Exome Sequencing Reveals Germline SMAD9 Mutation That Reduces Phosphatase and Tensin Homolog Expression and Is Associated With Hamartomatous Polyposis and Gastrointestinal Ganglioneuromas
Hamartomatous polyposis syndromes (HPS) account for a small but appreciable proportion of inherited gastrointestinal cancer predisposition syndromes; patients with HPS have an increased risk for colon and extracolonic malignancies. We present a unique case of familial juvenile polyposis syndrome ass...
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| Veröffentlicht in: | Gastroenterology (New York, N.Y. 1943) N.Y. 1943), 2015-10, Vol.149 (4), p.886-889.e5 |
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| creator | Ngeow, Joanne Yu, Wanfeng Yehia, Lamis Niazi, Farshad Chen, Jinlian Tang, Xuhua Heald, Brandie Lei, Junying Romigh, Todd Tucker-Kellogg, Lisa Lim, Kiat Hon Song, Haiwei Eng, Charis |
| description | Hamartomatous polyposis syndromes (HPS) account for a small but appreciable proportion of inherited gastrointestinal cancer predisposition syndromes; patients with HPS have an increased risk for colon and extracolonic malignancies. We present a unique case of familial juvenile polyposis syndrome associated with gastrointestinal ganglioneuromas of unknown etiology. The patient was tested for HPS-associated genes, but no mutation was detected. Exome sequencing identified a germline heterozygous mutation in SMAD9 ( SMAD9 V90M ). This mutation was predicted to be an activating mutation. HEK cells transfected to express SMAD9V90M had reduced expression of phosphatase and tensin homolog; this reduction was also observed in a polyp from the patient. We have therefore identified a new susceptibility locus for HPS. Patients with hamartomatous polyposis in the colon associated with ganglioneuromatosis should be referred for genetic assessments. |
| doi_str_mv | 10.1053/j.gastro.2015.06.027 |
| format | Article |
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We present a unique case of familial juvenile polyposis syndrome associated with gastrointestinal ganglioneuromas of unknown etiology. The patient was tested for HPS-associated genes, but no mutation was detected. Exome sequencing identified a germline heterozygous mutation in SMAD9 ( SMAD9 V90M ). This mutation was predicted to be an activating mutation. HEK cells transfected to express SMAD9V90M had reduced expression of phosphatase and tensin homolog; this reduction was also observed in a polyp from the patient. We have therefore identified a new susceptibility locus for HPS. Patients with hamartomatous polyposis in the colon associated with ganglioneuromatosis should be referred for genetic assessments.</description><identifier>ISSN: 0016-5085</identifier><identifier>EISSN: 1528-0012</identifier><identifier>DOI: 10.1053/j.gastro.2015.06.027</identifier><identifier>PMID: 26122142</identifier><language>eng</language><publisher>United States: Elsevier Inc</publisher><subject>Adult ; Colonic Polyps - diagnosis ; Colonic Polyps - enzymology ; Colonic Polyps - genetics ; Colorectal Cancer ; Digestive System Neoplasms - diagnosis ; Digestive System Neoplasms - enzymology ; Digestive System Neoplasms - genetics ; DNA Mutational Analysis ; Down-Regulation ; Exome ; Female ; Ganglioneuroma - diagnosis ; Ganglioneuroma - enzymology ; Ganglioneuroma - genetics ; Ganglioneuromas ; Gastroenterology and Hepatology ; Gene Expression Regulation, Enzymologic ; Gene Expression Regulation, Neoplastic ; Genetic Predisposition to Disease ; Germ-Line Mutation ; Hamartomatous Polyps ; HEK293 Cells ; Humans ; Male ; Multiple Endocrine Neoplasia Type 2b - diagnosis ; Multiple Endocrine Neoplasia Type 2b - enzymology ; Multiple Endocrine Neoplasia Type 2b - genetics ; Peutz-Jeghers Syndrome - diagnosis ; Peutz-Jeghers Syndrome - enzymology ; Peutz-Jeghers Syndrome - genetics ; Phenotype ; PTEN Phosphohydrolase - genetics ; PTEN Phosphohydrolase - metabolism ; SMAD Signaling ; Smad8 Protein - genetics ; Smad8 Protein - metabolism ; Transfection</subject><ispartof>Gastroenterology (New York, N.Y. 1943), 2015-10, Vol.149 (4), p.886-889.e5</ispartof><rights>AGA Institute</rights><rights>2015 AGA Institute</rights><rights>Copyright © 2015 AGA Institute. Published by Elsevier Inc. All rights reserved.</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c463t-c7b5734530fd00b29e043b4444514314482c3e347e7676373ee884a40aa84ae63</citedby><cites>FETCH-LOGICAL-c463t-c7b5734530fd00b29e043b4444514314482c3e347e7676373ee884a40aa84ae63</cites><orcidid>0000-0002-3693-5145</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktohtml>$$Uhttps://dx.doi.org/10.1053/j.gastro.2015.06.027$$EHTML$$P50$$Gelsevier$$H</linktohtml><link.rule.ids>314,777,781,3537,27905,27906,45976</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/26122142$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Ngeow, Joanne</creatorcontrib><creatorcontrib>Yu, Wanfeng</creatorcontrib><creatorcontrib>Yehia, Lamis</creatorcontrib><creatorcontrib>Niazi, Farshad</creatorcontrib><creatorcontrib>Chen, Jinlian</creatorcontrib><creatorcontrib>Tang, Xuhua</creatorcontrib><creatorcontrib>Heald, Brandie</creatorcontrib><creatorcontrib>Lei, Junying</creatorcontrib><creatorcontrib>Romigh, Todd</creatorcontrib><creatorcontrib>Tucker-Kellogg, Lisa</creatorcontrib><creatorcontrib>Lim, Kiat Hon</creatorcontrib><creatorcontrib>Song, Haiwei</creatorcontrib><creatorcontrib>Eng, Charis</creatorcontrib><title>Exome Sequencing Reveals Germline SMAD9 Mutation That Reduces Phosphatase and Tensin Homolog Expression and Is Associated With Hamartomatous Polyposis and Gastrointestinal Ganglioneuromas</title><title>Gastroenterology (New York, N.Y. 1943)</title><addtitle>Gastroenterology</addtitle><description>Hamartomatous polyposis syndromes (HPS) account for a small but appreciable proportion of inherited gastrointestinal cancer predisposition syndromes; patients with HPS have an increased risk for colon and extracolonic malignancies. We present a unique case of familial juvenile polyposis syndrome associated with gastrointestinal ganglioneuromas of unknown etiology. The patient was tested for HPS-associated genes, but no mutation was detected. Exome sequencing identified a germline heterozygous mutation in SMAD9 ( SMAD9 V90M ). This mutation was predicted to be an activating mutation. HEK cells transfected to express SMAD9V90M had reduced expression of phosphatase and tensin homolog; this reduction was also observed in a polyp from the patient. We have therefore identified a new susceptibility locus for HPS. Patients with hamartomatous polyposis in the colon associated with ganglioneuromatosis should be referred for genetic assessments.</description><subject>Adult</subject><subject>Colonic Polyps - diagnosis</subject><subject>Colonic Polyps - enzymology</subject><subject>Colonic Polyps - genetics</subject><subject>Colorectal Cancer</subject><subject>Digestive System Neoplasms - diagnosis</subject><subject>Digestive System Neoplasms - enzymology</subject><subject>Digestive System Neoplasms - genetics</subject><subject>DNA Mutational Analysis</subject><subject>Down-Regulation</subject><subject>Exome</subject><subject>Female</subject><subject>Ganglioneuroma - diagnosis</subject><subject>Ganglioneuroma - enzymology</subject><subject>Ganglioneuroma - genetics</subject><subject>Ganglioneuromas</subject><subject>Gastroenterology and Hepatology</subject><subject>Gene Expression Regulation, Enzymologic</subject><subject>Gene Expression Regulation, Neoplastic</subject><subject>Genetic Predisposition to Disease</subject><subject>Germ-Line Mutation</subject><subject>Hamartomatous Polyps</subject><subject>HEK293 Cells</subject><subject>Humans</subject><subject>Male</subject><subject>Multiple Endocrine Neoplasia Type 2b - diagnosis</subject><subject>Multiple Endocrine Neoplasia Type 2b - enzymology</subject><subject>Multiple Endocrine Neoplasia Type 2b - genetics</subject><subject>Peutz-Jeghers Syndrome - diagnosis</subject><subject>Peutz-Jeghers Syndrome - enzymology</subject><subject>Peutz-Jeghers Syndrome - genetics</subject><subject>Phenotype</subject><subject>PTEN Phosphohydrolase - genetics</subject><subject>PTEN Phosphohydrolase - metabolism</subject><subject>SMAD Signaling</subject><subject>Smad8 Protein - genetics</subject><subject>Smad8 Protein - metabolism</subject><subject>Transfection</subject><issn>0016-5085</issn><issn>1528-0012</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2015</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNqFUk1vEzEQXSEQDYV_gJCPXJL6az9yQYpKSCq1AtEgjpbjnSQOu-vU462a38af62xTOHDBl5E8783MmzdZ9l7wieC5uthPthZTDBPJRT7hxYTL8kU2ErmsxpwL-TIbUSjGOa_ys-wN4p5zPlWVeJ2dyUJIKbQcZb_nD6EFdgt3PXTOd1v2He7BNsgWENvGd5S7mX2esps-2eRDx1Y7mwhU9w6QfdsFPNCHRWC2q9kKOvQdW4Y2NGHL5g-HCIgDbcheIZshBudtgpr99GnHlra1MYXWptBTudAcDwE9PsEXT_p8lwCT72xDH922oWLQR2Lg2-zVhiaFd8_xPPvxZb66XI6vvy6uLmfXY6cLlcauXOel0rnim5rztZwC12qt6eVCK6F1JZ0CpUsoi7JQpQKoKm01t5YCFOo8-3iqe4iB1oTJtB4dNI3tgKY2ohTFVAtVlgTVJ6iLATHCxhyiJ4VHI7gZbDN7c7LNDLYZXhiyjWgfnjv06xbqv6Q_PhHg0wkApPPeQzToPBkGtY_gkqmD_1-Hfws4Mtc72_yCI-A-9JE2TFoMSsPN7XA6w-WInPOqKrh6BDmTwsI</recordid><startdate>20151001</startdate><enddate>20151001</enddate><creator>Ngeow, Joanne</creator><creator>Yu, Wanfeng</creator><creator>Yehia, Lamis</creator><creator>Niazi, Farshad</creator><creator>Chen, Jinlian</creator><creator>Tang, Xuhua</creator><creator>Heald, Brandie</creator><creator>Lei, Junying</creator><creator>Romigh, Todd</creator><creator>Tucker-Kellogg, Lisa</creator><creator>Lim, Kiat Hon</creator><creator>Song, Haiwei</creator><creator>Eng, Charis</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>7X8</scope><orcidid>https://orcid.org/0000-0002-3693-5145</orcidid></search><sort><creationdate>20151001</creationdate><title>Exome Sequencing Reveals Germline SMAD9 Mutation That Reduces Phosphatase and Tensin Homolog Expression and Is Associated With Hamartomatous Polyposis and Gastrointestinal Ganglioneuromas</title><author>Ngeow, Joanne ; Yu, Wanfeng ; Yehia, Lamis ; Niazi, Farshad ; Chen, Jinlian ; Tang, Xuhua ; Heald, Brandie ; Lei, Junying ; Romigh, Todd ; Tucker-Kellogg, Lisa ; Lim, Kiat Hon ; Song, Haiwei ; Eng, Charis</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c463t-c7b5734530fd00b29e043b4444514314482c3e347e7676373ee884a40aa84ae63</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2015</creationdate><topic>Adult</topic><topic>Colonic Polyps - diagnosis</topic><topic>Colonic Polyps - enzymology</topic><topic>Colonic Polyps - genetics</topic><topic>Colorectal Cancer</topic><topic>Digestive System Neoplasms - diagnosis</topic><topic>Digestive System Neoplasms - enzymology</topic><topic>Digestive System Neoplasms - genetics</topic><topic>DNA Mutational Analysis</topic><topic>Down-Regulation</topic><topic>Exome</topic><topic>Female</topic><topic>Ganglioneuroma - diagnosis</topic><topic>Ganglioneuroma - enzymology</topic><topic>Ganglioneuroma - genetics</topic><topic>Ganglioneuromas</topic><topic>Gastroenterology and Hepatology</topic><topic>Gene Expression Regulation, Enzymologic</topic><topic>Gene Expression Regulation, Neoplastic</topic><topic>Genetic Predisposition to Disease</topic><topic>Germ-Line Mutation</topic><topic>Hamartomatous Polyps</topic><topic>HEK293 Cells</topic><topic>Humans</topic><topic>Male</topic><topic>Multiple Endocrine Neoplasia Type 2b - diagnosis</topic><topic>Multiple Endocrine Neoplasia Type 2b - enzymology</topic><topic>Multiple Endocrine Neoplasia Type 2b - genetics</topic><topic>Peutz-Jeghers Syndrome - diagnosis</topic><topic>Peutz-Jeghers Syndrome - enzymology</topic><topic>Peutz-Jeghers Syndrome - genetics</topic><topic>Phenotype</topic><topic>PTEN Phosphohydrolase - genetics</topic><topic>PTEN Phosphohydrolase - metabolism</topic><topic>SMAD Signaling</topic><topic>Smad8 Protein - genetics</topic><topic>Smad8 Protein - metabolism</topic><topic>Transfection</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Ngeow, Joanne</creatorcontrib><creatorcontrib>Yu, Wanfeng</creatorcontrib><creatorcontrib>Yehia, Lamis</creatorcontrib><creatorcontrib>Niazi, Farshad</creatorcontrib><creatorcontrib>Chen, Jinlian</creatorcontrib><creatorcontrib>Tang, Xuhua</creatorcontrib><creatorcontrib>Heald, Brandie</creatorcontrib><creatorcontrib>Lei, Junying</creatorcontrib><creatorcontrib>Romigh, Todd</creatorcontrib><creatorcontrib>Tucker-Kellogg, Lisa</creatorcontrib><creatorcontrib>Lim, Kiat Hon</creatorcontrib><creatorcontrib>Song, Haiwei</creatorcontrib><creatorcontrib>Eng, Charis</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>MEDLINE - Academic</collection><jtitle>Gastroenterology (New York, N.Y. 1943)</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Ngeow, Joanne</au><au>Yu, Wanfeng</au><au>Yehia, Lamis</au><au>Niazi, Farshad</au><au>Chen, Jinlian</au><au>Tang, Xuhua</au><au>Heald, Brandie</au><au>Lei, Junying</au><au>Romigh, Todd</au><au>Tucker-Kellogg, Lisa</au><au>Lim, Kiat Hon</au><au>Song, Haiwei</au><au>Eng, Charis</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Exome Sequencing Reveals Germline SMAD9 Mutation That Reduces Phosphatase and Tensin Homolog Expression and Is Associated With Hamartomatous Polyposis and Gastrointestinal Ganglioneuromas</atitle><jtitle>Gastroenterology (New York, N.Y. 1943)</jtitle><addtitle>Gastroenterology</addtitle><date>2015-10-01</date><risdate>2015</risdate><volume>149</volume><issue>4</issue><spage>886</spage><epage>889.e5</epage><pages>886-889.e5</pages><issn>0016-5085</issn><eissn>1528-0012</eissn><abstract>Hamartomatous polyposis syndromes (HPS) account for a small but appreciable proportion of inherited gastrointestinal cancer predisposition syndromes; patients with HPS have an increased risk for colon and extracolonic malignancies. We present a unique case of familial juvenile polyposis syndrome associated with gastrointestinal ganglioneuromas of unknown etiology. The patient was tested for HPS-associated genes, but no mutation was detected. Exome sequencing identified a germline heterozygous mutation in SMAD9 ( SMAD9 V90M ). This mutation was predicted to be an activating mutation. HEK cells transfected to express SMAD9V90M had reduced expression of phosphatase and tensin homolog; this reduction was also observed in a polyp from the patient. We have therefore identified a new susceptibility locus for HPS. Patients with hamartomatous polyposis in the colon associated with ganglioneuromatosis should be referred for genetic assessments.</abstract><cop>United States</cop><pub>Elsevier Inc</pub><pmid>26122142</pmid><doi>10.1053/j.gastro.2015.06.027</doi><orcidid>https://orcid.org/0000-0002-3693-5145</orcidid><oa>free_for_read</oa></addata></record> |
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| subjects | Adult Colonic Polyps - diagnosis Colonic Polyps - enzymology Colonic Polyps - genetics Colorectal Cancer Digestive System Neoplasms - diagnosis Digestive System Neoplasms - enzymology Digestive System Neoplasms - genetics DNA Mutational Analysis Down-Regulation Exome Female Ganglioneuroma - diagnosis Ganglioneuroma - enzymology Ganglioneuroma - genetics Ganglioneuromas Gastroenterology and Hepatology Gene Expression Regulation, Enzymologic Gene Expression Regulation, Neoplastic Genetic Predisposition to Disease Germ-Line Mutation Hamartomatous Polyps HEK293 Cells Humans Male Multiple Endocrine Neoplasia Type 2b - diagnosis Multiple Endocrine Neoplasia Type 2b - enzymology Multiple Endocrine Neoplasia Type 2b - genetics Peutz-Jeghers Syndrome - diagnosis Peutz-Jeghers Syndrome - enzymology Peutz-Jeghers Syndrome - genetics Phenotype PTEN Phosphohydrolase - genetics PTEN Phosphohydrolase - metabolism SMAD Signaling Smad8 Protein - genetics Smad8 Protein - metabolism Transfection |
| title | Exome Sequencing Reveals Germline SMAD9 Mutation That Reduces Phosphatase and Tensin Homolog Expression and Is Associated With Hamartomatous Polyposis and Gastrointestinal Ganglioneuromas |
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