[Relationship between alterations of p16INK4a and p14ARF genes of CDKN2A locus and gastric carcinogenesis].
OBJECTIVE
To investigate the relationship between alterations of p16INK4a and p14ARF genes and gastric carcinogenesis.


METHODS
Tumors and gastric tissues neighboring carcinoma from 48 patients with gastric cancer were studied. Homozygous deletion, mutation, methylation of the CpG islands, mRNA expression of p16INK4a and p14ARF genes were assessed by polymerase chain reaction (PCR), PCR-single strand conformation polymorphism (SSCP), PCR based methylation assay, and reverse transcription (RT)-PCR.


RESULTS
(1) The overall homozygous deletion rate of p16INK4a and p14ARF was 35.4% (17/48), and no homozygous deletion was examined in all the gastric tissues neighboring tumor. (2) There was no point mutation of p16INK4a and p14ARF in 31 gastric cancers without homozygous deletion and in the matched gastric tissues adjacent to tumor. (3) Methylation of the CpG islands of p16INK4a and p14ARF was detected in 47.9% (23/48) of gastric cancers, while methylation was observed only in 2 of 48 gastric tissues neighboring cancers with a significant difference (P <0.01). (4) The rate of p16INK4a mRNA loss was 47.9% (23/48) in gastric cancer, and the cases of combined methylation of exons 1alpha and 2 had a higher loss rate (100%, 6/6) of p16INK4a mRNA than those of methylation form the other exons (11.8%, 2/17) (P <0.01). The loss rate of p14ARF mRNA was 45.8% (22/48) in gastric cancer, and patients with combined methylation of exons 1beta and 2 had a higher loss rate (100%, 3/3) of p14ARF mRNA than those of the methylation from the other exons (15%, 3/20) (P < 0.05). (5) The combined loss of p16INK4a and p14ARF mRNAs was examined in 1 (5.6%) of 18 cases of well and moderately-differentiated carcinomas, and 11 (36.7%) of 30 cases of poorly and not-differentiated carcinomas with significant difference (P <0.05).


CONCLUSIONS
p16INK4a and p14ARF genes were frequently inactivated by homozygous deletion and methylation of the 5' CpG islands in gastric cancer, which might have played an important role in the development of gastric cancer.
Tang
Shao-Hui
SH
Department of Gastroenterology, First Affiliated Hospital of Jinan University, Guangzhou 510630, China.
Yang
Dong-Hua
DH
Luo
He-Sheng
HS
Yu
Jie-Ping
JP
Shu
Jian-Chang
JC
D000230:Adenocarcinoma / Q000235:genetics; D000293:Adolescent; D000328:Adult; D000368:Aged; D019941:Cyclin-Dependent Kinase Inhibitor p16 / Q000235:genetics*; D019175:DNA Methylation; D005260:Female; D017353:Gene Deletion; D019942:Genes, p16; D006801:Humans; D008297:Male; D008875:Middle Aged; D012333:RNA, Messenger / Q000032:analysis; D013274:Stomach Neoplasms / Q000235:genetics*; D025803:Tumor Suppressor Protein p14ARF / Q000235:genetics*
D019941:Cyclin-Dependent Kinase Inhibitor p16; D012333:RNA, Messenger; D025803:Tumor Suppressor Protein p14ARF