Deep Sequencing Reveals Novel Mutations in Androgen Receptor-Related Genes in Prostate Cancer

Prostate cancer (PCa) is the second most frequent tumor and the fifth leading cause of cancer-related death in men worldwide. PCa shows the largest clinical disparities across Asian, Caucasian, and African descendants among all cancer types, proving that the ethnic genetic background plays a significant role in PCa. Androgen Receptor (AR) gene malfunctioning represents the most prevalent cause of PCa. AR also displays a broad spectrum of genetic variability across ethnic backgrounds differently associated with cancer risk. We conducted a massive sequencing analysis of 15 genes highly relevant for PCa or the AR activation pathway in biopsies from 64 tumors and 36 benign prostate samples from Mexican patients. We identified 3414 genomic mutations and observed that AR, SPOP, TP53, FOXA1, and MTOR had the highest rate of pathogenic mutations in tumors, evidencing their relevance in PCa. AR showed 13 unique mutations, followed by SPOP (6), TP53 (5), FOXA1 (4), and MTOR (3). We discovered 19 novel mutations specific of Hispanic patients, a population only scarcely studied, thus adding critical information on the genetic diversity of the mutational landscape in genes key for PCa. We discuss the clinical relevance of these mutations and predict the structural consequences on the proteins. Mutations in FOXA1 showed significant negative association with patient survival and might be used as novel PCa markers, at least for Hispanic men.