Inherited Variants in Wnt Pathway Genes Influence Outcomes of Prostate Cancer Patients Receiving Androgen Deprivation Therapy

Abstract

Aberrant Wnt signaling has been associated with many types of cancer. However, the association of inherited Wnt pathway variants with clinical outcomes in prostate cancer patients receiving androgen deprivation therapy (ADT) has not been determined. Here, we comprehensively studied the contribution of common single nucleotide polymorphisms (SNPs) in Wnt pathway genes to the clinical outcomes of 465 advanced prostate cancer patients treated with ADT. Two SNPs, adenomatous polyposis coli (APC) rs2707765 and rs497844, were significantly (p ≤ 0.009 and q ≤ 0.043) associated with both prostate cancer progression and all-cause mortality, even after multivariate analyses and multiple testing correction. Patients with a greater number of favorable alleles had a longer time to disease progression and better overall survival during ADT (p for trend ≤ 0.003). Additional, cDNA array and in silico analyses of prostate cancer tissue suggested that rs2707765 affects APC expression, which in turn is correlated with tumor aggressiveness and patient prognosis. This study identifies the influence of inherited variants in the Wnt pathway on the efficacy of ADT and highlights a preclinical rationale for using APC as a prognostic marker in advanced prostate cancer.

Keywords: Wnt pathway; androgen deprivation therapy; genetic variation; outcomes; prostate cancer.

Figure 1

Kaplan-Meier curves of time to progression (left panel) and all-cause mortality (ACM) (right panel) during androgen deprivation therapy (ADT) for patients with 0, 1, 2 or 3–4 protective alleles at APC rs2707765 and rs497844. The protective alleles refer to C in rs2707765 and T in rs497844. The more protective alleles a prostate cancer patient carries, the longer their time to progression and ACM. Numbers in parentheses indicate the number of patients.

Figure 2

Correlation of rs2707765 and rs497844 genotypes and APC gene expression in prostate tissues. Boxplots represent APC mRNA expression according to the rs2707765 (left panel) and rs497844 (right panel) genotypes in 87 human prostate tissues (Genotype-Tissue Expression (GTEx) dataset). There is a trend toward increased APC mRNA expression in the prostate tissues of rs2707765 protective allele C carriers and rs497844 protective allele T carriers. The numbers in parentheses indicate the number of cases.

Figure 3

Correlation of APC mRNA expression with prostate cancer progression. (A) APC mRNA expression in 40 prostate cancers and eight normal human prostate tissue specimens, as determined by qRT-PCR, indicates that APC is downregulated in the cancer tissues, especially in those from patients with more advanced stages of cancer; (B) The associations between APC expression and prostate cancer aggressiveness were analyzed using an independent set of Memorial Sloan-Kettering Cancer Center Prostate Oncogenome data. Primary and metastatic prostate cancers display significantly lower APC mRNA expression. rho, Spearman’s rank correlation coefficient. Data points beyond the quartiles are outliers. Kaplan-Meier curves of recurrence-free survival according to the alterations in APC are shown. Patients were dichotomized with or without APC homozygous deletion, mutation and mRNA downregulation. Numbers in parentheses indicate the number of patients.