A novel gain-of-function mutation of c-kit gene in gastrointestinal stromal tumors

Nakahara, Masanori; Isozaki, Koji; Hirota, Seiichi; Miyagawa, Jun‐ichiro; Hase-Sawada, Naoko; Taniguchi, Masahiko; Nishida, Toshirou; Kanayama, Suji; Kitamura, Yukihiko; Shinomura, Yasuhisa; Matsuzawa, Yūji

doi:10.1016/s0016-5085(98)70079-4

Cited by 200 publications

(135 citation statements)

References 22 publications

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“…Recent studies show that specific RTK activating mechanisms can bring about transformation of different human cell lineages. For example, activating KIT point mutations are found in human mast cell neoplasms, myeloid leukemia, germ cell tumors, and gastrointestinal stromal tumors, [35][36][37][38] and ETV6-NTRK3 fusion oncogenes are found in both myeloid leukemia and congenital fibrosarcoma. 39,40 Irrespective, our studies reveal the first example of an identical RTK fusion oncogene in lymphoid and mesenchymal neoplasia.…”

Section: Discussionmentioning

confidence: 99%

TPM3-ALK and TPM4-ALK Oncogenes in Inflammatory Myofibroblastic Tumors

Lawrence

Perez‐Atayde

Hibbard

et al. 2000

The American Journal of Pathology

649

426

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Inflammatory myofibroblastic tumors (IMTs) are neoplastic mesenchymal proliferations featuring an inflammatory infiltrate composed primarily of lymphocytes and plasma cells. The myofibroblastic cells in some IMTs contain chromosomal rearrangements involving the ALK receptor tyrosine-kinase locus region (chromosome band 2p23). ALK-which is normally restricted in its expression to neural tissues-is expressed strikingly in the IMT cells with 2p23 rearrangements. We now report a recurrent oncogenic mechanism, in IMTs, in which tropomyosin (TPM) N-terminal coiled-coil domains are fused to the ALK C-terminal kinase domain. We have cloned two ALK fusion genes, TPM4-ALK and TPM3-ALK, which encode ϳ95-kd fusion oncoproteins characterized by constitutive kinase activity and tyrosylphosphorylation. Immunohistochemical and molecular correlations, in other IMTs, implicate non-TPM ALK oncoproteins that are predominantly cytoplasmic or predominantly nuclear, presumably depending on the subcellular localization of the ALK fusion partner. Notably, a TPM3-ALK oncogene was reported recently in anaplastic lymphoma, and TPM3-ALK is thereby the first known fusion oncogene that transforms, in vivo, both mesenchymal and lymphoid human cell lineages. (Am J Pathol 2000, 157:377-384)

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Section: Discussionmentioning

confidence: 99%

TPM3-ALK and TPM4-ALK Oncogenes in Inflammatory Myofibroblastic Tumors

Lawrence

Perez‐Atayde

Hibbard

et al. 2000

The American Journal of Pathology

649

426

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“…High-resolution amplicon melting analyses followed by direct DNA sequencing revealed that three of them harbored a L576P mutation with selective loss of the normal allele (Willmore-Payne et al 2005, 2006. L576P is a known GIST-associated mutation that maps to the 5Ј juxtamembrane domain where most activating KIT mutations cluster (Nakahara et al 1998;Fukuda et al 2001). Although likely representing an uncommon path to melanoma, the example of EGFR mutational status as a predictor for therapeutic responses in NSCLC (Lynch et al 2004;Paez et al 2004) suggests the possibility of identifying a melanoma patient subpopulation that will respond to imatinib based on c-Kit mutational status.…”

Section: Receptor Tyrosine Kinase (Rtks) Activationmentioning

confidence: 99%

Malignant melanoma: genetics and therapeutics in the genomic era

2006

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Cell for cell, probably no human cancer is as aggressive as melanoma. It is among a handful of cancers whose dimensions are reported in millimeters. Tumor thickness approaching 4 mm presents a high risk of metastasis, and a diagnosis of metastatic melanoma carries with it an abysmal median survival of 6-9 mo. What features of this malignancy account for such aggressive behavior? Is it the migratory history of its cell of origin or the programmed adaptation of its differentiated progeny to environmental stress, particularly ultraviolet radiation? While the answers to these questions are far from complete, major strides have been made in our understanding of the cellular, molecular, and genetic underpinnings of melanoma. More importantly, these discoveries carry profound implications for the development of therapies focused directly at the molecular engines driving melanoma, suggesting that we may have reached the brink of an unprecedented opportunity to translate basic science into clinical advances. In this review, we attempt to summarize our current understanding of the genetics and biology of this disease, drawing from expanding genomic information and lessons from development and genetically engineered mouse models. In addition, we look forward toward how these new insights will impact on therapeutic options for metastatic melanoma in the near future. The diseaseMelanomas most often arise within epidermal melanocytes of the skin, although they can also derive from noncutaneous melanocytes such as those lining the choroidal layer of the eye, GI and GU mucosal surfaces, or the meninges. Melanoma is also among the more common causes of "metastatic cancer of unknown primary," which may reflect either a propensity to arise in unexpected sites along the neural crest migratory route, or rapid growth of poorly differentiated lesions arising from indolent or unrecognized cutaneous primary lesions. Clinical staging for primary cutaneous melanoma employs measurements of thickness (in millimeters), presence of ulceration, penetration through cutaneous layers, mitotic rate, evidence of "in transit" metastasis, tumor spread to draining lymph nodes, and evidence of distant metastasis. Management issues in melanoma can be classified in terms of prevention, diagnosis, local disease management, and treatment of metastatic disease.In view of the epidemiological and emerging experimental evidence linking melanoma incidence to UV exposure and skin phototype, prevention and screening strategies represent key areas for reduction of disease incidence and severity. For most cutaneous melanomas in the so-called radial growth phase (e.g., thin melanomas), surgical removal affords curative treatment. In contrast, a significant fraction of patients diagnosed with intermediate-thickness (2-4 mm) cutaneous melanoma eventually succumb to recurrence at regional or distant sites.Critical biological questions facing the melanoma research community include: (1) What genetic and environmental factors contribute to and/or modulate risk of melanom...

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“…Recent molecular genetic studies have demonstrated that gain-of-function mutations of the v-kit HardyZuckerman 4 feline sarcoma viral oncogene homolog (KIT) proto-oncogene, a member of receptor tyrosine kinase III family (Besmer et al, 1986), are the most frequent and important changes in the development of GISTs (Besmer et al, 1986;Hirota et al, 1998;Nakahara et al, 1998). Mutations in KIT result in ligand-independent kinase activity and autophosphorylation of KIT (Kitayama et al, 1995;Ma et al, 1999).…”

Section: Introductionmentioning

confidence: 99%

Correlation of KIT and platelet-derived growth factor receptor α mutations with gene activation and expression profiles in gastrointestinal stromal tumors

et al. 2004

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Activating mutations of KIT and platelet-derived growth factor receptor a (PDGFRA) are known to be alternative and mutually exclusive genetic events in the development of gastrointestinal stromal tumors (GISTs). We examined the effect of the mutations of these two genes on the gene expression profile of 22 GISTs using the oligonucleotide microarray. Mutations of KIT and PDGFRA were found in 17 cases and three cases, respectively. The remaining two cases had no detectable mutations in either gene. The mutation status of KIT and PDGFRA was directly related to the expression levels of activated KIT and PDGFRA, and was also related to the different expression levels of activated proteins that play key roles in the downstream of the receptor tyrosine kinase III family. To evaluate the impact of mutation status and the importance of the type of mutation in gene expression and clinical features, microarray-derived data from 22 GISTs were interpreted using a principal component analysis (PCA). Three relevant principal component representing mutation of KIT, PDGFRA and chromosome 14q deletion were identified from the interpretation of the oligonucleotide microarray data with PCA. After supervised analysis, there was at least a two fold difference in expression between GISTs with KIT and PDGFRA mutation in 70 genes. Our findings demonstrate that mutations of KIT and PDGFRA affect differential activation and expression of some genes, and can be used for the molecular classification of GISTs.

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A novel gain-of-function mutation of c-kit gene in gastrointestinal stromal tumors

Cited by 200 publications

References 22 publications

TPM3-ALK and TPM4-ALK Oncogenes in Inflammatory Myofibroblastic Tumors

TPM3-ALK and TPM4-ALK Oncogenes in Inflammatory Myofibroblastic Tumors

Malignant melanoma: genetics and therapeutics in the genomic era

Correlation of KIT and platelet-derived growth factor receptor α mutations with gene activation and expression profiles in gastrointestinal stromal tumors

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