Abstract P3-12-03: Polymorphisms in HumanHDAC9 Associates with Earlier Age of Onset and Recurrence of Hormone Receptor Positive Breast Cancer

Abstract

Abstract Background: Breast cancer exhibits familiar aggregation. Such susceptibility is found to be largely polygenic-with susceptibility conferred by a large number of low-penetrance loci. We have been using a bioinformatics approach to identify potential functional genetic variants, reducing the test complexities and costs compared to Genome Wide Association Study. Several single nucleotide polymorphisms (SNPs) in human histone deacetylase (HDAC) 9 were identified via such approach to test for associations with breast cancer risk and prognosis. It is well known that estrogen receptor (ER) and progesterone receptor (PR) expression are important markers for prognosis and prediction of response to endocrine therapy. Recent studies and clinical trials suggest that inhibition of HDAC may represent a novel strategy to modulate ER expression through epigenetic regulation of ER-a. Methods: This study evaluated the association of human HDAC9 SNPs at three loci (rs2239926, rs2240279 and rs2286003) with age of onset and recurrence of breast cancer in a cohort of 1101 patients enrolled prospectively from 2004 to 2009 at The Cancer Institute of New Jersey. Genotyping was performed using an Applied Biosystems TaqMan assay on the ABI 7900HT Fast Real-Time PCR System. A permutation test was performed to determine the statistical significance of differences in mean age at diagnosis between different genotypes. Logistic regression model was used to determine odds ratios for recurrence. Results: To limit potential differences due to the ethnicity and breast cancer subtypes, the association between the HDAC9 genotypes and the age at diagnosis was evaluated in Caucasian women with ductal carcinomas. Of the 1101 patients, 516 patients were Caucasians with ductal carcinomas; among which 74.8% were ER(+) with a mean age of diagnosis of 53.7 years; 25.2% were ER(-) with a mean age of diagnosis of 48.4 years. For patients with ER(+) breast cancer, the homozygous variant CC at HDAC9 rs2239926 developed breast cancer at an earlier age (49.3 years) than G allele carriers (GG+CG) (54.1 years) such that the age at diagnosis was accelerated by 4.8 years (P = 0.043). Conversely, for patients with ER(-) breast cancer, the CC variant appears to develop breast cancer at a later age (53.7 years) than G allele carriers (48.0 years) such that the age at diagnosis was delayed by 5.7 years, although this comparison was statistically limited due to the fewer number of cases. SNPs at the two other HDAC9 loci (rs2240279 and rs2286003) were not shown to be associated with age of onset of breast cancer. However, the homozygous variant CC at rs2240279 exhibits a strong association with recurrence in Caucasians with PR(+) breast cancer: OR 4.1, 95% CI (1.18-7.85) (P = 0.01). Conclusions: A polymorphic variant of human HDAC9 rs2239926 associates with an earlier age of onset of ER positive breast cancer while rs2240279 associates with recurrence of PR positive disease. We hypothesize that such polymorphisms may modulate ER and/or PR and its downstream gene expression leading to alteration of the clinical features of breast cancer including age of diagnosis and natural biology. Citation Information: Cancer Res 2010;70(24 Suppl):Abstract nr P3-12-03.