SNP-SNP interactions as risk factors for aggressive prostate cancer

Introduction

Prostate cancer (PCa) is highly prevalent, and around 1 in 6 patients are at risk of developing the aggressive form of the disease¹. It has become one of the most significant male health concerns worldwide². An individual is diagnosed as having high-risk or aggressive PCa based on the classification by the American Urological Association³, when the clinical T stage ≥cT2c, and/or the Gleason score ≥8, and/or the serum prostate serum antigen (PSA) level >20ng/ml⁴.

Although a hereditary aspect is well known for this disease⁵, various studies have also shown that genetic interactions with biological and behavioral factors play an important role in the overall risk and prognosis of PCa^6–8. Variations in the genome are a major contributor to the differences in disease susceptibly amongst individuals⁹. Single nucleotide polymorphisms (SNPs) are the most commonly identified variations in a genome.

Analysing the role of SNP-SNP interactions and epistasis¹⁰ is very appealing among researchers working on risk factors for various cancers^11–13, including prostate cancer¹⁴. Here we have identified a SNP-SNP interaction as a risk factor for aggressive PCa, by comparing the data generated after carrying out SNP genotyping using the SEQUENOM MassARRAY iPLEX^® assay, and the TaqMan^® assay (depending on the gene of interest) from the DNA extracted from blood samples. These samples were taken from a New Zealand cohort of men with self-reported European ethnicity that have been clinically diagnosed with aggressive and non-aggressive PCa, and healthy controls with no reported symptoms of the disease. Symptoms include increased urination during night time along with a frequent urge to urinate problems maintaining a steady flow of urine, hematuria and dysuria¹⁵. Our results indicate a strong influence of gene x environment interaction in overall gene expression and epistasis.

Methods

Results

Table 1 shows the statistically significant SNP-SNP interaction discovered in patients with aggressive PCa when compared to healthy controls. The results obtained for other categorical analyses are not discussed here, as they were not statistically significant in our study and have been mentioned in Supplementary Table 2. The SNP rs2121875, an intronic SNP present in chromosomal position 5p12 near the fibroblast growth factor 10 (FGF10) gene²⁴, has been identified to be associated with the SNP rs4809960, an intronic SNP present in chromosomal position 20q13 near the gene cytochrome P450 family 24 subfamily A member 1 (CYP24A1)²⁵, such that the latter SNP raises the odds of having the prior.

Discussion

Epistatic effects that are crucial to define various biologically-intuitive models of interaction between two SNPs have already been observed in a variety of species¹¹. We believe this is the first study on SNP-SNP interactions associated with aggressive PCa carried out with patients from a New Zealand population.

The SNP rs4809960 in the gene CYP24A1 has been reported by Holt et al., (2010) to be associated with prostate cancer-specific mortality, and was not evolutionarily conserved²⁵. It was also found to have an effect on the body mass index (BMI), but due to a small sample size the hazard ratios for the BMI strata were not considered reliable enough to be reported²⁵. The protein encoded by CYP24A1 initiates the degradation of the physiologically active form of Vitamin D3 (VD3)²⁶. VD3 is an important hormone that is actively involved in regulating cell proliferation in the prostate, and has also been identified to have increased expression in PCa cell lines²⁷. It is well established that, with ageing, the skin cannot synthesize VD3 as effectively as desirable and the kidney’s ability to convert VD3 to its active form decreases²⁸. This is of relevance because PCa has always been considered as a disease of elderly men²⁹ who have had less exposure to sunlight and thereby Vitamin D3³⁰. It is even more intriguing for the other epistatic SNP to be identified in FGF10.

According to Paul et al. (2013), during mesenchymal development, eFGF10 protein can trigger PCa development through increased androgen receptor expression in the neoplastic epithelium³¹. It is also worthy to mention that FGF10 is closest to FGF7 based on its evolutionary history³², and according to Emoto et al. (1997), is suggested to have no activity for fibroblasts³². We do not agree with this, because fibroblasts in certain organs, senesce due to aging³³, and can promote tumour invasion³⁴. This logical progression of ageing-led senescence and promotion of tumour invasion holds true for ageing and risk of aggressive PCa¹⁶ as well.

We suggest that the intronic SNP rs2121875 in the gene FGF10 may be causing alterations in gene expression, perhaps due to the prevalent external/environmental conditions in the elderly men with PCa. Our theory is based on the recent discovery in a study by Zhang et al. (2007) that even intronic SNPs (such as the ones identified in FGF10 and CYP24A1) can change the outcome and usage of exons^35,36. This unique and novel epistatic finding emphasizes the fact that intronic SNPs (and SNP-SNP interactions) can also have a significant effect on the risk of diseases such as aggressive PCa, and need to be investigated further.

Data availability

Dataset 1: Raw data from the current study. DOI, 10.5256/f1000research.11027.d158605¹⁷

Dataset 2: Epistasis results after analysis of the data for SNP-SNP interactions. DOI, 10.5256/f1000research.11027.d158606³⁷