Protein-altering point mutations are uncommon in prostate cancer. The overall and protein-altering mutation rate of primary prostate cancer is among the lowest reported, approximately an order of magnitude lower than other cancers. Consistent with this, recurrent protein-altering mutations are rare in prostate cancer. Mutations in AR, PTEN, and AKT1 are among the most common;these occur rarely in primary prostate cancer, with reported frequency around 1%. The SPOP gene (Speckle-type POZ Protein) encodes for the substrate-recognition component of a Cullin3- based E3-ubiquitin ligase. Mutations in SPOP in prostate cancer were recently reported in two systematic sequencing studies. We have identified the presence of recurrent mutations in SPOP in 6-13% of human prostate cancers in multiple independent patient cohorts (Barbieri et al., Nature Genetics 2012). Recurrent missense mutations were found exclusively in the structurally-defined substrate-binding cleft of SPOP, and structural analysis suggests that these mutations will inactivate SPOP function by disrupting SPOP-substrate interaction. Further, we found that loss of SPOP function in prostate cell lines resulted in increased invasion, and altered gene expression;evidence of this expression signature was identified in primary tumors harboring SPOP mutation. Importantly, all SPOP mutations occurred in tumors that were negative for ERG rearrangement and PTEN deletion;these tumors displayed characteristic somatic copy number aberrations. Taken together, these findings support a distinct molecular class of prostate cancer. The overall goal of this proposal is to define the role of SPOP mutations in prostate cancer and elucidate the biology of SPOP mutant prostate cancer as a distinct molecular subclass. We propose three specific Aims that together will examine the substrate specificity of SPOP mutant proteins, test the common SPOP mutations in an in vivo model of prostate cancer, identify cooperating and mutually exclusive genetic events, and examine the impact of SPOP mutation on prostate cancer patients. We will use a combination of biochemical, structural biology, in vivo and molecular biology approaches to study these events in prostate cancer models systems, while also employing large cohorts of primary and metastatic human prostate cancer samples to integrate genetic and epidemiologic analyses. Furthermore, we have assembled an outstanding team of co- investigators with complementary skills and resources to execute these proposed studies.

Public Health Relevance

Prostate Cancer is the most common non-cutaneous cancer and the second leading cause of cancer death in American men with over 31,000 estimated deaths in 2010. The recent discovery that approximately 10% of prostate cancers harbor a mutation in a gene known as SPOP suggests that this is the most common recurrent non-gene fusion mutation in prostate cancer. The current proposal will attempt to understand the role SPOP mutations play in prostate cancer disease progression by untangling the biology of this newly identified mutation.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
2R01CA125612-05A1
Application #
8506437
Study Section
Molecular Oncogenesis Study Section (MONC)
Program Officer
Nelson, Stefanie A
Project Start
2006-12-01
Project End
2018-03-31
Budget Start
2013-04-01
Budget End
2014-03-31
Support Year
5
Fiscal Year
2013
Total Cost
$408,737
Indirect Cost
$159,124
Name
Weill Medical College of Cornell University
Department
Pathology
Type
Schools of Medicine
DUNS #
060217502
City
New York
State
NY
Country
United States
Zip Code
10065
Blattner, Mirjam; Lee, Daniel J; O'Reilly, Catherine et al. (2014) SPOP mutations in prostate cancer across demographically diverse patient cohorts. Neoplasia 16:14-20
Khani, Francesca; Mosquera, Juan Miguel; Park, Kyung et al. (2014) Evidence for molecular differences in prostate cancer between African American and Caucasian men. Clin Cancer Res 20:4925-34
Prandi, Davide; Baca, Sylvan C; Romanel, Alessandro et al. (2014) Unraveling the clonal hierarchy of somatic genomic aberrations. Genome Biol 15:439
Baca, Sylvan C; Prandi, Davide; Lawrence, Michael S et al. (2013) Punctuated evolution of prostate cancer genomes. Cell 153:666-77
Demichelis, Francesca; Garraway, Levi A; Rubin, Mark A (2013) Molecular archeology: unearthing androgen-induced structural rearrangements in prostate cancer genomes. Cancer Cell 23:133-5
Svensson, Maria A; LaFargue, Christopher J; MacDonald, Theresa Y et al. (2011) Testing mutual exclusivity of ETS rearranged prostate cancer. Lab Invest 91:404-12
Wang, Xiao-Song; Shankar, Sunita; Dhanasekaran, Saravana M et al. (2011) Characterization of KRAS rearrangements in metastatic prostate cancer. Cancer Discov 1:35-43
Pflueger, Dorothee; Terry, Stephane; Sboner, Andrea et al. (2011) Discovery of non-ETS gene fusions in human prostate cancer using next-generation RNA sequencing. Genome Res 21:56-67
Esgueva, Raquel; Perner, Sven; J LaFargue, Christopher et al. (2010) Prevalence of TMPRSS2-ERG and SLC45A3-ERG gene fusions in a large prostatectomy cohort. Mod Pathol 23:539-46
Perner, Sven; Svensson, Maria A; Hossain, Ruhella R et al. (2010) ERG rearrangement metastasis patterns in locally advanced prostate cancer. Urology 75:762-7

Showing the most recent 10 out of 17 publications