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.

Download full-text


Available from: Francis Brasseur
  • Source
    • "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. "
    [Show abstract] [Hide abstract]
    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.
    Full-text · Article · Apr 2014 · Computational and Mathematical Methods in Medicine
  • Source
    • "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]. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Fibroblast growth factor receptor 4 (FGFR4) is vital in early development and tissue repair. FGFR4 expression levels are very restricted in adult tissues, except in several solid tumors including colorectal cancer, which showed overexpression of FGFR4. Here, FGFR4 mutation analysis discarded the presence of activating mutations, other than Arg(388), in different colorectal cancer cell lines and tumoral samples. Stable shRNA FGFR4-silencing in SW480 and SW48 cell lines resulted in a significant decrease in cell proliferation, adhesion, cell migration and invasion. This decrease in the tumorigenic and invasive capabilities of colorectal cancer cells was accompanied by a decrease of Snail, Twist and TGFβ gene expression levels and an increase of E-cadherin, causing a reversion to a more epithelial phenotype, in three different cell lines. In addition, FGFR4-signaling activated the oncogenic SRC, ERK1/2 and AKT pathways in colon cancer cells and promoted an increase in cell survival. The relevance of FGFR4 in tumor growth was supported by two different strategies. Kinase inhibitors abrogated FGFR4-related cell growth and signaling pathways at the same extent than FGFR4-silenced cells. Specific FGFR4-targeting using antibodies provoked a similar reduction in cell growth. Moreover, FGFR4 knock-down cells displayed a reduced capacity for in vivo tumor formation and angiogenesis in nude mice. Collectively, our data support a crucial role for FGFR4 in tumorigenesis, invasion and survival in colorectal cancer. In addition, FGFR4 targeting demonstrated its applicability for colorectal cancer therapy.
    Full-text · Article · May 2013 · PLoS ONE
  • Source
    • "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). "
    [Show abstract] [Hide abstract]
    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.
    Full-text · Article · Mar 2013 · PLoS ONE
Show more

Similar Publications