Exome sequencing identifies recurrent SPOP, FOXA1 and MED12 mutations in prostate cancer

By C. Barbieri, S. Baca, M. Lawrence, F. Demichelis, Mirjam Blattner, Jean-Philippe P. Theurillat, Thomas A. White, P. Stojanov, E. Allen, Nicolas Stransky and 36 more. Nature Genetics, 2012

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Prostate cancer is the second most common cancer in men worldwide and causes over 250,000 deaths each year. Overtreatment of indolent disease also results in significant morbidity. Common genetic alterations in prostate cancer include losses of NKX3.1 (8p21) and PTEN (10q23), gains of AR (the androgen receptor gene) and fusion of ETS family transcription factor genes with androgen-responsive promoters. Recurrent somatic base-pair substitutions are believed to be less contributory in prostate tumorigenesis but have not been systematically analyzed in large cohorts. Here, we sequenced the exomes of 112 prostate tumor and normal tissue pairs. New recurrent mutations were identified in multiple genes, including MED12 and FOXA1. SPOP was the most frequently mutated gene, with mutations involving the SPOP substrate-binding cleft in 6–15% of tumors across multiple independent cohorts. Prostate cancers with mutant SPOP lacked ETS family gene rearrangements and showed a distinct pattern of genomic alterations. Thus, SPOP mutations may define a new molecular subtype of prostate cancer.

Subfields: Molecular Biology, Pulmonary and Respiratory Medicine

View Paper: https://www.semanticscholar.org/paper/11f83e397eee2d33bb82c4d93e5616d0ad74eec9

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Citations in the corpus

Lessons from the cancer genome. (2013, neutral): “These mutations are mutually exclusive with ETS rearrangements, thereby defining a distinct genetic subtype of prostate cancer (Barbieri et al., 2012).”
Comprehensive molecular portraits of invasive lobular breast cancer (2015, methodology): “A similar mutational pattern was observed by combining multiple prostate cancer sequencing studies (Baca et al., 2013; Barbieri et al., 2012; Grasso et al., 2012; Robinson et al., 2015) (Figure S3A), and confirmed by the TCGA prostate cancer project (Robinson et al., 2015).”
Organoid cultures derived from patients with advanced prostate cancer (2014, positive): “4 per sample, consistent with reported mutation frequency in CRPC tissue (Baca et al., 2013; Barbieri et al., 2012; Grasso et al., 2012) (Figure 2A, Table S2), and the specific genes are similar to those reported in metastatic CRPC (Figure 2B, Table S3).”
Punctuated Evolution of Prostate Cancer Genomes (2013, positive): “0 human SNP microarray (Affymetrix, Santa Clara, CA, USA) data as described previously (Barbieri et al., 2012).”
Cyclin D-CDK4 kinase destabilizes PD-L1 via Cul3SPOP to control cancer immune surveillance (2017, positive): “SPOP mutations occur in 10–15% of human prostate cancers, and are largely clustered within the MATH domain 24,25 (Extended Data Fig.”
The long tail of oncogenic drivers in prostate cancer (2018, neutral): “When possible, we used ERG fusions calls defined as per the original source data 2,4 .”
Genomic correlates of clinical outcome in advanced prostate cancer (2019, background): “CHD1 alterations also tended to co-occur with SPOP mutations (3).”
The Genomic Landscape of Endocrine-Resistant Advanced Breast Cancers (2018, background): “Unlike the SPOP mutations described in prostate cancers (Barbieri et al., 2012), the E78K mutation affects a unique region of the MATH domain where rare loss-of-function mutations prevent SPOP-mediated degradation of ER in endometrial cancers (McCleskey et al.”
Genetics and biology of prostate cancer (2018, background): “Further study is warranted to evaluate CHD1 function in the SPOP mutant subtype.”
Transcriptional Regulation and its Misregulation in Disease (2013, positive): “MED12 mutations also occur frequently in prostate cancer (Barbieri et al., 2012).”
Resistance to vemurafenib resulting from a novel mutation in the BRAFV600E kinase domain (2013, background): “, 2011) revealed that the T1514A mutation was recently found in an individual with prostate cancer (Barbieri et al., 2012), suggesting that the elevated kinase activity of BRAFL505H may contribute to cancer development.”