Allele-specific expression of mutated in colorectal cancer (MCC) gene and alternative susceptibility to colorectal cancer in schizophrenia.

John Mcgrath,Zhihai Peng,Fei Xu,Tao Yu,Xia Zou,Zhiyun Wei,Yan Bi,Yanzeng Xiao,Xiaoye Huang,Yan Zhang,Weidong Li,Yang Wang,Guang He,Lin He,Fengping Yang,Xingwang Li,Yanfei Cao

doi:10.1038/srep26688

Abstract

Evidence has indicated that the incidence of colorectal cancer (CRC) among schizophrenia is lower than normal. To explore this potential protective effect, we employed an innovative strategy combining association study with allele-specific expression (ASE) analysis in MCC gene. We first genotyped four polymorphisms within MCC in 312 CRC patients, 270 schizophrenia patients and 270 controls. Using the MassArray technique, we performed ASE measurements in a second sample series consisting of 50 sporadic CRC patients, 50 schizophrenia patients and 52 controls. Rs2227947 showed significant differences between schizophrenia cases and controls, and haplotype analysis reported some significant discrepancies among these three subject groups. ASE values of rs2227948 and rs2227947 presented consistently differences between CRC (or schizophrenia) patients and controls. Of the three groups, highest frequencies of ASE in MCC were concordantly found in CRC group, whereas lowest frequencies of ASE were observed in schizophrenia group. Similar trends were confirmed in both haplotype frequencies and ASE frequencies (i.e. CRC > control > schizophrenia). We provide a first indication that MCC might confer alterative genetic susceptibility to CRC in individuals with schizophrenia promising to shed more light on the relationship between schizophrenia and cancer progression.

Highlights

Since the Commissioners in Lunacy for England and Wales proposed in 1909 that a reduced incidence of cancer might be linked to schizophrenia[1], considerable attention has been paid to this century-old enigma
The mutated in colorectal cancer (MCC) gene is located on chromosome 5q21 and encodes a protein comprised of 829 amino acids that is highly conserved with orthologs across many species[8]
We found a similar distribution of the allele frequencies in the two sample series, and rs2227947 showed significant differences in the allele frequencies between SZ and NC in the second sample set (p = 0.039, p > 0.05 after the false discovery rate (FDR) correction) (Table 2)

Summary

Introduction

Since the Commissioners in Lunacy for England and Wales proposed in 1909 that a reduced incidence of cancer might be linked to schizophrenia[1], considerable attention has been paid to this century-old enigma. Kohonen-Corish et al.[8] have further suggested that promoter methylation of MCC is an early event in colon carcinogenesis leading to loss of RNA and protein expression of this gene. This evidence points strongly to MCC as a potential suppressor gene in CRC tumorigenesis. The quantitative differences in gene expression levels are heritable and context-specific, and have been mentioned as an incomplete-penetrance marker involved in predisposition to both CRC and schizophrenia[18,19,20]. We aimed to confirm the hypothesis that the MCC gene may be involved in the genetically reduced susceptibility to colorectal cancer in patients with schizophrenia

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Results

Conclusion