Dominant‐negative pathogenic variant BRIP1 c.1045G>C is a high‐risk allele for non‐mucinous epithelial ovarian cancer: A case‐control study
BRIP1 is a moderate susceptibility epithelial ovarian cancer (EOC) gene. Having identified the BRIP1 c.1045G>C missense variant in a number of families with EOC, we aimed to investigate the frequency of this and BRIP1.2392C>T pathogenic variant in patients with breast cancer (BC) and/or EOC. A...
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| Veröffentlicht in: | Clinical genetics 2022-01, Vol.101 (1), p.48-54 |
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| creator | Flaum, Nicola Veen, Elke M. Smith, Olivia Amico, Stephanie Newman, William G. Crosbie, Emma J. Edmondson, Richard Smith, Miriam J. Evans, D. Gareth |
| description | BRIP1 is a moderate susceptibility epithelial ovarian cancer (EOC) gene. Having identified the BRIP1 c.1045G>C missense variant in a number of families with EOC, we aimed to investigate the frequency of this and BRIP1.2392C>T pathogenic variant in patients with breast cancer (BC) and/or EOC. A case‐control study of 3767 cases and 2043 controls was undertaken investigating the presence of these variants using Sanger sequencing and gene panel data. Individuals with BC and/or EOC were grouped by family history. BRIP1 c.1045G>C was associated with increased risk of BC/EOC (OR = 37.7; 95% CI 5.3–444.2; P = 0.0001). The risk was highest for women with EOC (OR = 140.8; 95% CI 23.5–1723.0; P T was associated with smaller risks for BC/EOC (OR = 5.4; 95%CI 2.4–12.7; P = 0.0003), EOC (OR = 5.9; 95% CI 1.3–23.0; p = 0.0550) and BC (OR = 5.3; 95%CI 2.3–12.9; P = 0.0009). Our study highlights the importance of BRIP1 as an EOC susceptibility gene, especially in familial EOC. The variant BRIP1 c.1045G>C, rs149364097, is of particular interest as its dominant‐negative effect may confer a higher risk of EOC than that of the previously reported BRIP1 c.2392C>T nonsense variant. Dominant‐negative missense variants may confer higher risks than their loss‐of‐function counterparts. |
| doi_str_mv | 10.1111/cge.14068 |
| format | Article |
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Gareth</creator><creatorcontrib>Flaum, Nicola ; Veen, Elke M. ; Smith, Olivia ; Amico, Stephanie ; Newman, William G. ; Crosbie, Emma J. ; Edmondson, Richard ; Smith, Miriam J. ; Evans, D. Gareth</creatorcontrib><description>BRIP1 is a moderate susceptibility epithelial ovarian cancer (EOC) gene. Having identified the BRIP1 c.1045G>C missense variant in a number of families with EOC, we aimed to investigate the frequency of this and BRIP1.2392C>T pathogenic variant in patients with breast cancer (BC) and/or EOC. A case‐control study of 3767 cases and 2043 controls was undertaken investigating the presence of these variants using Sanger sequencing and gene panel data. Individuals with BC and/or EOC were grouped by family history. BRIP1 c.1045G>C was associated with increased risk of BC/EOC (OR = 37.7; 95% CI 5.3–444.2; P = 0.0001). The risk was highest for women with EOC (OR = 140.8; 95% CI 23.5–1723.0; P < 0.0001) and lower for BC (OR = 11.1; 95% CI 1.2–106.5; P = 0.1588). BRIP1 c.2392C>T was associated with smaller risks for BC/EOC (OR = 5.4; 95%CI 2.4–12.7; P = 0.0003), EOC (OR = 5.9; 95% CI 1.3–23.0; p = 0.0550) and BC (OR = 5.3; 95%CI 2.3–12.9; P = 0.0009). Our study highlights the importance of BRIP1 as an EOC susceptibility gene, especially in familial EOC. The variant BRIP1 c.1045G>C, rs149364097, is of particular interest as its dominant‐negative effect may confer a higher risk of EOC than that of the previously reported BRIP1 c.2392C>T nonsense variant. Dominant‐negative missense variants may confer higher risks than their loss‐of‐function counterparts.</description><identifier>ISSN: 0009-9163</identifier><identifier>EISSN: 1399-0004</identifier><identifier>DOI: 10.1111/cge.14068</identifier><identifier>PMID: 34585738</identifier><language>eng</language><publisher>Oxford, UK: Blackwell Publishing Ltd</publisher><subject>Aged ; Alleles ; Breast cancer ; BRIP1 ; Carcinoma, Ovarian Epithelial - diagnosis ; Carcinoma, Ovarian Epithelial - genetics ; Carcinoma, Ovarian Epithelial - therapy ; Case-Control Studies ; epithelial ovarian cancer ; familial cancer predisposition ; Fanconi Anemia Complementation Group Proteins - genetics ; Female ; Gene Frequency ; Genes, Dominant ; Genetic Association Studies ; Genetic Predisposition to Disease ; genetics ; Humans ; Middle Aged ; Ovarian cancer ; Ovarian Neoplasms - diagnosis ; Ovarian Neoplasms - genetics ; Ovarian Neoplasms - therapy ; RNA Helicases - genetics ; Sequence Analysis, DNA</subject><ispartof>Clinical genetics, 2022-01, Vol.101 (1), p.48-54</ispartof><rights>2021 The Authors. published by John Wiley & Sons Ltd.</rights><rights>2021 The Authors. Clinical Genetics published by John Wiley & Sons Ltd.</rights><rights>2021. This article 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><orcidid>0000-0002-3184-0817 ; 0000-0002-6098-9995 ; 0000-0001-8900-0645 ; 0000-0001-8618-2332</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://onlinelibrary.wiley.com/doi/pdf/10.1111%2Fcge.14068$$EPDF$$P50$$Gwiley$$Hfree_for_read</linktopdf><linktohtml>$$Uhttps://onlinelibrary.wiley.com/doi/full/10.1111%2Fcge.14068$$EHTML$$P50$$Gwiley$$Hfree_for_read</linktohtml><link.rule.ids>315,781,785,1418,27929,27930,45579,45580</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/34585738$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Flaum, Nicola</creatorcontrib><creatorcontrib>Veen, Elke M.</creatorcontrib><creatorcontrib>Smith, Olivia</creatorcontrib><creatorcontrib>Amico, Stephanie</creatorcontrib><creatorcontrib>Newman, William G.</creatorcontrib><creatorcontrib>Crosbie, Emma J.</creatorcontrib><creatorcontrib>Edmondson, Richard</creatorcontrib><creatorcontrib>Smith, Miriam J.</creatorcontrib><creatorcontrib>Evans, D. Gareth</creatorcontrib><title>Dominant‐negative pathogenic variant BRIP1 c.1045G>C is a high‐risk allele for non‐mucinous epithelial ovarian cancer: A case‐control study</title><title>Clinical genetics</title><addtitle>Clin Genet</addtitle><description>BRIP1 is a moderate susceptibility epithelial ovarian cancer (EOC) gene. Having identified the BRIP1 c.1045G>C missense variant in a number of families with EOC, we aimed to investigate the frequency of this and BRIP1.2392C>T pathogenic variant in patients with breast cancer (BC) and/or EOC. A case‐control study of 3767 cases and 2043 controls was undertaken investigating the presence of these variants using Sanger sequencing and gene panel data. Individuals with BC and/or EOC were grouped by family history. BRIP1 c.1045G>C was associated with increased risk of BC/EOC (OR = 37.7; 95% CI 5.3–444.2; P = 0.0001). The risk was highest for women with EOC (OR = 140.8; 95% CI 23.5–1723.0; P < 0.0001) and lower for BC (OR = 11.1; 95% CI 1.2–106.5; P = 0.1588). BRIP1 c.2392C>T was associated with smaller risks for BC/EOC (OR = 5.4; 95%CI 2.4–12.7; P = 0.0003), EOC (OR = 5.9; 95% CI 1.3–23.0; p = 0.0550) and BC (OR = 5.3; 95%CI 2.3–12.9; P = 0.0009). Our study highlights the importance of BRIP1 as an EOC susceptibility gene, especially in familial EOC. The variant BRIP1 c.1045G>C, rs149364097, is of particular interest as its dominant‐negative effect may confer a higher risk of EOC than that of the previously reported BRIP1 c.2392C>T nonsense variant. Dominant‐negative missense variants may confer higher risks than their loss‐of‐function counterparts.</description><subject>Aged</subject><subject>Alleles</subject><subject>Breast cancer</subject><subject>BRIP1</subject><subject>Carcinoma, Ovarian Epithelial - diagnosis</subject><subject>Carcinoma, Ovarian Epithelial - genetics</subject><subject>Carcinoma, Ovarian Epithelial - therapy</subject><subject>Case-Control Studies</subject><subject>epithelial ovarian cancer</subject><subject>familial cancer predisposition</subject><subject>Fanconi Anemia Complementation Group Proteins - genetics</subject><subject>Female</subject><subject>Gene Frequency</subject><subject>Genes, Dominant</subject><subject>Genetic Association Studies</subject><subject>Genetic Predisposition to Disease</subject><subject>genetics</subject><subject>Humans</subject><subject>Middle Aged</subject><subject>Ovarian cancer</subject><subject>Ovarian Neoplasms - diagnosis</subject><subject>Ovarian Neoplasms - genetics</subject><subject>Ovarian Neoplasms - therapy</subject><subject>RNA Helicases - genetics</subject><subject>Sequence Analysis, DNA</subject><issn>0009-9163</issn><issn>1399-0004</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2022</creationdate><recordtype>article</recordtype><sourceid>24P</sourceid><sourceid>WIN</sourceid><sourceid>EIF</sourceid><recordid>eNpdkc1u1DAQxy0EokvhwAsgS1y4ZGvHjh1zQCpLWSpVAqHeLccfuy6OHeykaG88AhJvyJNguoUDc5mv34xG8wfgOUZrXO1M7-waU8T6B2CFiRANQog-BKvqRCMwIyfgSSk3NSW8E4_BCaFd33HSr8DPd2n0UcX51_cf0e7U7G8tnNS8TzsbvYa3KvvahW8_X37CUK8xot32zQb6AhXc-92-zmVfvkAVgg0WupRhTLFWx0X7mJYC7eTnvQ1eBZiO66BWUdv8Gp7XqNgK6xTnnAIs82IOT8Ejp0Kxz-79Kbh-f3G9-dBcfdxebs6vmgkL2jfYmBZTwQzuuBGOoJYbRgRprXOOC9f1A9X9QAx1ROBBI8ycMmawjPW6c-QUvDqunXL6utgyy9EXbUNQ0da7ZdtxzklLEa_oy__Qm7TkWI-TLUMcMcp4W6kX99QyjNbIKftR5YP8--0KnB2Bbz7Yw78-RvKPjLLKKO9klJvtxV1AfgN7h5Mm</recordid><startdate>202201</startdate><enddate>202201</enddate><creator>Flaum, Nicola</creator><creator>Veen, Elke M.</creator><creator>Smith, Olivia</creator><creator>Amico, Stephanie</creator><creator>Newman, William G.</creator><creator>Crosbie, Emma J.</creator><creator>Edmondson, Richard</creator><creator>Smith, Miriam J.</creator><creator>Evans, D. Gareth</creator><general>Blackwell Publishing Ltd</general><scope>24P</scope><scope>WIN</scope><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>7TK</scope><scope>8FD</scope><scope>FR3</scope><scope>P64</scope><scope>RC3</scope><scope>7X8</scope><orcidid>https://orcid.org/0000-0002-3184-0817</orcidid><orcidid>https://orcid.org/0000-0002-6098-9995</orcidid><orcidid>https://orcid.org/0000-0001-8900-0645</orcidid><orcidid>https://orcid.org/0000-0001-8618-2332</orcidid></search><sort><creationdate>202201</creationdate><title>Dominant‐negative pathogenic variant BRIP1 c.1045G>C is a high‐risk allele for non‐mucinous epithelial ovarian cancer: A case‐control study</title><author>Flaum, Nicola ; Veen, Elke M. ; Smith, Olivia ; Amico, Stephanie ; Newman, William G. ; Crosbie, Emma J. ; Edmondson, Richard ; Smith, Miriam J. ; Evans, D. 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Gareth</creatorcontrib><collection>Wiley-Blackwell Open Access Titles</collection><collection>Wiley Free Content</collection><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>Neurosciences Abstracts</collection><collection>Technology Research Database</collection><collection>Engineering Research Database</collection><collection>Biotechnology and BioEngineering Abstracts</collection><collection>Genetics Abstracts</collection><collection>MEDLINE - Academic</collection><jtitle>Clinical genetics</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Flaum, Nicola</au><au>Veen, Elke M.</au><au>Smith, Olivia</au><au>Amico, Stephanie</au><au>Newman, William G.</au><au>Crosbie, Emma J.</au><au>Edmondson, Richard</au><au>Smith, Miriam J.</au><au>Evans, D. Gareth</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Dominant‐negative pathogenic variant BRIP1 c.1045G>C is a high‐risk allele for non‐mucinous epithelial ovarian cancer: A case‐control study</atitle><jtitle>Clinical genetics</jtitle><addtitle>Clin Genet</addtitle><date>2022-01</date><risdate>2022</risdate><volume>101</volume><issue>1</issue><spage>48</spage><epage>54</epage><pages>48-54</pages><issn>0009-9163</issn><eissn>1399-0004</eissn><abstract>BRIP1 is a moderate susceptibility epithelial ovarian cancer (EOC) gene. Having identified the BRIP1 c.1045G>C missense variant in a number of families with EOC, we aimed to investigate the frequency of this and BRIP1.2392C>T pathogenic variant in patients with breast cancer (BC) and/or EOC. A case‐control study of 3767 cases and 2043 controls was undertaken investigating the presence of these variants using Sanger sequencing and gene panel data. Individuals with BC and/or EOC were grouped by family history. BRIP1 c.1045G>C was associated with increased risk of BC/EOC (OR = 37.7; 95% CI 5.3–444.2; P = 0.0001). The risk was highest for women with EOC (OR = 140.8; 95% CI 23.5–1723.0; P < 0.0001) and lower for BC (OR = 11.1; 95% CI 1.2–106.5; P = 0.1588). BRIP1 c.2392C>T was associated with smaller risks for BC/EOC (OR = 5.4; 95%CI 2.4–12.7; P = 0.0003), EOC (OR = 5.9; 95% CI 1.3–23.0; p = 0.0550) and BC (OR = 5.3; 95%CI 2.3–12.9; P = 0.0009). Our study highlights the importance of BRIP1 as an EOC susceptibility gene, especially in familial EOC. The variant BRIP1 c.1045G>C, rs149364097, is of particular interest as its dominant‐negative effect may confer a higher risk of EOC than that of the previously reported BRIP1 c.2392C>T nonsense variant. Dominant‐negative missense variants may confer higher risks than their loss‐of‐function counterparts.</abstract><cop>Oxford, UK</cop><pub>Blackwell Publishing Ltd</pub><pmid>34585738</pmid><doi>10.1111/cge.14068</doi><tpages>7</tpages><orcidid>https://orcid.org/0000-0002-3184-0817</orcidid><orcidid>https://orcid.org/0000-0002-6098-9995</orcidid><orcidid>https://orcid.org/0000-0001-8900-0645</orcidid><orcidid>https://orcid.org/0000-0001-8618-2332</orcidid><oa>free_for_read</oa></addata></record> |
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| subjects | Aged Alleles Breast cancer BRIP1 Carcinoma, Ovarian Epithelial - diagnosis Carcinoma, Ovarian Epithelial - genetics Carcinoma, Ovarian Epithelial - therapy Case-Control Studies epithelial ovarian cancer familial cancer predisposition Fanconi Anemia Complementation Group Proteins - genetics Female Gene Frequency Genes, Dominant Genetic Association Studies Genetic Predisposition to Disease genetics Humans Middle Aged Ovarian cancer Ovarian Neoplasms - diagnosis Ovarian Neoplasms - genetics Ovarian Neoplasms - therapy RNA Helicases - genetics Sequence Analysis, DNA |
| title | Dominant‐negative pathogenic variant BRIP1 c.1045G>C is a high‐risk allele for non‐mucinous epithelial ovarian cancer: A case‐control study |
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