Significance of Gene Polymorphism and Gene Expression of BACE2 in Swedish Patients with Colorectal Cancer

Abstract

<b><i>Introduction:</i></b> β-site amyloid precursor protein (APP) cleaving enzyme 2 (BACE2) cleaves APP which is ubiquitously expressed in a variety of cell types including cancer cells. BACE2 can process APP in several ways and appears to be involved in the pathogenesis of cancer. Our purpose was to assess the association of mRNA expression and genetic polymorphism of BACE2 in colorectal cancer (CRC) susceptibility and its association to clinicopathological factors in Swedish patients with CRC. <b><i>Methods:</i></b> A total of 720 CRC patients and 470 healthy controls were genotyped for <i>BACE2</i> gene polymorphism rs2012050, using TaqMan single nucleotide polymorphism (SNP) assays based on polymerase chain reaction. Reverse transcription quantitative PCR was used to investigate the <i>BACE2</i> gene expression in 192 CRC tissue and 181 paired normal tissue. <b><i>Results:</i></b> Assessing clinicopathological factors, we noted that carrying of T allele in C/T and C/T+T/T was significantly associated with a protective role against disseminated cancer and higher lymph node status. Moreover, individuals carrying T/T genotype were significantly more likely to have poorly differentiated cancer. Follow-up data for patients in poorly differentiated cancer and the Kaplan-Meier analysis showed that the cancer-specific survival curves differed between C/C and C/T+T/T for the <i>BACE2</i> gene polymorphism and that the carriers of the genotype C/C were associated with more favorable prognosis. We found no significant differences in the genotypic frequencies between the patients and healthy controls. BACE2 mRNA level was significantly 2.2-fold upregulated in CRC tissue when compared to noncancerous tissue. A higher BACE2 mRNA level was observed in smaller tumors and in rectal cancer when compared to colon cancer. <b><i>Conclusion:</i></b> In patients with CRC, our results indicate BACE2 rs2012050 as a useful potential predictor of poor differentiation, disseminated cancer and lymph node status and that the BACE2 mRNA expression is associated to tumor size and cancer location.