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

Barbieri, Christopher E.; Baca, Sylvan C.; Lawrence, Michael S.; Demichelis, Francesca; Blattner, Mirjam; Theurillat, Jean Philippe; White, Thomas A.; Stojanov, Petar; Allen, Eliezer M. Van; Stransky, Nicolas; Nickerson, Elizabeth; Chae, Sung Suk; Boysen, Gunther; Auclair, Daniel; Onofrio, Robert C.; Park, Kyung; Kitabayashi, Naoki; MacDonald, Theresa Y.; Sheikh, Karen; Vuong, Terry; Guiducci, Candace; Cibulskis, Kristian; Sivachenko, Andrey; Carter, Scott L.; Saksena, Gordon; Voet, Douglas; Hussain, Wasay; Ramos, Alex H.; Winckler, Wendy; Redman, Michelle C; Ardlie, Kristin; Tewari, Ashutosh; Mosquera, Juan Miguel; Rupp, Niels J.; Wild, Peter J.; Moch, Holger; Morrissey, Colm; Nelson, Peter S.; Kantoff, Philip W.; Gabriel, Stacey; Golub, Todd R.; Meyerson, Matthew; Lander, Eric S.; Getz, Gad; Rubin, Mark A.; Garraway, Levi A.

doi:10.1038/ng.2279

Cited by 1,316 publications

(1,621 citation statements)

References 52 publications

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“…SPOP cancer mutations are not usually accompanied by loss of heterozygosity (Barbieri et al , 2012), raising the possibility that mutant and WT SPOP form mixed oligomers. The dominant‐negative phenotype observed for the SPOP BTB domain mutant in fly wings supports this hypothesis.…”

Section: Discussionmentioning

confidence: 99%

Higher‐order oligomerization promotes localization of SPOP to liquid nuclear speckles

et al. 2016

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Membrane‐less organelles in cells are large, dynamic protein/protein or protein/RNA assemblies that have been reported in some cases to have liquid droplet properties. However, the molecular interactions underlying the recruitment of components are not well understood. Herein, we study how the ability to form higher‐order assemblies influences the recruitment of the speckle‐type POZ protein (SPOP) to nuclear speckles. SPOP, a cullin‐3‐RING ubiquitin ligase (CRL3) substrate adaptor, self‐associates into higher‐order oligomers; that is, the number of monomers in an oligomer is broadly distributed and can be large. While wild‐type SPOP localizes to liquid nuclear speckles, self‐association‐deficient SPOP mutants have a diffuse distribution in the nucleus. SPOP oligomerizes through its BTB and BACK domains. We show that BTB‐mediated SPOP dimers form linear oligomers via BACK domain dimerization, and we determine the concentration‐dependent populations of the resulting oligomeric species. Higher‐order oligomerization of SPOP stimulates CRL3SPOP ubiquitination efficiency for its physiological substrate Gli3, suggesting that nuclear speckles are hotspots of ubiquitination. Dynamic, higher‐order protein self‐association may be a general mechanism to concentrate functional components in membrane‐less cellular bodies.

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Section: Discussionmentioning

confidence: 99%

Higher‐order oligomerization promotes localization of SPOP to liquid nuclear speckles

et al. 2016

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“…Three studies [45][46][47] have been published to date with genome/exome sequence of more than 10 prostate tumors. One challenge with PCa is the high proportion of normal cells and heterogeneity in the primary tumor.…”

Section: Somatic Alterations In Tumorsmentioning

confidence: 99%

“…Barbieri et al 46 performed exome capture and sequenced 112 treatment naive prostate adenocarcinomas and matched normal samples from the United States and Australia. They identified mutations in the known genes, PIK3CA, TP53 and PTEN as well as FOXA1, MED12, THSD7B, SCN11A and ZNF595, and CDKN1B was mutated in three and deleted in 16 tumors, indicating that this gene is another common driver.…”

Section: Somatic Alterations In Tumorsmentioning

confidence: 99%

“…46 The SPOP gene had been previously shown to be mutated in PCa 50 and was sequenced in an additional 300 primary tumors and metastases from the United States and Europe and recurrent heterozygous SPOP substitutions were identified in 6%-13% of primary tumors and in 15% of subjects with metastatic disease. 46 These SPOP mutations affect conserved residues in the putative substrate-binding cleft and these altered residues (Tyr87, Trp131 and Phe133) have key roles in substrate interaction, 51 and knockdown of SPOP increases invasiveness of PCa cell lines. 46 Grasso et al 47 sequenced the exomes of 50 lethal, metastatic castrate-resistant PCas and 11 treatment-naive, high-grade localized tumors.…”

Section: Somatic Alterations In Tumorsmentioning

confidence: 99%

“…46 These SPOP mutations affect conserved residues in the putative substrate-binding cleft and these altered residues (Tyr87, Trp131 and Phe133) have key roles in substrate interaction, 51 and knockdown of SPOP increases invasiveness of PCa cell lines. 46 Grasso et al 47 sequenced the exomes of 50 lethal, metastatic castrate-resistant PCas and 11 treatment-naive, high-grade localized tumors. They identified mutations in the known genes TP53, AR, ZFHX3, RB1, PTEN and APC and described three additional significantly mutated genes: MLL2, OR5L1 and CDK12.…”

Section: Somatic Alterations In Tumorsmentioning

confidence: 99%

See 2 more Smart Citations

Genetics and genomics of prostate cancer

Dean¹,

Li²

2013

Asian J Androl

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Prostate cancer (PCa) is one of the most common malignancies in the world with over 890 000 cases and over 258 000 deaths worldwide each year. Nearly all mortalities from PCa are due to metastatic disease, typically through tumors that evolve to be hormone-refractory or castrate-resistant. Despite intensive epidemiological study, there are few known environmental risk factors, and age and family history are the major determinants. However, there is extreme heterogeneity in PCa incidence worldwide, suggesting that major determining factors have not been described. Genome-wide association studies have been performed and a considerable number of significant, but low-risk loci have been identified. In addition, several groups have analyzed PCa by determination of genomic copy number, fusion gene generation and targeted resequencing of candidate genes, as well as exome and whole genome sequencing. These initial studies have examined both primary and metastatic tumors as well as murine xenografts and identified somatic alterations in TP53 and other potential driver genes, and the disturbance of androgen response and cell cycle pathways. It is hoped that continued characterization of risk factors as well as gene mutation and misregulation in tumors will aid in understanding, diagnosing and better treating PCa.

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Somatic cancer mutations in the MLL1 histone methyltransferase modulate its enzymatic activity and dependence on the WDR5/RBBP5/ASH2L complex

2017

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Somatic missense mutations in the mixed lineage leukemia 1 (MLL1) histone H3K4 methyltransferase are often observed in cancers. MLL1 forms a complex with WDR5, RBBP5, and ASH2L (WRA) which stimulates its activity. The MM‐102 compound prevents the interaction between MLL1 and WDR5 and functions as an MLL1 inhibitor. We have studied the effects of four cancer mutations in the catalytic SET domain of MLL1 on the enzymatic activity of MLL1 and MLL1–WRA complexes. In addition, we studied the interaction of the MLL1 mutants with the WRA proteins and inhibition of MLL1–WRA complexes by MM‐102. All four investigated mutations had strong effects on the activity of MLL1. R3903H was inactive and S3865F showed reduced activity both alone and in complex with WRA, but its activity was stimulated by the WRA complex. By contrast, R3864C and R3841W were both more active than wild‐type MLL1, but still less active than the wild‐type MLL1–WRA complex. Both mutants were not stimulated by complex formation with WRA, although no differences in the interaction with the complex proteins were observed. These results indicate that both mutants are in an active conformation even in the absence of the WRA complex and their normal control of activity by the WRA complex is altered. In agreement with this observation, the activity of R3864C and R3841W was not reduced by addition of the MM‐102 inhibitor. We show that different cancer mutations in MLL1 lead to a loss or increase in activity, illustrating the complex and tumor‐specific role of MLL1 in carcinogenesis. Our data exemplify that biochemical investigations of somatic tumor mutations are required to decipher their pathological role. Moreover, our data indicate that MM‐102 may not be used as an MLL1 inhibitor if the R3864C and R3841W mutations are present. More generally, the efficacy of any enzyme inhibitor must be experimentally confirmed for mutant enzymes before an application can be considered.

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

Cited by 1,316 publications

References 52 publications

Higher‐order oligomerization promotes localization of SPOP to liquid nuclear speckles

Higher‐order oligomerization promotes localization of SPOP to liquid nuclear speckles

Genetics and genomics of prostate cancer

Somatic cancer mutations in the MLL1 histone methyltransferase modulate its enzymatic activity and dependence on the WDR5/RBBP5/ASH2L complex

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