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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Bibliographic Details
Published in:PloS one 2013-03, Vol.8 (3), p.e58731-e58731
Main Authors: Shull, Austin Y, Clendenning, Megan L, Ghoshal-Gupta, Sampa, Farrell, Christopher L, Vangapandu, Hima V, Dudas, Larry, Wilkerson, Brent J, Buckhaults, Phillip J
Format: Article
Language:English
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
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Summary: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.
ISSN:1932-6203
1932-6203
DOI:10.1371/journal.pone.0058731