title: Novel CDH1 germline mutations identified in Chinese gastric cancer patients.
abstract: OBJECTIVE
  To give a comprehensive report of E-cadherin gene (CDH1) variations in a population at a high risk for gastric cancer (GC).
  
  
  METHODS
  The samples consisted of 178 men and 58 women with a mean age of 62.3 ± 9.4 years and an age range of 30-84 years. A total of 240 cancer-free controls were recruited (mean age of 61.8 ± 10.1 years, age range of 26-82 years). Samples were screened for CDH1 germline mutations by high-resolution melting analysis or directly sequencing. Luciferase reporter assay, RNA splicing assay and bioinformatic analysis were used to evaluate the effect of mutations.
  
  
  RESULTS
  Four novel CDH1 sequence alterations were identified in GC patients including a G>T transition 49 bp before the start codon; a three-nucleotide deletion, c.44_46del TGC; one missense mutation, c.604G>A (V202I); and one variation in the intron, c.1320+7A>G. In addition, polymorphism frequencies were observed for CDH1-164delT, -161C>A, -73A>C, c.48+6C>T, c.48+62_48+63delinsCGTGCCCCAGCCC, c.894C>T (A298A), c.1224G>A (A408A), c.1888C>G (L630V), c.2076T>C (A692A), and c.2253C>T (N751N) which is similar to the data reported in http://www.ncbi.nlm.nih.gov/projects/SNP/. RNA splicing analysis suggested that the c.1320+7A>G and c.1224G>A variations did not affect exon splicing ability. Luciferase reporter assay demonstrated that the c.-49T variation might be helpful for E-cadherin transcription, though the increase in transcription activity is limited (only 33%). SIFT score and PolyPhen analysis both demonstrated that the L630V missense mutation probably damages protein function, while the V202I variant does not.
  
  
  CONCLUSIONS
  This study reveals novel mutations in sporadic GC patients which had been poorly investigated for susceptibility genes.
authors: Department of Medical Genetics, Medical School, Nanjing University, Nanjing 210093, Jiangsu Province, China.
authors: Qin-Hua
authors: QH
authors: Chen
authors: Wei
authors: W
authors: Deng
authors: Xiao-Wei
authors: XW
authors: Li
authors: Xiu-Fang
authors: XF
authors: Liu
authors: Jing-Mei
authors: JM
authors: Wang
authors: Li-Feng
authors: LF
authors: Wang
authors: Nong
authors: N
authors: Xiao
authors: Qiong
authors: Q
authors: He
authors: Ya-Ping
authors: YP
authors: Wang
authors: Yi-Mei
authors: YM
authors: Fan
mesh_terms: D000230:Adenocarcinoma / Q000208:ethnology / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D015703:Antigens, CD; D044466:Asian People / Q000235:genetics*; D015820:Cadherins / Q000235:genetics* / Q000378:metabolism; D016022:Case-Control Studies; D016009:Chi-Square Distribution; D002681:China / Q000453:epidemiology; D004252:DNA Mutational Analysis; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D017930:Genes, Reporter; D020022:Genetic Predisposition to Disease; D018095:Germ-Line Mutation; D006367:HeLa Cells; D006801:Humans; D008297:Male; D008875:Middle Aged; D010641:Phenotype; D012307:Risk Factors; D013274:Stomach Neoplasms / Q000208:ethnology / Q000235:genetics* / Q000378:metabolism / Q000473:pathology
chemical_list: D015703:Antigens, CD; C513384:CDH1 protein, human; D015820:Cadherins
keywords: CDH1; Gastric cancer; Germline mutation; Luciferase reporter assay; RNA splicing analysis