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Somatic mutations, allele loss, and DNA methylation of the Cub and Sushi Multiple Domains 1 (CSMD1) gene reveals association with early age of diagnosis in colorectal cancer patients
The Cub and Sushi Multiple Domains 1 (CSMD1) gene, located on the short arm of chromosome 8, codes for a type I transmembrane protein whose function is currently unknown. CSMD1 expression is frequently lost in many epithelial cancers. Our goal was to characterize the relationships between CSMD1 soma...
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Published in: | PloS one 2013-03, Vol.8 (3), p.e58731-e58731 |
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description | The Cub and Sushi Multiple Domains 1 (CSMD1) gene, located on the short arm of chromosome 8, codes for a type I transmembrane protein whose function is currently unknown. CSMD1 expression is frequently lost in many epithelial cancers. Our goal was to characterize the relationships between CSMD1 somatic mutations, allele imbalance, DNA methylation, and the clinical characteristics in colorectal cancer patients.
We sequenced the CSMD1 coding regions in 54 colorectal tumors using the 454FLX pyrosequencing platform to interrogate 72 amplicons covering the entire coding sequence. We used heterozygous SNP allele ratios at multiple CSMD1 loci to determine allelic balance and infer loss of heterozygosity. Finally, we performed methylation-specific PCR on 76 colorectal tumors to determine DNA methylation status for CSMD1 and known methylation targets ALX4, RUNX3, NEUROG1, and CDKN2A.
Using 454FLX sequencing and confirming with Sanger sequencing, 16 CSMD1 somatic mutations were identified in 6 of the 54 colorectal tumors (11%). The nonsynonymous to synonymous mutation ratio of the 16 somatic mutations was 15:1, a ratio significantly higher than the expected 2:1 ratio (p = 0.014). This ratio indicates a presence of positive selection for mutations in the CSMD1 protein sequence. CSMD1 allelic imbalance was present in 19 of 37 informative cases (56%). Patients with allelic imbalance and CSMD1 mutations were significantly younger (average age, 41 years) than those without somatic mutations (average age, 68 years). The majority of tumors were methylated at one or more CpG loci within the CSMD1 coding sequence, and CSMD1 methylation significantly correlated with two known methylation targets ALX4 and RUNX3. C:G>T:A substitutions were significantly overrepresented (47%), suggesting extensive cytosine methylation predisposing to somatic mutations.
Deep amplicon sequencing and methylation-specific PCR reveal that CSMD1 alterations can correlate with earlier clinical presentation in colorectal tumors, thus further implicating CSMD1 as a tumor suppressor gene. |
doi_str_mv | 10.1371/journal.pone.0058731 |
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We sequenced the CSMD1 coding regions in 54 colorectal tumors using the 454FLX pyrosequencing platform to interrogate 72 amplicons covering the entire coding sequence. We used heterozygous SNP allele ratios at multiple CSMD1 loci to determine allelic balance and infer loss of heterozygosity. Finally, we performed methylation-specific PCR on 76 colorectal tumors to determine DNA methylation status for CSMD1 and known methylation targets ALX4, RUNX3, NEUROG1, and CDKN2A.
Using 454FLX sequencing and confirming with Sanger sequencing, 16 CSMD1 somatic mutations were identified in 6 of the 54 colorectal tumors (11%). The nonsynonymous to synonymous mutation ratio of the 16 somatic mutations was 15:1, a ratio significantly higher than the expected 2:1 ratio (p = 0.014). This ratio indicates a presence of positive selection for mutations in the CSMD1 protein sequence. CSMD1 allelic imbalance was present in 19 of 37 informative cases (56%). Patients with allelic imbalance and CSMD1 mutations were significantly younger (average age, 41 years) than those without somatic mutations (average age, 68 years). The majority of tumors were methylated at one or more CpG loci within the CSMD1 coding sequence, and CSMD1 methylation significantly correlated with two known methylation targets ALX4 and RUNX3. C:G>T:A substitutions were significantly overrepresented (47%), suggesting extensive cytosine methylation predisposing to somatic mutations.
Deep amplicon sequencing and methylation-specific PCR reveal that CSMD1 alterations can correlate with earlier clinical presentation in colorectal tumors, thus further implicating CSMD1 as a tumor suppressor gene.</description><identifier>ISSN: 1932-6203</identifier><identifier>EISSN: 1932-6203</identifier><identifier>DOI: 10.1371/journal.pone.0058731</identifier><identifier>PMID: 23505554</identifier><language>eng</language><publisher>United States: Public Library of Science</publisher><subject>Adult ; Age ; Age Factors ; Aged ; Aged, 80 and over ; Alleles ; Allelic Imbalance ; Amino acid sequence ; Biology ; Cancer ; Cancer diagnosis ; Cancer genetics ; Care and treatment ; Cell Line, Tumor ; Chromosome 8 ; Coding ; Color coding ; Colorectal cancer ; Colorectal carcinoma ; Colorectal Neoplasms - diagnosis ; Colorectal Neoplasms - genetics ; CpG islands ; Cytosine ; Deoxyribonucleic acid ; DNA ; DNA Methylation ; DNA sequencing ; Female ; Gastrointestinal diseases ; Genes ; Genetic aspects ; Heterozygosity ; Humans ; Kinases ; Loci ; Loss of Heterozygosity ; Male ; Medical diagnosis ; Medicine ; Membrane Proteins - genetics ; Methylation ; Microsatellite Instability ; Middle Aged ; Mutation ; Mutation Rate ; Neoplasm Staging ; Patients ; Polymerase chain reaction ; Positive selection ; Runx3 protein ; Single nucleotide polymorphisms ; Single-nucleotide polymorphism ; Stem cells ; Tumor suppressor genes ; Tumor Suppressor Proteins ; Tumors ; Young Adult</subject><ispartof>PloS one, 2013-03, Vol.8 (3), p.e58731-e58731</ispartof><rights>COPYRIGHT 2013 Public Library of Science</rights><rights>2013. This is an open-access article, free of all copyright, and may be freely reproduced, distributed, transmitted, modified, built upon, or otherwise used by anyone for any lawful purpose. The work is made available under the Creative Commons CC0 public domain dedication. Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.</rights><rights>2013</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c593t-ff85dfbf7715664f97e8dfcdfdf727a08ef2b8953d4129ff8b2ecda6fb6cff83</citedby><cites>FETCH-LOGICAL-c593t-ff85dfbf7715664f97e8dfcdfdf727a08ef2b8953d4129ff8b2ecda6fb6cff83</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://www.proquest.com/docview/1330893071/fulltextPDF?pq-origsite=primo$$EPDF$$P50$$Gproquest$$Hfree_for_read</linktopdf><linktohtml>$$Uhttps://www.proquest.com/docview/1330893071?pq-origsite=primo$$EHTML$$P50$$Gproquest$$Hfree_for_read</linktohtml><link.rule.ids>230,314,727,780,784,885,25753,27924,27925,37012,37013,44590,53791,53793,75126</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/23505554$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><contributor>Ellis, Nathan A.</contributor><creatorcontrib>Shull, Austin Y</creatorcontrib><creatorcontrib>Clendenning, Megan L</creatorcontrib><creatorcontrib>Ghoshal-Gupta, Sampa</creatorcontrib><creatorcontrib>Farrell, Christopher L</creatorcontrib><creatorcontrib>Vangapandu, Hima V</creatorcontrib><creatorcontrib>Dudas, Larry</creatorcontrib><creatorcontrib>Wilkerson, Brent J</creatorcontrib><creatorcontrib>Buckhaults, Phillip J</creatorcontrib><title>Somatic mutations, allele loss, and DNA methylation of the Cub and Sushi Multiple Domains 1 (CSMD1) gene reveals association with early age of diagnosis in colorectal cancer patients</title><title>PloS one</title><addtitle>PLoS One</addtitle><description>The Cub and Sushi Multiple Domains 1 (CSMD1) gene, located on the short arm of chromosome 8, codes for a type I transmembrane protein whose function is currently unknown. CSMD1 expression is frequently lost in many epithelial cancers. Our goal was to characterize the relationships between CSMD1 somatic mutations, allele imbalance, DNA methylation, and the clinical characteristics in colorectal cancer patients.
We sequenced the CSMD1 coding regions in 54 colorectal tumors using the 454FLX pyrosequencing platform to interrogate 72 amplicons covering the entire coding sequence. We used heterozygous SNP allele ratios at multiple CSMD1 loci to determine allelic balance and infer loss of heterozygosity. Finally, we performed methylation-specific PCR on 76 colorectal tumors to determine DNA methylation status for CSMD1 and known methylation targets ALX4, RUNX3, NEUROG1, and CDKN2A.
Using 454FLX sequencing and confirming with Sanger sequencing, 16 CSMD1 somatic mutations were identified in 6 of the 54 colorectal tumors (11%). The nonsynonymous to synonymous mutation ratio of the 16 somatic mutations was 15:1, a ratio significantly higher than the expected 2:1 ratio (p = 0.014). This ratio indicates a presence of positive selection for mutations in the CSMD1 protein sequence. CSMD1 allelic imbalance was present in 19 of 37 informative cases (56%). Patients with allelic imbalance and CSMD1 mutations were significantly younger (average age, 41 years) than those without somatic mutations (average age, 68 years). The majority of tumors were methylated at one or more CpG loci within the CSMD1 coding sequence, and CSMD1 methylation significantly correlated with two known methylation targets ALX4 and RUNX3. C:G>T:A substitutions were significantly overrepresented (47%), suggesting extensive cytosine methylation predisposing to somatic mutations.
Deep amplicon sequencing and methylation-specific PCR reveal that CSMD1 alterations can correlate with earlier clinical presentation in colorectal tumors, thus further implicating CSMD1 as a tumor suppressor gene.</description><subject>Adult</subject><subject>Age</subject><subject>Age Factors</subject><subject>Aged</subject><subject>Aged, 80 and over</subject><subject>Alleles</subject><subject>Allelic Imbalance</subject><subject>Amino acid sequence</subject><subject>Biology</subject><subject>Cancer</subject><subject>Cancer diagnosis</subject><subject>Cancer genetics</subject><subject>Care and treatment</subject><subject>Cell Line, Tumor</subject><subject>Chromosome 8</subject><subject>Coding</subject><subject>Color coding</subject><subject>Colorectal cancer</subject><subject>Colorectal carcinoma</subject><subject>Colorectal Neoplasms - diagnosis</subject><subject>Colorectal Neoplasms - genetics</subject><subject>CpG islands</subject><subject>Cytosine</subject><subject>Deoxyribonucleic acid</subject><subject>DNA</subject><subject>DNA Methylation</subject><subject>DNA sequencing</subject><subject>Female</subject><subject>Gastrointestinal diseases</subject><subject>Genes</subject><subject>Genetic aspects</subject><subject>Heterozygosity</subject><subject>Humans</subject><subject>Kinases</subject><subject>Loci</subject><subject>Loss of Heterozygosity</subject><subject>Male</subject><subject>Medical diagnosis</subject><subject>Medicine</subject><subject>Membrane Proteins - genetics</subject><subject>Methylation</subject><subject>Microsatellite Instability</subject><subject>Middle Aged</subject><subject>Mutation</subject><subject>Mutation Rate</subject><subject>Neoplasm Staging</subject><subject>Patients</subject><subject>Polymerase chain reaction</subject><subject>Positive selection</subject><subject>Runx3 protein</subject><subject>Single nucleotide polymorphisms</subject><subject>Single-nucleotide polymorphism</subject><subject>Stem cells</subject><subject>Tumor suppressor genes</subject><subject>Tumor Suppressor Proteins</subject><subject>Tumors</subject><subject>Young Adult</subject><issn>1932-6203</issn><issn>1932-6203</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2013</creationdate><recordtype>article</recordtype><sourceid>PIMPY</sourceid><sourceid>DOA</sourceid><recordid>eNptkt9u0zAUxiMEYmPwBggscTMkWuI4iZMbpKnlz6QNLrZ7y7GPW0-OXexkqC_G83HaZtOGplw4tn_fd3yOvix7S_M5ZZx-vglj9NLNN8HDPM-rhjP6LDumLStmdZGz5w_-j7JXKd0gxJq6fpkdFazKq6oqj7O_V6GXg1WkHwdcg0-fiHQOHBAX0m7jNVn-PCM9DOut2yMkGDKsgSzGbn99Naa1JZejG-wGdUt0tD4RSk4XV5dL-pGswAOJcAvSJSJTCsoejP7YYU1ARrclcgU7X23lyodkE7GeqOBCBDVIR5T0CiLZoA78kF5nLwyawZtpPcmuv329XvyYXfz6fr44u5ipqmXDzJim0qYznNOqrkvTcmi0Udpowwsu8wZM0TVtxXRJixbprgClZW26WuGOnWTvD7YbHIaYJp4EZSxvWpZzisT5gdBB3ohNtL2MWxGkFfuDEFdCRpyvA8FqXkva0lJXTcl13Rkj8Wkaa2vOa0CvL1O1setBK2w0SvfI9PGNt2uxCreCVS1GokaD08kght8jpEH0NilwTnoI4-7dlDcVz8sS0Q__oU93N1EriQ1YbwLWVTtTcVbyhrVlnhdIzZ-g8NPQW4XxNBbPHwnKg0BFzFgEc98jzcUu3HePEbtwiyncKHv3cD73ors0s3971foJ</recordid><startdate>20130307</startdate><enddate>20130307</enddate><creator>Shull, Austin Y</creator><creator>Clendenning, Megan L</creator><creator>Ghoshal-Gupta, Sampa</creator><creator>Farrell, Christopher L</creator><creator>Vangapandu, Hima V</creator><creator>Dudas, Larry</creator><creator>Wilkerson, Brent J</creator><creator>Buckhaults, Phillip J</creator><general>Public Library of Science</general><general>Public Library of Science (PLoS)</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>3V.</scope><scope>7QG</scope><scope>7QL</scope><scope>7QO</scope><scope>7RV</scope><scope>7SN</scope><scope>7SS</scope><scope>7T5</scope><scope>7TG</scope><scope>7TM</scope><scope>7U9</scope><scope>7X2</scope><scope>7X7</scope><scope>7XB</scope><scope>88E</scope><scope>8AO</scope><scope>8C1</scope><scope>8FD</scope><scope>8FE</scope><scope>8FG</scope><scope>8FH</scope><scope>8FI</scope><scope>8FJ</scope><scope>8FK</scope><scope>ABJCF</scope><scope>ABUWG</scope><scope>AFKRA</scope><scope>ARAPS</scope><scope>ATCPS</scope><scope>AZQEC</scope><scope>BBNVY</scope><scope>BENPR</scope><scope>BGLVJ</scope><scope>BHPHI</scope><scope>C1K</scope><scope>CCPQU</scope><scope>D1I</scope><scope>DWQXO</scope><scope>FR3</scope><scope>FYUFA</scope><scope>GHDGH</scope><scope>GNUQQ</scope><scope>H94</scope><scope>HCIFZ</scope><scope>K9.</scope><scope>KB.</scope><scope>KB0</scope><scope>KL.</scope><scope>L6V</scope><scope>LK8</scope><scope>M0K</scope><scope>M0S</scope><scope>M1P</scope><scope>M7N</scope><scope>M7P</scope><scope>M7S</scope><scope>NAPCQ</scope><scope>P5Z</scope><scope>P62</scope><scope>P64</scope><scope>PATMY</scope><scope>PDBOC</scope><scope>PIMPY</scope><scope>PQEST</scope><scope>PQQKQ</scope><scope>PQUKI</scope><scope>PRINS</scope><scope>PTHSS</scope><scope>PYCSY</scope><scope>RC3</scope><scope>7X8</scope><scope>5PM</scope><scope>DOA</scope></search><sort><creationdate>20130307</creationdate><title>Somatic mutations, allele loss, and DNA methylation of the Cub and Sushi Multiple Domains 1 (CSMD1) gene reveals association with early age of diagnosis in colorectal cancer patients</title><author>Shull, Austin Y ; Clendenning, Megan L ; Ghoshal-Gupta, Sampa ; Farrell, Christopher L ; Vangapandu, Hima V ; Dudas, Larry ; Wilkerson, Brent J ; Buckhaults, Phillip J</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c593t-ff85dfbf7715664f97e8dfcdfdf727a08ef2b8953d4129ff8b2ecda6fb6cff83</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2013</creationdate><topic>Adult</topic><topic>Age</topic><topic>Age Factors</topic><topic>Aged</topic><topic>Aged, 80 and over</topic><topic>Alleles</topic><topic>Allelic Imbalance</topic><topic>Amino acid sequence</topic><topic>Biology</topic><topic>Cancer</topic><topic>Cancer diagnosis</topic><topic>Cancer genetics</topic><topic>Care and treatment</topic><topic>Cell Line, Tumor</topic><topic>Chromosome 8</topic><topic>Coding</topic><topic>Color coding</topic><topic>Colorectal cancer</topic><topic>Colorectal carcinoma</topic><topic>Colorectal Neoplasms - diagnosis</topic><topic>Colorectal Neoplasms - genetics</topic><topic>CpG islands</topic><topic>Cytosine</topic><topic>Deoxyribonucleic acid</topic><topic>DNA</topic><topic>DNA Methylation</topic><topic>DNA sequencing</topic><topic>Female</topic><topic>Gastrointestinal diseases</topic><topic>Genes</topic><topic>Genetic aspects</topic><topic>Heterozygosity</topic><topic>Humans</topic><topic>Kinases</topic><topic>Loci</topic><topic>Loss of Heterozygosity</topic><topic>Male</topic><topic>Medical diagnosis</topic><topic>Medicine</topic><topic>Membrane Proteins - genetics</topic><topic>Methylation</topic><topic>Microsatellite Instability</topic><topic>Middle Aged</topic><topic>Mutation</topic><topic>Mutation Rate</topic><topic>Neoplasm Staging</topic><topic>Patients</topic><topic>Polymerase chain reaction</topic><topic>Positive selection</topic><topic>Runx3 protein</topic><topic>Single nucleotide polymorphisms</topic><topic>Single-nucleotide polymorphism</topic><topic>Stem cells</topic><topic>Tumor suppressor genes</topic><topic>Tumor Suppressor Proteins</topic><topic>Tumors</topic><topic>Young Adult</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Shull, Austin Y</creatorcontrib><creatorcontrib>Clendenning, Megan L</creatorcontrib><creatorcontrib>Ghoshal-Gupta, Sampa</creatorcontrib><creatorcontrib>Farrell, Christopher L</creatorcontrib><creatorcontrib>Vangapandu, Hima V</creatorcontrib><creatorcontrib>Dudas, Larry</creatorcontrib><creatorcontrib>Wilkerson, Brent J</creatorcontrib><creatorcontrib>Buckhaults, Phillip J</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 Central (Corporate)</collection><collection>Animal Behavior Abstracts</collection><collection>Bacteriology Abstracts (Microbiology B)</collection><collection>Biotechnology Research Abstracts</collection><collection>Nursing & Allied Health Database (ProQuest)</collection><collection>Ecology Abstracts</collection><collection>Entomology Abstracts (Full archive)</collection><collection>Immunology Abstracts</collection><collection>Meteorological & Geoastrophysical Abstracts</collection><collection>Nucleic Acids Abstracts</collection><collection>Virology and AIDS Abstracts</collection><collection>Agricultural Science Collection</collection><collection>ProQuest_Health & Medical Collection</collection><collection>ProQuest Central (purchase pre-March 2016)</collection><collection>Medical Database (Alumni Edition)</collection><collection>ProQuest Pharma Collection</collection><collection>Public Health Database (Proquest)</collection><collection>Technology Research Database</collection><collection>ProQuest SciTech Collection</collection><collection>ProQuest Technology Collection</collection><collection>ProQuest Natural Science Collection</collection><collection>Hospital Premium Collection</collection><collection>Hospital Premium Collection (Alumni Edition)</collection><collection>ProQuest Central (Alumni) (purchase pre-March 2016)</collection><collection>Materials Science & Engineering Collection</collection><collection>ProQuest Central (Alumni)</collection><collection>ProQuest Central</collection><collection>Advanced Technologies & Aerospace Collection</collection><collection>Agricultural & Environmental Science Collection</collection><collection>ProQuest Central Essentials</collection><collection>Biological Science Collection</collection><collection>AUTh Library subscriptions: ProQuest Central</collection><collection>Technology Collection</collection><collection>ProQuest Natural Science Collection</collection><collection>Environmental Sciences and Pollution Management</collection><collection>ProQuest One Community College</collection><collection>ProQuest Materials Science Collection</collection><collection>ProQuest Central</collection><collection>Engineering Research Database</collection><collection>Health Research Premium Collection</collection><collection>Health Research Premium Collection (Alumni)</collection><collection>ProQuest Central Student</collection><collection>AIDS and Cancer Research Abstracts</collection><collection>SciTech Premium Collection</collection><collection>ProQuest Health & Medical Complete (Alumni)</collection><collection>Materials Science Database</collection><collection>Nursing & Allied Health Database (Alumni Edition)</collection><collection>Meteorological & Geoastrophysical Abstracts - 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Academic</collection><collection>PubMed Central (Full Participant titles)</collection><collection>DOAJ Directory of Open Access Journals</collection><jtitle>PloS one</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Shull, Austin Y</au><au>Clendenning, Megan L</au><au>Ghoshal-Gupta, Sampa</au><au>Farrell, Christopher L</au><au>Vangapandu, Hima V</au><au>Dudas, Larry</au><au>Wilkerson, Brent J</au><au>Buckhaults, Phillip J</au><au>Ellis, Nathan A.</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Somatic mutations, allele loss, and DNA methylation of the Cub and Sushi Multiple Domains 1 (CSMD1) gene reveals association with early age of diagnosis in colorectal cancer patients</atitle><jtitle>PloS one</jtitle><addtitle>PLoS One</addtitle><date>2013-03-07</date><risdate>2013</risdate><volume>8</volume><issue>3</issue><spage>e58731</spage><epage>e58731</epage><pages>e58731-e58731</pages><issn>1932-6203</issn><eissn>1932-6203</eissn><abstract>The Cub and Sushi Multiple Domains 1 (CSMD1) gene, located on the short arm of chromosome 8, codes for a type I transmembrane protein whose function is currently unknown. CSMD1 expression is frequently lost in many epithelial cancers. Our goal was to characterize the relationships between CSMD1 somatic mutations, allele imbalance, DNA methylation, and the clinical characteristics in colorectal cancer patients.
We sequenced the CSMD1 coding regions in 54 colorectal tumors using the 454FLX pyrosequencing platform to interrogate 72 amplicons covering the entire coding sequence. We used heterozygous SNP allele ratios at multiple CSMD1 loci to determine allelic balance and infer loss of heterozygosity. Finally, we performed methylation-specific PCR on 76 colorectal tumors to determine DNA methylation status for CSMD1 and known methylation targets ALX4, RUNX3, NEUROG1, and CDKN2A.
Using 454FLX sequencing and confirming with Sanger sequencing, 16 CSMD1 somatic mutations were identified in 6 of the 54 colorectal tumors (11%). The nonsynonymous to synonymous mutation ratio of the 16 somatic mutations was 15:1, a ratio significantly higher than the expected 2:1 ratio (p = 0.014). This ratio indicates a presence of positive selection for mutations in the CSMD1 protein sequence. CSMD1 allelic imbalance was present in 19 of 37 informative cases (56%). Patients with allelic imbalance and CSMD1 mutations were significantly younger (average age, 41 years) than those without somatic mutations (average age, 68 years). The majority of tumors were methylated at one or more CpG loci within the CSMD1 coding sequence, and CSMD1 methylation significantly correlated with two known methylation targets ALX4 and RUNX3. C:G>T:A substitutions were significantly overrepresented (47%), suggesting extensive cytosine methylation predisposing to somatic mutations.
Deep amplicon sequencing and methylation-specific PCR reveal that CSMD1 alterations can correlate with earlier clinical presentation in colorectal tumors, thus further implicating CSMD1 as a tumor suppressor gene.</abstract><cop>United States</cop><pub>Public Library of Science</pub><pmid>23505554</pmid><doi>10.1371/journal.pone.0058731</doi><oa>free_for_read</oa></addata></record> |
fulltext | fulltext |
identifier | ISSN: 1932-6203 |
ispartof | PloS one, 2013-03, Vol.8 (3), p.e58731-e58731 |
issn | 1932-6203 1932-6203 |
language | eng |
recordid | cdi_plos_journals_1330893071 |
source | PubMed (Medline); ProQuest Publicly Available Content database |
subjects | Adult Age Age Factors Aged Aged, 80 and over Alleles Allelic Imbalance Amino acid sequence Biology Cancer Cancer diagnosis Cancer genetics Care and treatment Cell Line, Tumor Chromosome 8 Coding Color coding Colorectal cancer Colorectal carcinoma Colorectal Neoplasms - diagnosis Colorectal Neoplasms - genetics CpG islands Cytosine Deoxyribonucleic acid DNA DNA Methylation DNA sequencing Female Gastrointestinal diseases Genes Genetic aspects Heterozygosity Humans Kinases Loci Loss of Heterozygosity Male Medical diagnosis Medicine Membrane Proteins - genetics Methylation Microsatellite Instability Middle Aged Mutation Mutation Rate Neoplasm Staging Patients Polymerase chain reaction Positive selection Runx3 protein Single nucleotide polymorphisms Single-nucleotide polymorphism Stem cells Tumor suppressor genes Tumor Suppressor Proteins Tumors Young Adult |
title | Somatic mutations, allele loss, and DNA methylation of the Cub and Sushi Multiple Domains 1 (CSMD1) gene reveals association with early age of diagnosis in colorectal cancer patients |
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