different mechanisms that are rarely evaluated concomitantly. We aimed to analyze BRCA1 germline mutations, loss of heterozygosity (LOH) and promoter methylation in unselected ovarian carcinomas in the context of their clinicopathologic characteristics and other molecu...
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| Veröffentlicht in: | Cancer genetics 2012-03, Vol.205 (3), p.94-100 |
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| creator | Rzepecka, Iwona K Szafron, Lukasz Stys, Agnieszka Bujko, Mateusz Plisiecka-Halasa, Joanna Madry, Radoslaw Osuch, Beata Markowska, Janina Bidzinski, Mariusz Kupryjanczyk, Jolanta |
| description | BRCA1 dysfunction may occur by different mechanisms that are rarely evaluated concomitantly. We aimed to analyze BRCA1 germline mutations, loss of heterozygosity (LOH) and promoter methylation in unselected ovarian carcinomas in the context of their clinicopathologic characteristics and other molecular changes. BRCA1 mutations were analyzed in 257 carcinomas using single-strand conformation polymorphism (SSCP), heteroduplex, and sequencing methods. LOH at the BRCA1 locus was screened for in 180 cancers. Methylation analysis was performed for 241 tumors using quantitative methylation specific PCR (qMSP). BRCA1 alterations, comprising germline mutations, allelic loss, and/or aberrant promoter methylation, were found in 77.6% (125/161) of ovarian carcinomas. Patients with germline mutations were younger than non-carriers ( P < 0.0001). Germline mutations and LOH were associated with advanced stages ( P = 0.009, P < 0.0001), high tumor grade ( P = 0.005, P |
| doi_str_mv | 10.1016/j.cancergen.2011.12.005 |
| format | Article |
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We aimed to analyze BRCA1 germline mutations, loss of heterozygosity (LOH) and promoter methylation in unselected ovarian carcinomas in the context of their clinicopathologic characteristics and other molecular changes. BRCA1 mutations were analyzed in 257 carcinomas using single-strand conformation polymorphism (SSCP), heteroduplex, and sequencing methods. LOH at the BRCA1 locus was screened for in 180 cancers. Methylation analysis was performed for 241 tumors using quantitative methylation specific PCR (qMSP). BRCA1 alterations, comprising germline mutations, allelic loss, and/or aberrant promoter methylation, were found in 77.6% (125/161) of ovarian carcinomas. Patients with germline mutations were younger than non-carriers ( P < 0.0001). Germline mutations and LOH were associated with advanced stages ( P = 0.009, P < 0.0001), high tumor grade ( P = 0.005, P < 0.0001), and TP53 mutations ( P = 0.003, P < 0.0001, for mutations and LOH, respectively). LOH was also associated with the serous histological type ( P = 0.004) and PIK3CA amplification ( P = 0.003). Aberrant promoter methylation was associated with LOH ( P = 0.017) and absence of germline mutations ( P = 0.037). The high frequency of LOH at the BRCA1 locus suggests that LOH may be an important mechanism of BRCA1 deficiency in ovarian carcinomas. Tumors with various BRCA1 alterations have a similar phenotype of high-grade, high-stage carcinomas with frequent TP53 mutations.</description><identifier>ISSN: 2210-7762</identifier><identifier>EISSN: 2210-7770</identifier><identifier>DOI: 10.1016/j.cancergen.2011.12.005</identifier><identifier>PMID: 22469508</identifier><language>eng</language><publisher>United States: Elsevier Inc</publisher><subject>Adolescent ; Adult ; Aged ; Aged, 80 and over ; Base Sequence ; BRCA1 germline mutations ; Class I Phosphatidylinositol 3-Kinases ; DNA Methylation ; Female ; Gene Amplification ; Genes, BRCA1 ; Germ-Line Mutation ; Hematology, Oncology and Palliative Medicine ; Humans ; Loss of Heterozygosity ; Medical Education ; methylation ; Middle Aged ; Ovarian Neoplasms - genetics ; Phosphatidylinositol 3-Kinases - genetics ; PIK3CA ; Polymorphism, Single Nucleotide ; Promoter Regions, Genetic ; Sequence Analysis, DNA ; TP53 ; Young Adult</subject><ispartof>Cancer genetics, 2012-03, Vol.205 (3), p.94-100</ispartof><rights>Elsevier Inc.</rights><rights>2012 Elsevier Inc.</rights><rights>Copyright © 2012 Elsevier Inc. All rights reserved.</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c458t-f36aead6edf311444e93c3733d669c5229fa3ca0d908f1a711dfde36cb76f7ab3</citedby><cites>FETCH-LOGICAL-c458t-f36aead6edf311444e93c3733d669c5229fa3ca0d908f1a711dfde36cb76f7ab3</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktohtml>$$Uhttps://www.sciencedirect.com/science/article/pii/S2210776212000026$$EHTML$$P50$$Gelsevier$$H</linktohtml><link.rule.ids>314,776,780,3537,27901,27902,65306</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/22469508$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Rzepecka, Iwona K</creatorcontrib><creatorcontrib>Szafron, Lukasz</creatorcontrib><creatorcontrib>Stys, Agnieszka</creatorcontrib><creatorcontrib>Bujko, Mateusz</creatorcontrib><creatorcontrib>Plisiecka-Halasa, Joanna</creatorcontrib><creatorcontrib>Madry, Radoslaw</creatorcontrib><creatorcontrib>Osuch, Beata</creatorcontrib><creatorcontrib>Markowska, Janina</creatorcontrib><creatorcontrib>Bidzinski, Mariusz</creatorcontrib><creatorcontrib>Kupryjanczyk, Jolanta</creatorcontrib><title>High frequency of allelic loss at the BRCA1 locus in ovarian cancers: clinicopathologic and molecular associations</title><title>Cancer genetics</title><addtitle>Cancer Genet</addtitle><description>BRCA1 dysfunction may occur by different mechanisms that are rarely evaluated concomitantly. We aimed to analyze BRCA1 germline mutations, loss of heterozygosity (LOH) and promoter methylation in unselected ovarian carcinomas in the context of their clinicopathologic characteristics and other molecular changes. BRCA1 mutations were analyzed in 257 carcinomas using single-strand conformation polymorphism (SSCP), heteroduplex, and sequencing methods. LOH at the BRCA1 locus was screened for in 180 cancers. Methylation analysis was performed for 241 tumors using quantitative methylation specific PCR (qMSP). BRCA1 alterations, comprising germline mutations, allelic loss, and/or aberrant promoter methylation, were found in 77.6% (125/161) of ovarian carcinomas. Patients with germline mutations were younger than non-carriers ( P < 0.0001). Germline mutations and LOH were associated with advanced stages ( P = 0.009, P < 0.0001), high tumor grade ( P = 0.005, P < 0.0001), and TP53 mutations ( P = 0.003, P < 0.0001, for mutations and LOH, respectively). LOH was also associated with the serous histological type ( P = 0.004) and PIK3CA amplification ( P = 0.003). Aberrant promoter methylation was associated with LOH ( P = 0.017) and absence of germline mutations ( P = 0.037). The high frequency of LOH at the BRCA1 locus suggests that LOH may be an important mechanism of BRCA1 deficiency in ovarian carcinomas. Tumors with various BRCA1 alterations have a similar phenotype of high-grade, high-stage carcinomas with frequent TP53 mutations.</description><subject>Adolescent</subject><subject>Adult</subject><subject>Aged</subject><subject>Aged, 80 and over</subject><subject>Base Sequence</subject><subject>BRCA1 germline mutations</subject><subject>Class I Phosphatidylinositol 3-Kinases</subject><subject>DNA Methylation</subject><subject>Female</subject><subject>Gene Amplification</subject><subject>Genes, BRCA1</subject><subject>Germ-Line Mutation</subject><subject>Hematology, Oncology and Palliative Medicine</subject><subject>Humans</subject><subject>Loss of Heterozygosity</subject><subject>Medical Education</subject><subject>methylation</subject><subject>Middle Aged</subject><subject>Ovarian Neoplasms - genetics</subject><subject>Phosphatidylinositol 3-Kinases - genetics</subject><subject>PIK3CA</subject><subject>Polymorphism, Single Nucleotide</subject><subject>Promoter Regions, Genetic</subject><subject>Sequence Analysis, DNA</subject><subject>TP53</subject><subject>Young Adult</subject><issn>2210-7762</issn><issn>2210-7770</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2012</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNqNkk1vEzEQhlcIRKvSvwC-wSWLPzbeLAekNKIfUqVKBc7WxB4nDo4d7N1K-fd4tSUHDqi--EPPzHjed6rqA6M1o0x-3tUagsa0wVBzyljNeE3p_FV1zjmjs7Zt6evTWfKz6jLnHS2rmdNFK95WZ5w3siuX8yrdus2W2IS_Bwz6SKIl4D16p4mPORPoSb9FcvW4WrLyoodMXCDxCZKDQKZ_5C9Eexecjgfot9HHTYmGYMg-etSDh0Qg56gd9C6G_K56Y8FnvHzeL6qf199-rG5n9w83d6vl_Uw380U_s0ICgpForGCsaRrshBatEEbKTs857ywIDdR0dGEZtIwZa1BIvW6lbWEtLqqPU95DiqW73Ku9yxq9h4BxyKqTDS-a8KaQn_5LFtUZZ0JyWdB2QnUq8iS06pDcHtKxQCMn1U6d3FGjO4pxVdwpke-fiwzrPZpT3F8vCrCcACyiPDlMKmtXTEHjEupemeheUOTrPzkmZ8D_wiPmXRxSKJorpnIJUN_HIRlnhPFxPkp_fwDjk7o3</recordid><startdate>20120301</startdate><enddate>20120301</enddate><creator>Rzepecka, Iwona K</creator><creator>Szafron, Lukasz</creator><creator>Stys, Agnieszka</creator><creator>Bujko, Mateusz</creator><creator>Plisiecka-Halasa, Joanna</creator><creator>Madry, Radoslaw</creator><creator>Osuch, Beata</creator><creator>Markowska, Janina</creator><creator>Bidzinski, Mariusz</creator><creator>Kupryjanczyk, Jolanta</creator><general>Elsevier Inc</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>7TO</scope><scope>8FD</scope><scope>FR3</scope><scope>H94</scope><scope>P64</scope><scope>RC3</scope><scope>7X8</scope></search><sort><creationdate>20120301</creationdate><title>High frequency of allelic loss at the BRCA1 locus in ovarian cancers: clinicopathologic and molecular associations</title><author>Rzepecka, Iwona K ; Szafron, Lukasz ; Stys, Agnieszka ; Bujko, Mateusz ; Plisiecka-Halasa, Joanna ; Madry, Radoslaw ; Osuch, Beata ; Markowska, Janina ; Bidzinski, Mariusz ; Kupryjanczyk, Jolanta</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c458t-f36aead6edf311444e93c3733d669c5229fa3ca0d908f1a711dfde36cb76f7ab3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2012</creationdate><topic>Adolescent</topic><topic>Adult</topic><topic>Aged</topic><topic>Aged, 80 and over</topic><topic>Base Sequence</topic><topic>BRCA1 germline mutations</topic><topic>Class I Phosphatidylinositol 3-Kinases</topic><topic>DNA Methylation</topic><topic>Female</topic><topic>Gene Amplification</topic><topic>Genes, BRCA1</topic><topic>Germ-Line Mutation</topic><topic>Hematology, Oncology and Palliative Medicine</topic><topic>Humans</topic><topic>Loss of Heterozygosity</topic><topic>Medical Education</topic><topic>methylation</topic><topic>Middle Aged</topic><topic>Ovarian Neoplasms - genetics</topic><topic>Phosphatidylinositol 3-Kinases - genetics</topic><topic>PIK3CA</topic><topic>Polymorphism, Single Nucleotide</topic><topic>Promoter Regions, Genetic</topic><topic>Sequence Analysis, DNA</topic><topic>TP53</topic><topic>Young Adult</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Rzepecka, Iwona K</creatorcontrib><creatorcontrib>Szafron, Lukasz</creatorcontrib><creatorcontrib>Stys, Agnieszka</creatorcontrib><creatorcontrib>Bujko, Mateusz</creatorcontrib><creatorcontrib>Plisiecka-Halasa, Joanna</creatorcontrib><creatorcontrib>Madry, Radoslaw</creatorcontrib><creatorcontrib>Osuch, Beata</creatorcontrib><creatorcontrib>Markowska, Janina</creatorcontrib><creatorcontrib>Bidzinski, Mariusz</creatorcontrib><creatorcontrib>Kupryjanczyk, Jolanta</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>Oncogenes and Growth Factors Abstracts</collection><collection>Technology Research Database</collection><collection>Engineering Research Database</collection><collection>AIDS and Cancer Research Abstracts</collection><collection>Biotechnology and BioEngineering Abstracts</collection><collection>Genetics Abstracts</collection><collection>MEDLINE - Academic</collection><jtitle>Cancer genetics</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Rzepecka, Iwona K</au><au>Szafron, Lukasz</au><au>Stys, Agnieszka</au><au>Bujko, Mateusz</au><au>Plisiecka-Halasa, Joanna</au><au>Madry, Radoslaw</au><au>Osuch, Beata</au><au>Markowska, Janina</au><au>Bidzinski, Mariusz</au><au>Kupryjanczyk, Jolanta</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>High frequency of allelic loss at the BRCA1 locus in ovarian cancers: clinicopathologic and molecular associations</atitle><jtitle>Cancer genetics</jtitle><addtitle>Cancer Genet</addtitle><date>2012-03-01</date><risdate>2012</risdate><volume>205</volume><issue>3</issue><spage>94</spage><epage>100</epage><pages>94-100</pages><issn>2210-7762</issn><eissn>2210-7770</eissn><abstract>BRCA1 dysfunction may occur by different mechanisms that are rarely evaluated concomitantly. We aimed to analyze BRCA1 germline mutations, loss of heterozygosity (LOH) and promoter methylation in unselected ovarian carcinomas in the context of their clinicopathologic characteristics and other molecular changes. BRCA1 mutations were analyzed in 257 carcinomas using single-strand conformation polymorphism (SSCP), heteroduplex, and sequencing methods. LOH at the BRCA1 locus was screened for in 180 cancers. Methylation analysis was performed for 241 tumors using quantitative methylation specific PCR (qMSP). BRCA1 alterations, comprising germline mutations, allelic loss, and/or aberrant promoter methylation, were found in 77.6% (125/161) of ovarian carcinomas. Patients with germline mutations were younger than non-carriers ( P < 0.0001). Germline mutations and LOH were associated with advanced stages ( P = 0.009, P < 0.0001), high tumor grade ( P = 0.005, P < 0.0001), and TP53 mutations ( P = 0.003, P < 0.0001, for mutations and LOH, respectively). LOH was also associated with the serous histological type ( P = 0.004) and PIK3CA amplification ( P = 0.003). Aberrant promoter methylation was associated with LOH ( P = 0.017) and absence of germline mutations ( P = 0.037). The high frequency of LOH at the BRCA1 locus suggests that LOH may be an important mechanism of BRCA1 deficiency in ovarian carcinomas. Tumors with various BRCA1 alterations have a similar phenotype of high-grade, high-stage carcinomas with frequent TP53 mutations.</abstract><cop>United States</cop><pub>Elsevier Inc</pub><pmid>22469508</pmid><doi>10.1016/j.cancergen.2011.12.005</doi><tpages>7</tpages></addata></record> |
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| subjects | Adolescent Adult Aged Aged, 80 and over Base Sequence BRCA1 germline mutations Class I Phosphatidylinositol 3-Kinases DNA Methylation Female Gene Amplification Genes, BRCA1 Germ-Line Mutation Hematology, Oncology and Palliative Medicine Humans Loss of Heterozygosity Medical Education methylation Middle Aged Ovarian Neoplasms - genetics Phosphatidylinositol 3-Kinases - genetics PIK3CA Polymorphism, Single Nucleotide Promoter Regions, Genetic Sequence Analysis, DNA TP53 Young Adult |
| title | High frequency of allelic loss at the BRCA1 locus in ovarian cancers: clinicopathologic and molecular associations |
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