Characterization of Novel Genetic Alterations in Prostate Cancer

Abstract

Prostate cancer (PCa) is a common disease of the western society. Although it is mostly an indolent and slow-growing cancer, progression to late-stage PCa often results in a life threatening disease. At the molecular level, PTEN loss and ETS gene fusions are the most common genetic abnormalities observed. In order to identify novel candidate markers and/or treatment targets in PCa, we performed DNA and RNA microarrays together with whole genome sequencing of several PCa samples. We identified several novel gene fusions both in PCa cell lines and patients. The functional relevance of the gene fusions GPS2-MPP2 in the LNCaP cell line and MPP5-FAM71D in the PC346C cell line, both in-frame, was addressed. GPS2-MPP2 and MPP5-FAM71D were shown to promote proliferation in the cell lines carrying the fusion. In addition, GPS2-MPP2 also had a suppressive effect of apoptosis. Both these gene fusions seem to be patient specific, although the upregulation of FAM71D, a switched off gene in normal cells, was observed in 10 out of 201 other PCa samples. Whole genome sequencing of a mismatch repair (MMR) deficient PCa cell line, PC346C, allowed the identification of gene mutations due to MMR deficiency. A mutation in a 9C repeat of the PRRT2 gene was frequently observed in PCa, colorectal (CRC), endometrial and ovarian MMR deficient cell lines as well as CRC and endometrial microsatellite instable patient samples. The mutated PRRT2 increased both proliferation and migration. Finally, we detected in the VCaP PCa cell line a large number of rearrangements of chromosome arm 5q caused by chromothripsis. The number of gene fusions generated by chromothripsis was limited and only one fusion resulted in an in-frame transcript encoding a chimeric protein.