A regulatory polymorphism at position -309 in PTPRCAP is associated with susceptibility to diffuse-type gastric cancer and gene expression.
PTPRCAP (CD45-AP) is a positive regulator of protein tyrosine phosphatase PTPRC (CD45), which activates Src family kinases implicated in tumorigenesis. Single-nucleotide polymorphism (SNP) rs869736 located at position -309 of the PTPRCAP promoter was associated with susceptibility to diffuse-type gastric cancer in the current case-control study. The minor-allele homozygote was significantly associated with a 2.5-fold increased susceptibility to diffuse-type gastric cancer (P = .0021, n = 252), but not to intestinal-type (P = .30, n = 178), versus the major-allele homozygote, when comparing unrelated Korean patients with healthy controls (n = 406). Nine other SNPs were in nearly perfect linkage disequilibrium (r(2) >or= 0.97) with this SNP, exhibiting the same association, and spread out for 26 kb on chromosome 11q13.1 covering RPS6KB2, PTPRCAP, CORO1B, and GPR152. Among the four genes, however, only PTPRCAP expression was affected by haplotypes of the 10 SNPs. Endogenous transcript levels of PTPRCAP were linearly correlated with copy numbers (0, 1, and 2) of the risk-haplotype (P = .0060) in 12 lymphoblastoid cells derived from blood samples, but those of the other three genes were not. Furthermore, the cancer-risk, minor-allele T of rs869736 increased both promoter activity and specific nuclear protein-binding affinity than the nonrisk, major-allele G in luciferase reporter and electrophoretic mobility shift assays, respectively. Accordingly, the minor allele of rs869736 in the PTPRCAP promoter is associated with increased susceptibility to diffuse-type gastric cancer by increasing PTPRCAP expression, possibly leading to activation of the oncogenic Src family kinases.
Ju
Hyoungseok
H
Department of Biological Sciences, Korea Advanced Institute of Science and Technology, Daejeon, South Korea.
Lim
Byungho
B
Kim
Minjin
M
Kim
Yong Sung
YS
Kim
Woo Ho
WH
Ihm
Chunhwa
C
Noh
Seung-Moo
SM
Han
Dong Soo
DS
Yu
Hang-Jong
HJ
Choi
Bo Youl
BY
Kang
Changwon
C
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000483:Alleles; D016022:Case-Control Studies; D045744:Cell Line, Tumor; D002880:Chromosomes, Human, Pair 11 / Q000235:genetics; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D005787:Gene Frequency; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D005838:Genotype; D006239:Haplotypes; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics*; D015810:Linkage Disequilibrium; D008156:Luciferases / Q000235:genetics / Q000378:metabolism; D008297:Male; D008565:Membrane Proteins / Q000235:genetics*; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide; D011401:Promoter Regions, Genetic / Q000235:genetics; D013274:Stomach Neoplasms / Q000145:classification / Q000208:ethnology / Q000235:genetics*; D055815:Young Adult
D047908:Intracellular Signaling Peptides and Proteins; D008565:Membrane Proteins; C090519:PTPRCAP protein, human; D008156:Luciferases