Somatic driver mutation prevalence in 1844 prostate cancers identifies ZNRF3 loss as a predictor of metastatic relapse

Abstract

Driver gene mutations that are more prevalent in metastatic, castration-resistant prostate cancer (mCRPC) than localized disease represent candidate prognostic biomarkers. We analyze 1,844 localized (1,289) or mCRPC (555) tumors and quantify the prevalence of 113 somatic driver single nucleotide variants (SNVs), copy number aberrations (CNAs), and structural variants (SVs) in each state. One-third are significantly more prevalent in mCRPC than expected while a quarter are less prevalent. Mutations in AR and its enhancer are more prevalent in mCRPC, as are those in TP53, MYC, ZNRF3 and PRKDC. ZNRF3 loss is associated with decreased ZNRF3 mRNA abundance, WNT, cell cycle & PRC1/2 activity, and genomic instability. ZNRF3 loss, RNA downregulation and hypermethylation are prognostic of metastasis and overall survival, independent of clinical and pathologic indices. These data demonstrate a strategy for identifying biomarkers of localized cancer aggression, with ZNRF3 loss as a predictor of metastasis in prostate cancer.

Prognostic Values of Gene Copy Number Alterations in Prostate Cancer

“…We confirmed the prognostic and risk stratification utility of previously studied gene level CNAs and other alterations [2,[9][10][11][12]. For example, the CNAs of oncogenes and tumour suppressor genes, such as PIK3CA, CHD1, MYC, PTEN, CCND1, CDKN1B, TP53, CCNE1, NKX3.1, and RB1, have previously been shown to impact prognosis, tumour progression, and disease stage of PCa and other cancers [2,[17][18][19][20][21][23][24][25][26][27][28][29][30][31][32][33][34][35][36][37]. Furthermore, molecular alterations of androgen receptor pathway genes, including AR, MED12, FOXA1, NCOR1, NCOR2, SPOP, NCOA2, and ZBTB16, have similarly been associated with different disease stages [2,22,33,37,38,[48][49][50][51][52].…”

“…Furthermore, molecular alterations of androgen receptor pathway genes, including AR, MED12, FOXA1, NCOR1, NCOR2, SPOP, NCOA2, and ZBTB16, have similarly been associated with different disease stages [2,22,33,37,38,[48][49][50][51][52]. Besides AR, NCOA2, and ZBTB16, whose copy number changes were previously associated with late-stage diseases, the molecular alterations found in other members of the pathway were mainly somatic point mutations and altered expressions [2,18,30,34,35,[45][46][47][48]. However, this study found that MED12, FOXA1, NCOR1, NCOR2, and SPOP exhibited copy number changes that were associated with disease stages.…”

Methylation pattern of Caveolin-1 in prostate cancer as potential cfDNA biomarker

“…Blood is commonly used in diagnostics but low in cfDNA concentration while semen is, partly, secreted from the prostate and high in cfDNA concentrations [ 21 , 22 ]. Considering the variety of genetic alternations in PCa (113 mutations in 72 driver gene loci), we focused on epigenetic modifications which are restricted to promoters and retain specific patterns within the same cancer model [ 23–25 ]. DNA methylation microarray analysis containing 385,000 probes revealed 20 most significantly altered loci comparing PCa tissue and prostate tissue from BPH patients [ 26 ].…”

Exploring the Wnt Pathway as a Therapeutic Target for Prostate Cancer

“…Interestingly, ZNRF3 deep deletions are also observed in primary and metastatic prostate cancer (≤2%) ( Tables S1–S4 ), potentially promoting Wnt signaling via the stabilization of FZD receptors and Wnt co-receptors at the plasma membrane. Nevertheless, the frequency of ZNRF3 genomic loss was recently reported to be markedly higher (29.9% of metastatic and 9.54% of localized prostate cancers), and ZNRF3 loss positively correlates with biochemical recurrence and metastatic relapse of localized disease [ 140 ]. Future investigations exploring the role of clinically relevant genetic aberrations in RNF43 and ZNRF3 during primary and metastatic prostate cancer will be important to ascertain their impact on Wnt signaling.…”