Mutation Spectrum, Tumor Subtypes, and Risk factors of Prostate Cancer Seen at Ocean Road Cancer Institute and Muhimbili National Hospital, Dar Es Salaam-Tanzania

Abstract

Background: Prostate cancer (PCa) is a major health problem in Tanzania, with a high age standardised incidence rate of 10.7 per 100,000 males and a mortality rate of 9.4 per 100,000 males, which are among the highest in Africa and developing regions While studies worldwide have explored gene mutations, tumour molecular types, and risk factors for PCa, little is known about how these apply to Tanzania. Lack of local data makes it hard to understand what influences PCa in Tanzanian men. The study examined gene mutations, classified tumours based on ETS-related gene (ERG) fusion and phosphatase and tensin homolog (PTEN) expression, and identified PCa risk factors. Knowing whether a tumour is ERG-positive or PTEN-negative helps identify patients who may benefit from targeted therapies. The absence of localised data on genetic mutations, tumour subtyping and risk factors specific to PCa in Tanzania has led to reliance on findings from other populations despite known regional genetic and environmental differences. This study provides critical findings for developing precise therapeutic strategies tailored to the unique genetic landscape of Tanzanian patients Objective: To determine the mutation spectrum of BRCA1/2, ATM, PALB2, TP53, CHEK2, MLH1, MSH2, MSH6, and PMS2 genes, ERG/PTEN tumour subtypes, and risk factors associated with PCa among Tanzanian cancer patients Methods: This study combined a case-control design to assess PCa risk factors with a cross sectional study on tumour subtypes and genetic mutations. Ethical approvals for the study were obtained. Consented participants were recruited from Muhimbili National Hospital and Ocean Road Cancer Institute. Risk factors were assessed in 166 participants using a questionnaire. Tumour subtyping was conducted on 83 PCa cases using immunohistochemistry (IHC) staining for ERG and PTEN on archived tissue samples. Targeted next-generation sequencing (NGS) was performed on dried blood spots from 30 individuals who met the NCCN genetic testing criteria. Logistic regression and Chi-Square were used to examine the association between ERG expression and the Gleason class (P=0.05). NGS data underwent quality control, read alignment, variant calling, and pathogenicity prediction using bioinformatic tools. Results: Significant risk factors included advanced age (AOR = 1.05, 95% CI = 1.01–1.09). alcohol consumption (AOR = 2.75), high red meat intake (AOR = 7.88), family history of cancer (AOR = 6.38), and history of gonorrhea infection (AOR = 6.52). Protective factors were regular consumption of soy products (AOR = 0.285), coffee (AOR = 0.57), and tomatoes (AOR = 0.17), as well as higher income levels (AOR = 0.51), and not being married (AOR = 0.23). The most common tumour subtypes were ERG-/PTEN- (68.68%) and ERG+/PTEN- (30.12%), with PTEN loss linked to aggressive tumour behaviour. Likely pathogenic variants were ATM gene (c.131A>G, c.2289T>A) and PMS2 gene (c.497T>C), suggesting impaired DNA repair mechanisms. ERG expression showed a significant association with Gleason class ( p = 0.05), while mutations in ATM, PMS2, BRCA1, and MLH1 were associated with high pre-operative PSA levels. Conclusion and recommendation: Mutations in ATM and PMS2 were identified as key genetic alterations associated with PCa, while the most prevalent tumour subtypes were ERG-/PTEN- and ERG+/PTEN-. Significant risk factors included advanced age, frequent alcohol consumption, high red meat intake, a history of gonorrhea infection, and a family history of PCa. Also, ERG expression was strongly associated with higher Gleason scores and high pre-operative PSA levels, indicating its potential as a prognostic marker. Findings recommend that Genetic testing for pathogenic mutations, especially in ATM and PMS2, should be prioritised for targeted therapies. Routine IHC staining for ERG and PTEN subtypes in referral hospitals will aid in molecular classification, while incorporating risk factor assessment can optimise patient management and treatment strategies.