Abstract 2564: Identification of a novel SPOP missense mutation from targeted next-generation sequencing of men with chromosome 17-q linkage.
Authors: Zuhlke Kimberly A. , Johnson Anna M. , Tomlins Scott A. , Palanisamy Nallasivam , Robbins Christiane M. , Tembe Waibhav A. , Carpten John D. , Lange Ethan M. , Isaacs William B. , Cooney Kathleen A. 
Published: August 2014

Abstract
Speckle-type POZ protein (SPOP), located on chromosome 17q21, encodes the substrate-binding subunit of a Cullin-based E3 ubiquitin ligase gene. The SPOP gene has been shown to be one of the most commonly mutated genes in studies focused on characterization of somatic mutations in prostate tumors. In light of the evidence for prostate cancer linkage to chromosome 17q21-22 markers, we hypothesized that germline variation in SPOP may increase the risk for prostate cancer. In this study, 94 unrelated familial prostate cancer cases from the University of Michigan Prostate Cancer Genetics Project (n= 54) and Johns Hopkins University (n=40) were selected from multiplex prostate cancer families based on evidence of linkage to chromosome 17q21-22. Germline DNA samples were subjected to targeted next-generation sequencing of more than 200 genes in the candidate region which included the exons and UTRs of SPOP. One individual, diagnosed with prostate cancer at age 43, was identified to have a novel missense mutation in exon 10 of the gene which results in an amino acid substitution of asparagine to isoleucine at codon 296 (N296I). Tumor DNA from this individual was positive for LOH at neighboring marker D17S943 as well as an ERG fusion documented by immunohistochemistry. Sanger sequencing was performed using genomic DNA from five additional male relatives and two female relatives. Notably, the N296I mutation completely segregates with prostate cancer affection status among the men in this family; the father and a brother with prostate cancer also carry the mutation, as does another brother affected with both prostate and kidney cancer. The mother and two unaffected brothers do not carry the N296I allele, however the sister of the proband was positive for the variant. To our knowledge, neither of the female relatives has been diagnosed with cancer. The SPOP N296I mutation was not detected in genomic DNA samples from a set of 1411 siblings with and without prostate cancer (775 cases and 636 controls) from 573 families. The N296I mutation is present in the evolutionarily conserved Bric-a-brac, Tramtrack, Broad-complex (BTB) domain. Changes to BTB may affect the ability of SPOP to recruit targets to Cul3 for degradation, thus suggesting a role for SPOP mutations in prostate cancer susceptibility. In conclusion, analysis of a set of chromosome 17q21-22 linked families has led to the identification of a novel rare missense mutation in the SPOP gene and further studies are ongoing to determine the potential role of this variant in prostate cancer susceptibility.
Citation Format: Kimberly A. Zuhlke, Anna M. Johnson, Scott A. Tomlins, Nallasivam Palanisamy, Christiane M. Robbins, Waibhav A. Tembe, John D. Carpten, Ethan M. Lange, William B. Isaacs, Kathleen A. Cooney. Identification of a novel SPOP missense mutation from targeted next-generation sequencing of men with chromosome 17-q linkage. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 2564. doi:10.1158/1538-7445.AM2013-2564