Association between a germline OCA2 polymorphism at chromosome 15q13.1 and estrogen receptor-negative breast cancer survival

Abstract

Background: Traditional prognostic factors for survival and treatment response of patients with breast cancer do not fully account for observed survival variation. We used available genotype data from a previously conducted two-stage, breast cancer susceptibility genome-wide association study (ie, Studies of Epidemiology and Risk factors in Cancer Heredity [SEARCH]) to investigate associations between variation in germline DNA and overall survival.

Methods: We evaluated possible associations between overall survival after a breast cancer diagnosis and 10 621 germline single-nucleotide polymorphisms (SNPs) from up to 3761 patients with invasive breast cancer (including 647 deaths and 26 978 person-years at risk) that were genotyped previously in the SEARCH study with high-density oligonucleotide microarrays (ie, hypothesis-generating set). Associations with all-cause mortality were assessed for each SNP by use of Cox regression analysis, generating a per rare allele hazard ratio (HR). To validate putative associations, we used patient genotype information that had been obtained with 5' nuclease assay or mass spectrometry and overall survival information for up to 14 096 patients with invasive breast cancer (including 2303 deaths and 70 019 person-years at risk) from 15 international case-control studies (ie, validation set). Fixed-effects meta-analysis was used to generate an overall effect estimate in the validation dataset and in combined SEARCH and validation datasets. All statistical tests were two-sided.

Results: In the hypothesis-generating dataset, SNP rs4778137 (C>G) of the OCA2 gene at 15q13.1 was statistically significantly associated with overall survival among patients with estrogen receptor-negative tumors, with the rare G allele being associated with increased overall survival (HR of death per rare allele carried = 0.56, 95% confidence interval [CI] = 0.41 to 0.75, P = 9.2 x 10(-5)). This association was also observed in the validation dataset (HR of death per rare allele carried = 0.88, 95% CI = 0.78 to 0.99, P = .03) and in the combined dataset (HR of death per rare allele carried = 0.82, 95% CI = 0.73 to 0.92, P = 5 x 10(-4)).

Conclusion: The rare G allele of the OCA2 polymorphism, rs4778137, may be associated with improved overall survival among patients with estrogen receptor-negative breast cancer.

Figure 1

Quantile–quantile plot for the test statistics for the 10 621 single-nucleotide polymorphisms (SNPs) evaluated in the Studies of Epidemiology and Risk factors in Cancer Heredity (SEARCH) dataset. The test statistic was the χ² statistic from two-sided χ² trend tests with 1 df. Solid circles represent the expected and observed test statistics for each SNP. Under the null hypothesis of no association at any locus, the points would be expected to follow the straight line. SNPs rs6626269 and rs4778137 are represented by a solid diamond and a solid square, respectively.

Figure 2

Associations between single-nucleotide polymorphism rs6626269 or rs4778137 and overall survival. Per-allele hazard ratios (HRs) and 95% confidence intervals (CIs) are presented. A) Nonstratified analyses for rs6626269 and rs4778137. B) Analyses for rs4778137 stratified by estrogen receptor (ER) status (ER positive [ER+] and ER negative [ER−]). Data are shown for analyses with the hypothesis-generating set (Studies of Epidemiology and Risk factors in Cancer Heredity [SEARCH]), individual studies in the validation dataset, the entire validation set, and a combined dataset (overall) containing data from the hypothesis-generating set and the validation set. Supplementary Table 1 (available online) presents descriptions of all studies. Squares = study-specific hazard ratios; area of the each square = inverse of the variance of the estimate; horizontal lines = 95% CIs; diamonds = summary hazard ratio estimates encompassing 95% CIs; dotted vertical line = combined summary hazard ratio. Hazard ratio statistical significance assessed by a trend test with 1 df. Study heterogeneity was assessed by use of the I² statistic. All statistical tests were two-sided. BBCC = Bavarian Breast Cancer Cases and Controls; CGPS = Copenhagen Breast Cancer Study and Copenhagen General Population Study; CNIO-BCS = Spanish National Cancer Centre Breast Cancer Study; GESBC = Genetic Epidemiology Study of Breast Cancer by Age 50; HEBCS = Helsinki Breast Cancer Study; KARBAC = Karolinska Breast Cancer Study; KBCP = Kuopio Breast Cancer Project; kConFab/AOCS = The Kathleen Cuningham Foundation Consortium for Research into Familial Breast Cancer/Australian Ovarian Cancer Study; MCBCS = Mayo Clinic Breast Cancer Study; MCCS = Melbourne Collaborative Cohort Study; ORIGO = Leiden University Medical Centre Breast Cancer Study; PBCS = Polish Breast Cancer Study; SASBAC = Singapore and Swedish Breast Cancer Study; SBCS = Sheffield Breast Cancer Study; UCIBCS = University of California Irvine Breast Cancer Study.

Figure 3

Cumulative overall survival among patients with estrogen receptor (ER)–negative breast cancer by genotype of the single-nucleotide polymorphism rs4778137. A Kaplan–Meier analysis was used. Total patients at risk in the analysis and number of patients at risk and overall survival rates with 95% confidence intervals (95% CI) for years 5, 10, and 15 after breast cancer diagnosis are presented. A) Cumulative survival for patients in the hypothesis-generating dataset from the Studies of Epidemiology and Risk factors in Cancer Heredity (SEARCH) study. B) Cumulative survival for patients in the validation set. C) Cumulative survival for patients in the combined hypothesis-generating and validation datasets. D) Predicted cumulative survival adjusted for study site for patients in the combined hypothesis-generating and validation datasets, adjusted to the baseline hazard function of the SEARCH study. All four analyses were stratified by rs4778137 genotype (C = common; G = rare). ** = patient numbers were too few to estimate a survival rate at this time point.