Next-Generation Sequencing Assay Raises New Questions in a Case of Metastatic Prostate Cancer.

Abstract

A 72-year-old man with a history of prostate cancer presented with metastases to the lung, liver, and bone. He had been initially diagnosed with prostate cancer 22 years prior and had been treated with radical prostatectomy, external beam radiation, and androgen deprivation therapy. The liver mass was sampled by fine-needle aspiration and submitted for genetic evaluation using the UCSF500 cancer gene panel (Version 2) that evaluates 484 genes for mutations. UCSF500 analysis involves sequencing of the patient's tumor and sequencing of a peripheral blood sample to evaluate germline variants. Deleterious somatic alterations commonly associated with advanced prostate cancer were identified in the patient's tumor sample (1–3). These included a TMPRSS2/ERG 3 fusion, homozygous deletions of PTEN and MAP3K1 , an APC frameshift mutation, and an SPTA1 nonsense mutation (Table 1). Four additional single-nucleotide variants of uncertain significance (VUS)4 were identified (Table 1), and multiple regions of copy number gain and loss were seen across the genome. View this table: Table 1. Summary of gene variants identified, their classification on the patient report in this case, and bioinformatics parameters. Sequencing also identified a 3-nucleotide germline heterozygous fumarate hydratase ( FH ) gene alteration, NM\_00143(FH):c.1431\_1433dup, which is predicted to result in a lysine duplication, p.Lys477dup. The allele frequencies for this variant in the peripheral blood and tumor samples …