Variants on the promoter region of PTEN affect breast cancer progression and patient survival

Abstract

Introduction: The PTEN gene, a regulator of the phosphatidylinositol-3-kinase (PI3K)/Akt oncogenic pathway, is mutated in various cancers and its expression has been associated with tumor progression in a dose-dependent fashion. We investigated the effect of germline variation in the promoter region of the PTEN gene on clinical characteristics and survival in breast cancer.

Methods: We screened the promoter region of the PTEN gene for germline variation in 330 familial breast cancer cases and further determined the genotypes of three detected PTEN promoter polymorphisms -903GA, -975GC, and -1026CA in a total of 2,412 breast cancer patients to evaluate the effects of the variants on tumor characteristics and disease outcome. We compared the gene expression profiles in breast cancers of 10 variant carriers and 10 matched non-carriers and performed further survival analyses based on the differentially expressed genes.

Results: All three promoter variants associated with worse prognosis. The Cox's regression hazard ratio for 10-year breast cancer specific survival in multivariate analysis was 2.01 (95% CI 1.17 to 3.46) P = 0.0119, and for 5-year breast cancer death or distant metastasis free survival 1.79 (95% CI 1.03 to 3.11) P = 0.0381 for the variant carriers, indicating PTEN promoter variants as an independent prognostic factor. The breast tumors from the promoter variant carriers exhibited a similar gene expression signature of 160 differentially expressed genes compared to matched non-carrier tumors. The signature further stratified patients into two groups with different recurrence free survival in independent breast cancer gene expression data sets.

Conclusions: Inherited variation in the PTEN promoter region affects the tumor progression and gene expression profile in breast cancer. Further studies are warranted to establish PTEN promoter variants as clinical markers for prognosis in breast cancer.

Figure 1

Kaplan-Meier plots of cumulative survival for breast cancer patients carrying a PTEN promoter variant. The plots for patients with different variants are shown for -903GA in green, -975GC in orange, -1026CA in red, and for non-carrier Wild type in blue. All variants showed significant long term survival effect in breast cancer specific 10-year analyses (A) with cumulative survival at 120 months of 82.7% (95% CI 80.7 to 84.7%) for non-carriers, 71.3% (95% CI 58.8 to 83.8%) for -903GA (P = 0.016), 57.2% (95% CI 33.1 to 81.3%) for -975GC (P = 0.002), and 65.3% (95% CI 47.1 to 83.5%) for -1026CA (P = 0.014). Two variants also showed significant effect in five year breast cancer death or distant metastasis free analysis (B) with cumulative survival at 60 months of 82.5% (95% CI 80.7 to 84.3%) for non-carriers, 64.3% (95% CI 51.2 to 77.3%) for -903GA (P = 0.002), 63.8% (95% CI 44.4 to 83.2%) for -975GC (P = 0.010), and 76.9% (95% CI 62.6 to 91.0%) for -1026CA (P = 0.279).

Figure 2

The tumor gene expression signatures of the 160 differentially expressed genes. The expression of the signature genes in the tumors of PTEN promoter variant carriers and non carriers show differential clustering separating the two groups.

Figure 3

Survival differences by the expression of the signature genes in independent breast cancer data sets. Expression patterns of the 160 signature genes affect the five-year breast cancer recurrence in Helsinki breast cancer data set GSE24450 (A) as well as in other publicly available breast cancer gene expression data sets from Stockholm GSE1456 (B) and from Rotterdam GSE2034 (C). Similar trend, although not significant was present also in Uppsala GSE4922 data set (D).