Stephens P, Edkins S, Davies H, Greenman C, Cox C, Hunter C et al.. A screen of the complete protein kinase gene family identifies diverse patterns of somatic mutations in human breast cancer. Nat Genet 37: 590-592

Erasmus Universiteit Rotterdam, Rotterdam, South Holland, Netherlands
Nature Genetics (Impact Factor: 29.35). 07/2005; 37(6):590-2. DOI: 10.1038/ng1571
Source: PubMed


We examined the coding sequence of 518 protein kinases, approximately 1.3 Mb of DNA per sample, in 25 breast cancers. In many tumors, we detected no somatic mutations. But a few had numerous somatic mutations with distinctive patterns indicative of either a mutator phenotype or a past exposure.

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    • "Mutations in protein kinases, which are often implicated in many cancers, can exemplify the phenomenon of “oncogene addiction,” whereby the structural effects of a specific set of mutations are necessary for a tumor to proliferate and hence have a selective advantage for the formation of the tumor during somatic cell replication. A recent sequencing study of kinase coding regions in tumors attempted to differentiate which kinase gene mutations can cause the cancer phenotype (known as “driver mutations”) and which mutations are simply neutral mutational byproducts of somatic cell replication (known as “passenger mutations”) [38]. This study identified ~200 putative driver mutations among ~100 out of 254 kinases in 139 tumors. "
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    ABSTRACT: A central goal of cancer research is to discover and characterize the functional effects of mutated genes that contribute to tumorigenesis. In this study, we provide a detailed structural classification and analysis of functional dynamics for members of protein kinase families that are known to harbor cancer mutations. We also present a systematic computational analysis that combines sequence and structure-based prediction models to characterize the effect of cancer mutations in protein kinases. We focus on the differential effects of activating point mutations that increase protein kinase activity and kinase-inactivating mutations that decrease activity. Mapping of cancer mutations onto the conformational mobility profiles of known crystal structures demonstrated that activating mutations could reduce a steric barrier for the movement from the basal "low" activity state to the "active" state. According to our analysis, the mechanism of activating mutations reflects a combined effect of partial destabilization of the kinase in its inactive state and a concomitant stabilization of its active-like form, which is likely to drive tumorigenesis at some level. Ultimately, the analysis of the evolutionary and structural features of the major cancer-causing mutational hotspot in kinases can also aid in the correlation of kinase mutation effects with clinical outcomes.
    Computational and Mathematical Methods in Medicine 04/2014; 2014:653487. DOI:10.1155/2014/653487 · 0.77 Impact Factor
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    • "Moreover, FGFR4 expression levels were associated with metastatic disease and poor survival in gastric, lung, breast adenocarcinoma and rhabdomyosarcoma [16], [17], [18]. FGFR4 somatic mutations are infrequent in cancer [11], [19], [20], [21]; Arg388 is the most common single nucleotide polymorphism (SNP) in FGFR4, which provokes enhanced stability and prolonged activation of the receptor. It has been associated with poor prognosis for positive node breast cancer, high-grade soft-tissue sarcoma, head and neck and lung squamous cell carcinoma [9], [16], [18], [22], [23]. "
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    PLoS ONE 05/2013; 8(5):e63695. DOI:10.1371/journal.pone.0063695 · 3.23 Impact Factor
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    • "In order to reveal the molecular mechanism of the p.K660N and another recently described somatic breast cancer mutation in FGFR2, p.R203C [32], expression vectors that direct the synthesis of FGFR2-IIIb carrying the breast cancer mutations were constructed and tested for their biological activity following transient expression in HEK293 cells. The p.R203C mutation is located in the extracellular Ig domain 2 of the receptor and the arginine at this position is highly conserved between species and all four human FGFRs (Fig. 2). "
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    ABSTRACT: It is known that FGFR2 gene variations confer a risk for breast cancer. FGFR2 and FGF10, the main ligand of FGFR2, are both overexpressed in 5-10% of breast tumors. In our study, we sequenced the most important coding regions of FGFR2 in somatic tumor tissue of 140 sporadic breast cancer patients and performed MLPA analysis to detect copy number variations in FGFR2 and FGF10. We identified one somatic heterozygous missense mutation, p.K660N (c.1980G>C), within the tyrosine kinase domain of FGFR2 in tumor tissue of a sporadic breast cancer patient, which is likely mediated by the FGFR2-IIIb isoform. The presence of wild type and mutated alleles in equal quantities suggests that the mutation has driven clonal amplification of mutant cells. We have analyzed the tyrosine kinase activity of p.K660N and another recently described somatic breast cancer mutation in FGFR2, p.R203C, after expression in HEK293 cells and demonstrated that the intrinsic tyrosine kinase activity of both mutant proteins is strongly increased resulting in elevated phosphorylation and activity of downstream effectors. To our knowledge, this is the first report of functional analysis of somatic breast cancer mutations in FGFR2 providing evidence for the activating nature of FGFR2-mediated signalling in the pathogenesis of breast cancer.
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