Rs35148638

rs35148638 is a single-nucleotide polymorphism (SNP) found in the gene RASA1 that has been associated with prostate cancer aggressiveness as measured by the Gleason score.

Prostate cancer is a type of cancer that forms in tissues of the prostate. It usually shows a slow growth and remains confined to the prostate gland not causing serious harm, but other types of prostate cancer can spread quickly and are aggressive. Aggressiveness can be measured with the Gleason score, a system which assigns a number from 2 to 10 to describe how abnormal the cells appear under a microscope. The higher the Gleason score is, the more aggressive the disease is.

To evaluate disease aggressiveness, a multi-stage, case-only GWAS was conducted with a total of 12,518 prostate cancer cases of European ancestry. Regression models were fit taking the Gleason score as a quantitative trait and adjusting for age. rs35148638 (5q14.3) reached genome-wide significance (p = 6.49x10-9), with the C allele associated with higher Gleason score (more aggressive disease). The estimated coefficient for this SNP in the regression model is 0.088 with standard error of 0.015. The risk allele (C) frequency among cases is 0.255. The non-risk allele at rs35148638 is A.

To evaluate the extent to which this locus could be associated with aggressive prostate cancer risk, two case-control analyses were conducted. One of them compared cases with non-aggressive disease (Gleason <=6) versus controls, and the other compared cases with aggressive disease (Gleason >7) versus controls. rs35148638 showed an association with aggressive prostate cancer (OR = 1.18 (1.09‐1.28), P = 8.85x10-5), but no differentiation was found between non-aggressive cases and controls (OR = 0.99 (0.94‐1.04), P = 0.57).

rs35148638 is intronic to the RAS p21 protein activator 1 (RASA1) gene, which suppresses RAS function, helps regulate cellular proliferation and differentiation, and controls blood vessel growth. Mutations in this gene are associated with capillary malformation, arteriovenous malformation, Parkes–Weber syndrome and lymphatic abnormalities.

Two susceptibility loci identified for prostate cancer aggressiveness.