Bạn đang ở trang: HomeNghiên cứuNghiên cứu của các tác giả khácAn association between a variation in the PSCA gene and upper gastrointestinal cancer in Caucasians

An association between a variation in the PSCA gene and upper gastrointestinal cancer in Caucasians Featured

Upper gastrointestinal cancers represent a significant global health burden. Gastric and esophageal cancers were, respectively, the second and sixth most common causes of cancerrelated mortality worldwide in 2008, accounting for over one million deaths.

Background & Aims—An association between gastric cancer and the rs2294008 (C>T) polymorphism in the prostate stem cell antigen (PSCA) gene has been reported for several Asian populations. We set out to determine whether such an association exists in Caucasians.

Methods—We genotyped 166 relatives of gastric cancer patients, including 43 H pylori-infected subjects with hypochlorhydria and gastric atrophy, 65 infected subjects without these abnormalities, 58 H pylori-negative relatives, and 100 population controls. Additionally, a population-based study of chronic atrophic gastritis provided 533 cases and 1054 controls. We then genotyped 2 population-based case-control studies of upper gastrointestinal cancer: the first included 312 gastric cancer cases and 383 controls; the second included 309 gastric cancer cases. 159 esophageal cancer cases, and 211 controls. Odds ratios were computed from logistic models and adjusted for confounding variables.

Results—Carriage of the risk allele (T) of rs2294008 in PSCA was associated with chronic atrophic gastritis (adjusted odds ratio [OR] = 1.5; 95% confidence interval [CI], 1.1–1.9) and noncardia gastric cancer (OR = 1.9; 95% CI, 1.3– 2.8). The association was strongest for the diffuse histological-type (OR = 3.2; 95% CI, 1.2–10.7). An inverse association was observed between carriage of the risk allele and gastric cardia cancer (OR = 0.5; 95% CI, 0.3–0.9), esophageal adenocarcinoma (OR = 0.5; 95% CI, 0.3–0.9), and esophageal squamous cell carcinoma (OR = 0.4; 95% CI, 0.2–0.9).

Conclusions—The rs2294008 polymorphism in PSCA increases the risk of non-cardia gastric cancer and its precursors in Caucasians but protects against proximal cancers.

Introduction

Upper gastrointestinal cancers represent a significant global health burden. Gastric and esophageal cancers were, respectively, the second and sixth most common causes of cancerrelated mortality worldwide in 2008, accounting for over one million deaths.
The identification of Helicobacter pylori as the major acquired etiological agent responsible for gastric carcinogenesis2,3 revolutionized our understanding of the inflammation and cancer paradigm, and prompted candidate gene approaches to host genetic susceptibility4,5. Consequently, gastric cancer is arguably better understood in terms of genetic susceptibility than other gastrointestinal malignancies. We, and other authors, have previously reported an increased risk of gastric cancer and its precursors (gastric atrophy and hypochlorhydria) in association with polymorphisms in pro-inflammatory cytokine genes (IL-1B, IL-1RN, TNFA and IL-10), and genes involved in the innate immune response (TLR4)4–8. Recently, genome wide association studies (GWAS) have permitted the identification of novel, high prevalence, low penetrance genetic polymorphisms associated with complex human traits, including sporadic cancer risk. Unlike candidate gene approaches, no prior knowledge of the locations of the loci or functions of the gene products is required. Indeed, the mechanism of action of many GWAS-identified genetic variants remains unknown, and the ability to stratify individual cancer risk on the basis of these variants is limited9.
Recently, the Study Group of the Millennium Genome Project for Cancer published findings of a two-stage GWAS, which demonstrated an association between the rs2294008 single nucleotide polymorphism (SNP) in the prostate stem cell antigen gene (PSCA), and the risk of gastric cancer in Japanese10. The authors subsequently validated the association in a Korean case-control study of gastric cancer. In both the Japanese and Korean study groups, the association was strongest for the diffuse histological-type of gastric cancer (OR = 4.18; 95% CI, 2.88–6.21 for Japanese). The finding of an association between gastric cancer and rs2294008 has now been replicated in several, independent, Asian case-control studies11–14, and was also confirmed in a recent gastric cancer GWAS in a Chinese population15. Limited functional data exist on the effect of the rs2294008 C>T transition, however results from a reporter assay suggest that the T allele reduces upstream PSCA transcriptional activity.

Free dowload fulltex here

Last modified on Thứ ba, 26 Tháng 5 2020 03:30
Rate this item
(0 votes)

Mẹo vặt cuộc sống

Đọc tiếp

Tư vấn

Bệnh trẻ em