rs12913975 is an A/G single nucleotide polymorphism (SNP) of the SMAD6 gene that has been associated with the prognosis of non-small cell lung cancer (NSCLC) patients. The most common nucleotide or 'major allele' of this SNP is G, which is also the dominant allele. The minor allele is A, which according to data from the 1000 Genomes project occurs in the sampled population at a frequency of 15.8% (observed 345 times in 2183 people). HapMap data (July 2005) from 1208 individuals from 13 populations included population specific genotype frequencies for this SNP dbSNP.
A 2011 study published by Li et al. examined 33 SNPs in 13 TGF-beta pathway genes to estimate the effect of genotype on brain metastasis in 116 NSCLC patients. The authors found that NSCLC patients with the G/G genotype of the rs12913975 SNP had a significantly increased risk of brain metastasis compared to patients with the A/G genotype over the two years following initial time of lung cancer diagnosis (hazard risk: 2.540, 95% confidence interval: 1.204-5.359, p = 0.014). Hazard ratios and confidence intervals were estimated using cox proportional hazards model for the multivariate survival analyses adjusted for sex, age, clinical stage, tumor histology, Karnofsky performance status, and smoking status. A two-tailed t- test was used to determine significance of associations. This finding may allow clinicians to use the rs12913975 SNP as a measure of an NSCLC patients’ risk of developing brain metastasis. It is not known whether this SNP plays a functional role in the potential of NSCLC tumors to metastasize to the brain. However, the SNP is located in the SMAD6 gene, an inhibitor of TGF-beta signaling that is a pathway affected in different cancers, so this may in fact be a functional variant [R].
In 2011 Lin et al. determined the effect of genotype on survival in 598 advanced-stage NSCLC patients across 227 SNPs in 23 TGF-beta pathway-related genes to estimate. The authors identified the rs12913975 SNP as a genetic variant significantly associated with the overall survival of NSCLC patients (hazard risk: 1.29, 95% confidence interval: 1.05-1.59, p = 0.01). Furthermore, they found that the G/G allele of this SNP had a significant positive effect on the survival of NSCLC patients using chemoradiation (hazard risk: 0.61, 95% confidence interval: 0.42-0.90, p = 0.01), but that this trend was not significant when patients used only chemotherapy (hazard risk: 0.76, 95% confidence interval: 0.56-1.02, p = 0.29). Hazard ratios and confidence intervals were estimated using cox proportional hazards model for the multivariate survival analyses adjusted for age, sex, ethnicity, smoking status, clinical stager, pretreatment PS, and therapy modality. A two-tailed chi-squared or Fisher’s exact test was used to determine significance of associations. [R]