Genetic regulation of MUC1 alternative splicing in human tissues

Abstract

The membrane mucin MUC1 is aberrantly expressed in a variety of cancers, and in stomach, it is a ligand for Helicobacter pylori where it plays a role in gastric carcinogenesis. Splicing variation, leading to a 9-amino acid insertion in the signal peptide region, was proposed to be because of a single-nucleotide polymorphism (rs4072037) at the 5 0 end of exon 2, but is also reported to be cancer-associated. However, the effect of rs4072037 on this splicing event in healthy non-cancer tissues and on the additional spliceoforms of MUC1, including those lacking the polymorphic tandem repeat (TR) domain, has never been investigated. Here we show that in both foetal and adult tissues of known genotype, there is clear evidence for the role of rs4072037 in controlling alternative splicing of the 5 0 exon 2 region of both full-length transcripts and those lacking the TR domain. Although there is some evidence for additional genetic and epigenetic influences, there is no indication of an effect of the TR domain on the proportions of the spliceoforms. In conclusion, overrepresentation of certain transcripts in tumour material cannot be evaluated without information on the SNP genotype as well.

Genetic factors related to gastric cancer susceptibility identified using a genome‐wide association study

“…(53,54) The A allele of rs4072037 identified using the GWAS is in a linkage disequilibrium with the S allele in Japanese and Caucasian patients. (13,55) The results of these association studies on different ethnic populations strongly support the result of the Japanese GWAS; MUC1 is a GC susceptibility gene.…”

“…3). (13,55) Consequently, the nine amino acid deletion in the second exon changes the supposed cleavage site of the N-terminal signal peptide, which might lead to a difference in the function of the encoded protein between the two splicing variants. It is understood that, in GC and other cancer cells that have lost cell polarity, the MUC1 protein interacts freely with other molecules including membrane receptors involved in cell growth and, consequently, it acts as an oncoprotein; in contrast, in normal epithelial cells, MUC1 is restricted to the apical surface of the cells where the interaction with other molecules is limited and it acts as a barrier against exogenous insults to the cells.…”

Association of Genetic Polymorphisms at 1q22 but not 10q23 with Gastric Cancer in a Southern Chinese Population

“…Two previous studies also found genetic variations in MUC1 that were associated with GC susceptibility (Jia et al, 2010;Xu et al, 2009). Regarding rs4072037, the MUC1 A/G polymorphism in exon 2 was reported to control alternative splicing of the 5'-exon 2 region in both fulllength transcripts and those lacking the polymorphic tandem repeat domain (Ng et al, 2008). Subsequently, the polymorphism was observed to disrupt the physiological functions of MUC1, which is important for protection of the gastric mucosa.…”

Lack of Association of Common Polymorphisms in MUC1 Gene with H. pylori Infection and Non-cardia Gastric Cancer Risk in a Chinese Population

“…The final selection comprised 4 SNPs. Additionally, SNP rs4072037 determining the major splicing variants of MUC1 and regulating MUC1 expression in the gastric epithelium (Ng et al, 2008;Xu et al, 2009) was also selected for this study.…”

“…Some works have documented the role of MUC1 in the H. pylori infection and gastric cancer risk. Thus, MUC1 is often aberrantly expressed in stomach cancer, and it is a ligand for H. pylori (Ng et al, 2008). Susceptibility to H. pylori infection and gastric cancer appears to be associated with MUC1 allele length (Costa et al, 2008;Vinall et al, 2002 (Xu et al, 2009;Jia et al, 2010;Zhang et al, 2011) with controversial results (Abnet et al, 2010;He et al, 2013).…”