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Chromosome position 9p21 encodes three-tumor suppressors p16 INK4a , p14 ARF , and p15 INK4b  and the long non-coding RNA  ANRIL  (antisense non-coding RNA in the INK4 locus). The rs11515 single-nucleotide polymorphism in the  p16  INK4a   /p14  ARF   3′-untranslated region is associated with glioblastoma, melanoma, and other cancers. This study investigated the frequency and effect of rs11515 genotypes in breast cancer. Genomic DNA samples from 400 women (200 with and 200 without a diagnosis of breast cancer) were genotyped for the rs11515 major (C) and minor (G) alleles. The rs11515 polymorphism was also investigated in 108 heart tissues to test for tissue-specific effects. Four 9p21 transcripts,  p16   INK4a  ,  p14  ARF   ,  p15  INK4b   , and  ANRIL  were measured in breast tumors and myocardium using quantitative PCR. Heterozygotes (CG genotype) were more frequent in women with breast cancer compared to the control population ( P  = 0.0039). In those with breast cancer, the CG genotype was associated with an older age ( P  = 0.016) and increased lymph node involvement ( P  = 0.007) compared to homozygotes for the major allele (CC genotype). In breast tumors, the CG genotype had higher  ANRIL  ( P  = 0.031) and lower  p16  INK4a    ( P  = 0.006) expression compared to the CC genotype. The CG genotype was not associated with altered 9p21 transcripts in heart tissue. In breast cancer, the rs11515 CG genotype is more frequent and associated with a more aggressive tumor that could be due to increased  ANRIL  and reduced  p16  INK4a    expression. The absence of association between rs11515 genotypes and 9p21 transcripts in heart tissue suggests this polymorphism has tissue- or disease-specific functions.

The rs11515 Polymorphism Is More Frequent and Associated With Aggressive Breast Tumors with Increased ANRIL and Decreased p16INK4a Expression