Activating Mutations of Gsα in Kidney Cancer

Kalfa, Nicolas; Lumbroso, Serge; Boulle, Nathalie; Guiter, J; Soustelle, Laurent; Costa, P.; Chapuis, H; Baldet, Piérre; Sultan, Charles

doi:10.1016/j.juro.2006.04.023

Cited by 38 publications

(33 citation statements)

References 20 publications

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“…35 GNAS mutations are uncommon in epithelial malignancies, occurring only in minor subsets of colorectal, prostate and breast cancers, renal cell carcinomas and small cell carcinomas of the lung, and these mutations are almost always restricted to codon 201. [36][37][38][39][40] In the hepatobiliary region, GNAS mutations have been reported in only two of 245 (~1%) hepatocellular carcinomas (HCCs) and in four of 164 (2.4%) hepatocellular adenomas. 41 Again, the mutations were all clustered at codon 201 and the corresponding HCCs were associated with an inflammatory infiltrate, postulated to reflect the activating of underlying proinflammatory pathways [interleukin-6 and STAT-3 (signal transducer and activator of transcription 3)] by the constitutively activated G-protein.…”

Section: Discussionmentioning

confidence: 99%

“…Another caveat may be that the activating hotspot mutation in IPNBs is not at GNAS codon 201, but, rather, at codon 227, which was not examined in the current study. However, based on the data that GNAS mutations in epithelial neoplasms (including IPMNs) are always restricted to codon 201, 9,35,42 the authors find this possibility unlikely. Finally, the issue of assay sensitivity, which is always a concern in a 'negative' study of this nature, should be addressed.…”

Section: Discussionmentioning

confidence: 99%

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GNAS Codon 201 mutations are uncommon in Intraductal Papillary Neoplasms of the Bile Duct

Matthaei¹,

Wu²,

Molin³

et al. 2012

Z Gastroenterol

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Abstracth pb_504 677..683Background: Activating point mutations of GNAS at codon 201 have been detected in approximately two thirds of intraductal papillary mucinous neoplasms (IPMNs) of the pancreas. Intraductal papillary neoplasms of the bile ducts (IPNBs) morphologically resemble pancreatic IPMNs. This study sought to assess the mutational status of GNAS at codon 201 in IPNBs.Methods: Thirty-four patients were included. DNA from microdissected IPNBs was subjected to a polymerase chain reaction and ligation method for the detection of GNAS mutations at codon 201 and of KRAS mutations at codon 12. Mutational status was compared with clinical and pathologic data.Results: The IPNBs had a median diameter of 3.5 cm and were located intrahepatically (n = 6), extrahepatically (n = 13), both intra-and extrahepatically (n = 4) or in the gallbladder (intracystic papillary neoplasms, n = 11). Most exhibited pancreatobiliary differentiation (n = 20), high-grade dysplasia (n = 26) and an associated adenocarcinoma (n = 20). Analysis of GNAS codon 201 identified only one mutant sample in a multifocal intestinal subtype intrahepatic IPNB with high-grade dysplasia. Six lesions harboured a KRAS codon 12 mutation. Conclusions: GNAS codon 201 mutations are uncommon in IPNBs, by contrast with pancreatic IPMNs.More comprehensive molecular profiling is needed to uncover the pathways involved in IPNB development.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

GNAS Codon 201 mutations are uncommon in Intraductal Papillary Neoplasms of the Bile Duct

Matthaei¹,

Wu²,

Molin³

et al. 2012

Z Gastroenterol

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“…Separately, hyperactivating mutations of Gαs can result in McCune Albright Syndrome (MAS) and are oncogenic in various endocrine cancers 4 ; 50. Gαs oncogenes have been shown to increase tumorogenicity and metastasis 51 , 52, and recent identification of Gαs-hyperactivating mutations in kidney cancer indicate that the subunit could be a therapeutic target in developed tumors 53 .…”

Section: Discussionmentioning

confidence: 99%

Evolution of Class-Specific Peptides Targeting a Hot Spot of the Gαs Subunit

Austin

Roberts

2008

Journal of Molecular Biology

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SUMMARYThe four classes of heterotrimeric G protein α subunits act as molecular routers inside cells, gating signals based on a bound guanosine nucleotide (GTP vs. GDP). Ligands that specifically target individual subunits provide new tools to monitor and modulate these networks, but are challenging to design due to the high sequence homology and structural plasticity of the Gα binding surface. Here we have created a mRNA display library of peptides based on the short Gα-modulating peptide R6A-1 and selected for variants that target a convergent protein-binding surface of Gαs•GDP. After selection/evolution, the most Gαs-specific peptide, GSP (Gαs specific peptide), was used to design a second-generation library, resulting in several new affinity-and selectivity-matured peptides denoted as mGSPs. The two-step evolutionary walk from R6A-1 to mGSP-1 resulted in an 8000-fold inversion in binding specificity, altered 7 out of 9 residues in the starting peptide core, and incorporated both positive and negative design steps. The resulting mGSP-1 peptide shows remarkable selectivity and affinity, exhibiting little or no binding to 9 homologous Gα subunits or human H-Ras and even discriminates the Gαs splice variant Gαs(l). Selected peptides make specific contacts with the effector-binding region of Gα, which may explain an interesting bifunctional activity observed in GSP. Overall, our work demonstrates design of simple, linear, highly specific peptides that target a protein-binding surface of Gαs and argues that mRNA display-based selection/ evolution is a powerful route to target protein families with high class-and state-specificity.

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“…The post zygotic mutation is responsible for the mosaic pattern of tissue distribution and the extreme variability of clinical changes (Weinstein et al, 1991). Endocrine and non-endocrine tumors: Somatic mutations of Arg201 or Gln227 have been identified in human growth hormone-secreting pituitary adenomas, (Landis et al, 1989;Landis et al, 1990), ACTHsecreting pituitary adenomas (Williamson et al, 1995;Riminucci et al, 2002), nonfunctioning pituitary tumors (Tordjman et al, 1993), thyroid tumors (Suarez et al, 1991), Leydig cell tumor (Libe et al, 2012), ovarian granulosa cell tumors (Kalfa et al, 2006a), renal cell carcinoma (Kalfa et al, 2006b), hepatocellular carcinoma (Nault et al, 2012) and myelodysplastic syndromes (Bejar et al, 2011). The mutation at codon 201 (Arg into Cys or His) is more frequent that the mutation at 227 (Gln into Arg, His, Lys or Leu).…”

Section: Mutationsmentioning

confidence: 99%