Genetic variants of the Wnt signaling pathway as predictors of aggressive disease and reclassification in men with early stage prostate cancer on active surveillance

203 Background: Aberrations in Wnt signaling pathway (WSP) are implicated in disease progression and resistance of multiple malignancies including prostate cancer (PCa). We sought to characterize the clinical phenotype and molecular genotype of PCa patients with WSP alterations. Methods: Eligible patients included those with PCa having undergone clinical-grade next generation DNA sequencing of tumor derived from prostate or metastasis tissue. We identified patients with somatic activating mutations in CTNNB1 and RSPO2, or inactivating mutations in APC, RNF43, or ZNRF3. Patient and disease characteristics were collected. Clinical and outcome parameters were associated with WSP mutation status using STATA(V. 13.1, College Station, Texas). Results: A total of 169 patients were identified of whom 29 (18.1%) had a WSP activating mutation. Median age of the overall cohort was 64.85 (IQR 56.77, 70.36). 115 (68.0%) patients had Gleason 8-10 disease, 34 (20.1%) presented with de novo metastatic disease, 85 (50.3%) developed CRPC and 23 (13.6%) developed visceral metastases. Clinical characteristics were similar between biomarker groups. There was no association with the presence of a Wnt activating mutation and RB1, p53, pTEN, or BRCA1/2 alteration. Median time to CRPC was 39.42 (IQR 14.50 – 87.52) and 24.39 (IQR 14.99 – 46.03) months for no-WSP and WSP-aberrant respectively. Median 5-year OS was 83.7% (95% CI 73.0-90.4%) and 79.6% (95% CI 52.9 – 92.2%) months for no-WSP and WSP-aberrant respectively. Table evaluates biomarker status with time to CRPC development and overall survival (OS). Conclusions: We observe that somatic WSP activating mutations are present in 18.1% of patients with mPCa, consist with prior reports. Understanding the clinical significance of WSP alterations is critical to inform treatment strategies in patients with advanced disease.[Table: see text]

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Reverse Regulation Between sFRP 5 and Dkk 1 Gene in Early Stage Lung Adenocancer

10.21203/rs.3.rs-434159/v1 ◽

2021 ◽

Author(s):

Arife Zeybek ◽

Necdet Oz ◽

Serdar Kalemci ◽

Kursad Tosun ◽

Tuba Gökdoğan Edgünlü ◽

...

Keyword(s):

Lung Adenocarcinoma ◽

Wnt Signaling ◽

Signaling Pathway ◽

Tumor Tissue ◽

Early Stage ◽

Wnt Signaling Pathway ◽

Normal Lung ◽

Pcr Analysis ◽

Related Protein ◽

Expression Levels

Abstract Purpose: We aimed to examine the expression levels of the genes of APC (Adenomatous Polyposis Coli) 1, APC 2, Dkk (Dickkopf related protein) 1, Dkk -3, sFRP (Secreted frizzled-related protein) -2, sFRP-4, and sFRP-5 genes which play a role in the Wnt signaling pathway in lung adenocarcinoma and adjacent normal lung tissues, and to evaluate their relationship with clinical-pathological factors.Materials and methods: Between 2011 and 2018, the expression levels of the relevant genes in formalin-fixed paraffin-embedded tumor and adjacent intact lung tissue samples of 57 patients who were operated for lung adenocarcinoma were determined by Real-time PCR analysis. Results: The expression levels of the Dkk-1 gene in the tumor tissue, especially in stage I-II, were statistically significantly suppressed compared to normal tissue (p <0.025 ). Although Dkk-1 gene expression was suppressed in the tumor tissue of patients with early-stage lung adenocarcinoma, the level of expression of the sFRP-5 gene was found to be statistically significantly higher (p<0.039). Conclusion: In our study, between the sFRP-5 and Dkk-1 genes, known as the extracellular antagonist of the Wnt signaling pathway was found the reverse regulation. sFRP-5 gene was found as having an oncogenic role in adenocarcinoma development. Reverse regulation between these genes in early-stage lung adenocarcinoma may shed light on the mechanisms associated with the development of carcinogenesis. For that reason, clinically, this relationship needs to research in a larger series of pure adenocarcinoma and normal human lung tissues, separated by its stage, for potential therapeutic target or prognostic its significance.

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