Cell Rep: How oncogenes regulate genetic variation in prostate cancer

Researchers from the Queen Mary University of London's Barts Cancer Institute (BCI), the Italian Institute for Genomic Medicine and the University of Milan have found that an oncogene plays a new role
in controlling important genetic variants in prostate cancer.

The findings, published in Cell Reports, reveal how the gene affects the production of prostate cancer gene variants that may predict disease recurrence and represent new drug targets to improve patient survival
.

Dr Prabhakar Rajan, co-senior author of the study, said: "Prostate cancer is the most common male cancer in the world and the leading cause
of cancer-related death in men.

Selective splicing is the process of recombining gene fragments to create different combinations of gene codes, known as "splicing variants," that provide instructions
for making proteins.

Selective splicing is an important process for regulating gene expression and generating genetic and protein diversity within normal cells; However, in many cancer types, including prostate cancer, it is destroyed
.

In this study, the team found that the oncogene FOXA1 is a key regulator of selective splicing in prostate cancer and may control the generation of splicing variants that can affect disease recurrence and patient survival
.

FOXA1 fine-tunes selective splicing for prostate cancer

FOXA1 is a protein
known as a pioneer transcription factor.

By evaluating cell line models and alternative splicing in primary cases of prostate cancer, the team found that high levels of FOXA1 limited the genetic diversity
of splicing variants that have functional benefits for cancer cells.

Dr Rajan said: "This unique finding has never been used to replace splicing controllers, which could mean that FOXA1 directs prostate cancer cells to act
in a specific way that could be harmful to patients.

Professor Matteo Cereda, co-senior author of the study, associate professor at the University of Milan and head of the Italian Institute of Genomic Medicine, added: "We show for the first time that early participants in transcriptional regulation are also responsible for the fine-tuning of alternative splicing
.

Potential new treatment targets

To determine whether foxa1-controlled selective splicing had an effect on patient survival, the team analyzed clinical data from more than 300 patients with primary prostate cancer, which were available
through the cancer genome map.

Although high levels of FOXA1 reduced the variability of splicing, the team found that FOXA1 enhanced the inclusion of genetic fragments of splicing variants, which are important markers
of prostate cancer recurrence.

Dr Rajan said: "This study illustrates how we can harness the power of genomics to make important scientific discoveries
in how to control genetic variation in prostate cancer.

The team now wants to further test whether the splicing variants they've identified associated with cancer recurrence are useful in predicting real-world disease recurrence, and conduct experiments to determine whether targeting these genes could represent a new way
to treat prostate cancer.

Dr Rajan's work on this research was supported by funding
from Cancer Research UK, the Butts Charity, the Orchid Charity, the Royal College of Surgeons and the Urology Foundation.

Professor Cereda's work on this research was funded
by AIRC, the University of São Paulo Foundation and the Piemontese sul Ricerca Fondazione del Piemonte per l' Oncology Foundation.