Genetic variants in PPP2CA are associated with gastric cancer risk in a Chinese population

Tongtong Huang,Li Liu,Yingying Mao,Qi Qi,Kexin He,Fei Yu,Caiwang Yan,Tianpei Wang,Jiangbo Du,Yan Wang,Meng Zhu

doi:10.1038/s41598-017-12040-z

Abstract

Protein phosphatase 2A (PP2A), a tumor suppressor protein, has been implicated in cell cycle and apoptosis. Additionally, studies have illustrated its crucial roles in transformation of normal human cells to tumorigenic status. PPP2CA, which encodes the alpha isoform of the catalytic subunit of PP2A, has been recently reported to be associated with several types of cancers. Therefore, we hypothesized that genetic variants in PPP2CA might influence susceptibility of gastric cancer. To test this hypothesis, three tagging single nucleotide polymorphisms (SNPs) in PPP2CA were genotyped in a case-control study including 1,113 cases and 1,848 controls in a Chinese population. Three tagging SNPs in PPP2CA were genotyped using Illumina Human Exome BeadChip. We observed that the A allele of rs13187105 was associated with an increased risk of gastric cancer (adjusted odds ratio (OR) = 1.14, 95% confidence interval (CI): 1.02–1.28, P = 0.017). Further analyses showed that rs13187105 [A] was associated with decreased expression of PPP2CA mRNA (P = 5.1 × 10−6), and PPP2CA mRNA was significantly lower in gastric tumor tissues when comparing that in their adjacent normal tissues (P = 0.037). These findings support our hypothesis that genetic variants in PPP2CA may be implicated in gastric cancer susceptibility in Chinese population.

Highlights

Gastric cancer is a major public health problem around the world, which led to 951,000 incident cases and 721,000 deaths worldwide in 20121
We found that rs13187105 in PPP2CA was significantly associated with an altered risk of gastric cancer
In silico analyses showed that the minor allele [A] of rs13187105 was significantly associated with reduced PPP2CA mRNA expression in peripheral blood samples

Summary

Introduction

Gastric cancer is a major public health problem around the world, which led to 951,000 incident cases and 721,000 deaths worldwide in 20121. Various risk factors are involved in gastric carcinogenesis, for instance, Helicobacter pylori infection, nitrites consumption and processed meat intake have been associated with risk of gastric cancer[3,4,5,6,7,8] Besides these environmental and life style factors, host genetic factors may play vital roles in the process of gastric cancer development, so that some individuals are prone to develop gastric cancer than the others[9]. Protein phosphatase 2A (PP2A), a heterotrimeric holoenzyme complex, is one of the major serine/threonine phosphatases and participates in a large proportion of phosphatase activity in eukaryotic cells[14,15,16] It has been demonstrated in previous studies that the activation of telomerase and Ras, along with the inactivation of tumor suppressor proteins p53 and retinoblastoma protein are sufficient to immortalize the majority of human cells. We used public databases to compare mRNA level of PPP2CA in gastric tumor tissues with that in adjacent normal tissues, and to explore potential function of the SNPs on gastric cancer development

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Results

Conclusion