Clinically significant prognostic and therapeutic pathogenic variants identified in advanced prostate cancer patients

Introduction

Prostate cancer is one of the most common types of cancer in men and develops from cells in the prostate gland. Multiple risk factors have been associated with prostate cancer such as family history, age, obesity, and others []. During prostate cancer development, genetic mutations that are either inherited – germline mutations – or acquired during the lifetime of a person – somatic mutations – cause the formation of malignant cancerous cells that divide uncontrollably leading to the formation of a tumour.

Genetic analysis of prostate tumours and identification of germline and somatic mutations that lead to prostate cancer development has high clinical benefit []. Apart from the eligibility for precision therapy drugs that specifically target mutations or proteins that contribute to cancer growth, the discovery of frequently mutated genes in prostate cancer patients can also have a prognostic value. Therefore, identification and evaluation of clinically significant genes is critical and can have a significant therapeutic impact on prostate cancer patients.

The aim

Although different studies have identified germline mutations linked to prostate cancer, studies that have investigated somatic mutations are limited. Therefore, the aim of this study was the identification of somatic mutations that contribute to prostate cancer development, the investigation into their prognostic and predictive significance as well as their therapeutic value for precision medicine.

Methodology and results

This study used the  prostate cancer panel in 196 patients with advanced prostate cancer. The ForeSENTIA tumour molecular profile genetic test, developed by Medicover Genetics, utilises a proprietary technology platform that combines target capture enrichment technology via next-generation sequencing (NGS) along with novel bioinformatic pipelines. By analysing the tumour molecular profile of advanced prostate cancer patients, clinically significant somatic gene alterations were identified in 26 genes. These include homologous recombination repair genes such as ATM, BRCA1, and BRCA2, and mismatch repair genes such as MSH2 and PMS2. Other commonly mutated genes identified in this study are TP53, TMPRSS2, PTEN, APC, MYC, BRAF, and PIK3CA; with TP53 being the most frequently mutated gene in this study. To evaluate the performance of different NGS platforms, randomly selected samples were additionally sequenced on another NGS-based panel. Results showed that ForeSENTIA exclusively identified TMPRSS2-ERG rearrangements, AR or MYC amplifications. This is due to the powerful technological features of ForeSENTIA, which enable testing of different types of genetic alterations, including structural variants not covered by the other assay. In addition, microsatellite instability, a predictive biomarker for immunotherapy options [], was detected in 3.1% of patients.

The prognostic and clinical significance of the identified somatic mutations in these genes were also evaluated, showing that patients with a mutation in the TP53 gene had worse overall survival compared to patients without the specific mutation.

Significance

This study highlights the importance of identifying somatic mutations and their clinical significance in prostate cancer patients. Evaluating the somatic genetic alterations correlated with pancreatic cancer contributes to developing novel drugs while advancing the field of precision medicine and maximising the clinical benefit for patients.