The association of two non-coding variants, Rs10993994 and Rs2046210, with hereditary cancer predisposition

Abstract

Hereditary cancer is the result of the inheritance of a cancer susceptibility gene followed by loss of heterozygosity. Local hereditary cancer screening (HCS) involves collecting the proband’s personal and family history, using specific algorithms to calculate the risk of hereditary cancer, and referring individuals at an increased risk for Next Generation Sequencing (NGS). Non-coding variants can alter gene regulatory elements, therefore having a potentially important role in hereditary cancer. This study aimed to gain a better understanding of the pathogenicity of two non-coding single nucleotide polymorphisms (SNPs), the reference (T) allele of MSMB c.-89T>C (rs10993994) and g.151627231 G>A (rs2046210), associated with hereditary prostate cancer and oestrogen resistance (ESTRR) and breast cancer, respectively. A tetra-primer amplification refractory mutation system-polymerase chain reaction (ARMS PCR) protocol was optimized for the detection of each of the two variants and used to genotype DNA extracted from 300 randomly selected cord blood samples. The genotype frequencies of rs2046210 were, 89 (29.7%) homozygous wildtype, 169 (56.3%) heterozygous and 42 (14%) homozygous variant. The genotype frequencies of rs10993994 were, 78 (26%) homozygous wildtype, 144 (48%) heterozygous and 78 (26%) homozygous variant. SNP rs2046210 was found not to be in Hardy Weiberg equilibrium (HWE) in the general population, which might indicate a change in the Maltese gene pool. Meanwhile, rs10993994 was found to be consistent with HWE in the both the sample and cancer patient populations. No statistically significant differences were observed in the proportions of the variant genotypes between the general and hereditary cancer populations, and the odds ratios for the estimation of risk were also non-significant with very wide confidence intervals. These findings indicate a limited effect of these two non-coding variants on their own on the risk of hereditary cancer.