Germline PIK3CA and AKT1 Mutations in Cowden and Cowden-like Syndromes
Cowden syndrome (CS) is a difficult-to-recognize multiple hamartoma syndrome with high risks of breast, thyroid, and other cancers. Germline mutations in PTEN on 10q23 were found to cause 85% of CS when accrued from tertiary academic centers, but prospective accrual from the community over the last...
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| Veröffentlicht in: | American journal of human genetics 2013-01, Vol.92 (1), p.76-80 |
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| creator | Orloff, Mohammed S. He, Xin Peterson, Charissa Chen, Fusong Chen, Jin-Lian Mester, Jessica L. Eng, Charis |
| description | Cowden syndrome (CS) is a difficult-to-recognize multiple hamartoma syndrome with high risks of breast, thyroid, and other cancers. Germline mutations in PTEN on 10q23 were found to cause 85% of CS when accrued from tertiary academic centers, but prospective accrual from the community over the last 12 years has revealed a 25% PTEN mutation frequency. PTEN is the phosphatase that has been implicated in a heritable cancer syndrome and subsequently in multiple sporadic cancers and developmental processes. PTEN antagonizes the AKT1/PI3K signaling pathway and has roles in cell cycle, migration, cell polarity, and apoptosis. We report that 8 of 91 (8.8%) unrelated CS individuals without germline PTEN mutations carried 10 germline PIK3CA mutations (7 missense, 1 nonsense, and 2 indels) and 2 (2.2%) AKT1 mutations. These mutations result in significantly increased P-Thr308-AKT and increased cellular PIP3. Our observations suggest that PIK3CA and AKT1 are CS susceptibility genes. |
| doi_str_mv | 10.1016/j.ajhg.2012.10.021 |
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Germline mutations in PTEN on 10q23 were found to cause 85% of CS when accrued from tertiary academic centers, but prospective accrual from the community over the last 12 years has revealed a 25% PTEN mutation frequency. PTEN is the phosphatase that has been implicated in a heritable cancer syndrome and subsequently in multiple sporadic cancers and developmental processes. PTEN antagonizes the AKT1/PI3K signaling pathway and has roles in cell cycle, migration, cell polarity, and apoptosis. We report that 8 of 91 (8.8%) unrelated CS individuals without germline PTEN mutations carried 10 germline PIK3CA mutations (7 missense, 1 nonsense, and 2 indels) and 2 (2.2%) AKT1 mutations. These mutations result in significantly increased P-Thr308-AKT and increased cellular PIP3. Our observations suggest that PIK3CA and AKT1 are CS susceptibility genes.</description><identifier>ISSN: 0002-9297</identifier><identifier>EISSN: 1537-6605</identifier><identifier>DOI: 10.1016/j.ajhg.2012.10.021</identifier><identifier>PMID: 23246288</identifier><language>eng</language><publisher>United States: Elsevier Inc</publisher><subject>1-Phosphatidylinositol 3-kinase ; AKT1 protein ; Apoptosis ; Cancer ; Cell cycle ; Cell migration ; Cellular biology ; Class I Phosphatidylinositol 3-Kinases ; Cowden syndrome ; Enzymes ; Genes ; Genetic disorders ; Genetic Predisposition to Disease ; Germ-Line Mutation ; Hamartoma Syndrome, Multiple - genetics ; Humans ; Mutation ; phosphatidylinositol 3,4,5-triphosphate ; Phosphatidylinositol 3-Kinases - genetics ; Polarity ; Proto-Oncogene Proteins c-akt - genetics ; PTEN Phosphohydrolase ; PTEN protein ; Risk factors ; Signal transduction ; Thyroid ; thyroid cancer</subject><ispartof>American journal of human genetics, 2013-01, Vol.92 (1), p.76-80</ispartof><rights>2013 The American Society of Human Genetics</rights><rights>Copyright © 2013 The American Society of Human Genetics. Published by Elsevier Inc. All rights reserved.</rights><rights>Copyright Cell Press Jan 10, 2013</rights><rights>2013 The American Society of Human Genetics. Published by Elsevier Ltd. All right reserved. 2013 The American Society of Human Genetics</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c582t-d452abeaec55d2e4cd171f59102f06743f046449c446e92544814d12967a3a473</citedby><cites>FETCH-LOGICAL-c582t-d452abeaec55d2e4cd171f59102f06743f046449c446e92544814d12967a3a473</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC3542473/pdf/$$EPDF$$P50$$Gpubmedcentral$$H</linktopdf><linktohtml>$$Uhttps://www.sciencedirect.com/science/article/pii/S0002929712005812$$EHTML$$P50$$Gelsevier$$Hfree_for_read</linktohtml><link.rule.ids>230,314,723,776,780,881,3537,27901,27902,53766,53768,65534</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/23246288$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Orloff, Mohammed S.</creatorcontrib><creatorcontrib>He, Xin</creatorcontrib><creatorcontrib>Peterson, Charissa</creatorcontrib><creatorcontrib>Chen, Fusong</creatorcontrib><creatorcontrib>Chen, Jin-Lian</creatorcontrib><creatorcontrib>Mester, Jessica L.</creatorcontrib><creatorcontrib>Eng, Charis</creatorcontrib><title>Germline PIK3CA and AKT1 Mutations in Cowden and Cowden-like Syndromes</title><title>American journal of human genetics</title><addtitle>Am J Hum Genet</addtitle><description>Cowden syndrome (CS) is a difficult-to-recognize multiple hamartoma syndrome with high risks of breast, thyroid, and other cancers. Germline mutations in PTEN on 10q23 were found to cause 85% of CS when accrued from tertiary academic centers, but prospective accrual from the community over the last 12 years has revealed a 25% PTEN mutation frequency. PTEN is the phosphatase that has been implicated in a heritable cancer syndrome and subsequently in multiple sporadic cancers and developmental processes. PTEN antagonizes the AKT1/PI3K signaling pathway and has roles in cell cycle, migration, cell polarity, and apoptosis. We report that 8 of 91 (8.8%) unrelated CS individuals without germline PTEN mutations carried 10 germline PIK3CA mutations (7 missense, 1 nonsense, and 2 indels) and 2 (2.2%) AKT1 mutations. These mutations result in significantly increased P-Thr308-AKT and increased cellular PIP3. Our observations suggest that PIK3CA and AKT1 are CS susceptibility genes.</description><subject>1-Phosphatidylinositol 3-kinase</subject><subject>AKT1 protein</subject><subject>Apoptosis</subject><subject>Cancer</subject><subject>Cell cycle</subject><subject>Cell migration</subject><subject>Cellular biology</subject><subject>Class I Phosphatidylinositol 3-Kinases</subject><subject>Cowden syndrome</subject><subject>Enzymes</subject><subject>Genes</subject><subject>Genetic disorders</subject><subject>Genetic Predisposition to Disease</subject><subject>Germ-Line Mutation</subject><subject>Hamartoma Syndrome, Multiple - genetics</subject><subject>Humans</subject><subject>Mutation</subject><subject>phosphatidylinositol 3,4,5-triphosphate</subject><subject>Phosphatidylinositol 3-Kinases - genetics</subject><subject>Polarity</subject><subject>Proto-Oncogene Proteins c-akt - genetics</subject><subject>PTEN Phosphohydrolase</subject><subject>PTEN protein</subject><subject>Risk factors</subject><subject>Signal transduction</subject><subject>Thyroid</subject><subject>thyroid cancer</subject><issn>0002-9297</issn><issn>1537-6605</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2013</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNqNUU1v1TAQtBCIPgp_gAOKxIVLHv5OLCGkp6e2VG0FEuVsufamdUjsYiet-u9xeKUCDhUnW7szs7szCL0meE0wke_7temvLtcUE1oKa0zJE7QigjW1lFg8RSuMMa0VVc0eepFzjzEhLWbP0R5llEvatit0eARpHHyA6svxCdtuKhNctTk5J9XZPJnJx5ArH6ptvHUQfjV333rw36H6ehdciiPkl-hZZ4YMr-7fffTt8OB8-6k-_Xx0vN2c1la0dKodF9RcgAErhKPArSMN6YQimHZYNpx1mEvOleVcgqKC85ZwR6iSjWGGN2wffdzpXs8XIzgLYUpm0NfJjybd6Wi8_rsT_JW-jDeaCU4Lvwi8uxdI8ccMedKjzxaGwQSIc9aEtmIxV9D_gDaMK9WKZa23_0D7OKdQnCgoqUijOFtm0x3Kpphzgu5hb4L1MlT3eklUL4kutZJoIb358-IHyu8IC-DDDgDF9xsPSWfrIVhwPoGdtIv-Mf2feu6uew</recordid><startdate>20130110</startdate><enddate>20130110</enddate><creator>Orloff, Mohammed S.</creator><creator>He, Xin</creator><creator>Peterson, Charissa</creator><creator>Chen, Fusong</creator><creator>Chen, Jin-Lian</creator><creator>Mester, Jessica L.</creator><creator>Eng, Charis</creator><general>Elsevier Inc</general><general>Cell Press</general><general>Elsevier</general><scope>6I.</scope><scope>AAFTH</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>7QP</scope><scope>7TK</scope><scope>7TM</scope><scope>7U7</scope><scope>8FD</scope><scope>C1K</scope><scope>FR3</scope><scope>K9.</scope><scope>NAPCQ</scope><scope>P64</scope><scope>RC3</scope><scope>7X8</scope><scope>5PM</scope></search><sort><creationdate>20130110</creationdate><title>Germline PIK3CA and AKT1 Mutations in Cowden and Cowden-like Syndromes</title><author>Orloff, Mohammed S. ; He, Xin ; Peterson, Charissa ; Chen, Fusong ; Chen, Jin-Lian ; Mester, Jessica L. ; Eng, Charis</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c582t-d452abeaec55d2e4cd171f59102f06743f046449c446e92544814d12967a3a473</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2013</creationdate><topic>1-Phosphatidylinositol 3-kinase</topic><topic>AKT1 protein</topic><topic>Apoptosis</topic><topic>Cancer</topic><topic>Cell cycle</topic><topic>Cell migration</topic><topic>Cellular biology</topic><topic>Class I Phosphatidylinositol 3-Kinases</topic><topic>Cowden syndrome</topic><topic>Enzymes</topic><topic>Genes</topic><topic>Genetic disorders</topic><topic>Genetic Predisposition to Disease</topic><topic>Germ-Line Mutation</topic><topic>Hamartoma Syndrome, Multiple - genetics</topic><topic>Humans</topic><topic>Mutation</topic><topic>phosphatidylinositol 3,4,5-triphosphate</topic><topic>Phosphatidylinositol 3-Kinases - genetics</topic><topic>Polarity</topic><topic>Proto-Oncogene Proteins c-akt - genetics</topic><topic>PTEN Phosphohydrolase</topic><topic>PTEN protein</topic><topic>Risk factors</topic><topic>Signal transduction</topic><topic>Thyroid</topic><topic>thyroid cancer</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Orloff, Mohammed S.</creatorcontrib><creatorcontrib>He, Xin</creatorcontrib><creatorcontrib>Peterson, Charissa</creatorcontrib><creatorcontrib>Chen, Fusong</creatorcontrib><creatorcontrib>Chen, Jin-Lian</creatorcontrib><creatorcontrib>Mester, Jessica L.</creatorcontrib><creatorcontrib>Eng, Charis</creatorcontrib><collection>ScienceDirect Open Access Titles</collection><collection>Elsevier:ScienceDirect:Open Access</collection><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>Calcium & Calcified Tissue Abstracts</collection><collection>Neurosciences Abstracts</collection><collection>Nucleic Acids Abstracts</collection><collection>Toxicology Abstracts</collection><collection>Technology Research Database</collection><collection>Environmental Sciences and Pollution Management</collection><collection>Engineering Research Database</collection><collection>ProQuest Health & Medical Complete (Alumni)</collection><collection>Nursing & Allied Health Premium</collection><collection>Biotechnology and BioEngineering Abstracts</collection><collection>Genetics Abstracts</collection><collection>MEDLINE - Academic</collection><collection>PubMed Central (Full Participant titles)</collection><jtitle>American journal of human genetics</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Orloff, Mohammed S.</au><au>He, Xin</au><au>Peterson, Charissa</au><au>Chen, Fusong</au><au>Chen, Jin-Lian</au><au>Mester, Jessica L.</au><au>Eng, Charis</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Germline PIK3CA and AKT1 Mutations in Cowden and Cowden-like Syndromes</atitle><jtitle>American journal of human genetics</jtitle><addtitle>Am J Hum Genet</addtitle><date>2013-01-10</date><risdate>2013</risdate><volume>92</volume><issue>1</issue><spage>76</spage><epage>80</epage><pages>76-80</pages><issn>0002-9297</issn><eissn>1537-6605</eissn><abstract>Cowden syndrome (CS) is a difficult-to-recognize multiple hamartoma syndrome with high risks of breast, thyroid, and other cancers. 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| subjects | 1-Phosphatidylinositol 3-kinase AKT1 protein Apoptosis Cancer Cell cycle Cell migration Cellular biology Class I Phosphatidylinositol 3-Kinases Cowden syndrome Enzymes Genes Genetic disorders Genetic Predisposition to Disease Germ-Line Mutation Hamartoma Syndrome, Multiple - genetics Humans Mutation phosphatidylinositol 3,4,5-triphosphate Phosphatidylinositol 3-Kinases - genetics Polarity Proto-Oncogene Proteins c-akt - genetics PTEN Phosphohydrolase PTEN protein Risk factors Signal transduction Thyroid thyroid cancer |
| title | Germline PIK3CA and AKT1 Mutations in Cowden and Cowden-like Syndromes |
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