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1.
Nat Genet ; 37(6): 590-2, 2005 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-15908952

RESUMEN

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.


Asunto(s)
Neoplasias de la Mama/genética , Carcinoma Ductal de Mama/genética , Mutación , Proteínas Quinasas/genética , Anciano , Análisis Mutacional de ADN , Femenino , Humanos , Familia de Multigenes
2.
Nature ; 431(7008): 525-6, 2004 Sep 30.
Artículo en Inglés | MEDLINE | ID: mdl-15457249

RESUMEN

The protein-kinase family is the most frequently mutated gene family found in human cancer and faulty kinase enzymes are being investigated as promising targets for the design of antitumour therapies. We have sequenced the gene encoding the transmembrane protein tyrosine kinase ERBB2 (also known as HER2 or Neu) from 120 primary lung tumours and identified 4% that have mutations within the kinase domain; in the adenocarcinoma subtype of lung cancer, 10% of cases had mutations. ERBB2 inhibitors, which have so far proved to be ineffective in treating lung cancer, should now be clinically re-evaluated in the specific subset of patients with lung cancer whose tumours carry ERBB2 mutations.


Asunto(s)
Neoplasias Pulmonares/genética , Mutación/genética , Receptor ErbB-2/genética , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Carcinoma de Pulmón de Células no Pequeñas/genética , Análisis Mutacional de ADN , Activación Enzimática , Receptores ErbB/química , Receptores ErbB/genética , Gefitinib , Humanos , Neoplasias Pulmonares/tratamiento farmacológico , Modelos Moleculares , Neoplasias/tratamiento farmacológico , Neoplasias/genética , Estructura Terciaria de Proteína , Quinazolinas/uso terapéutico , Receptor ErbB-2/química , Receptor ErbB-2/metabolismo
3.
Cancer Res ; 66(8): 3987-91, 2006 Apr 15.
Artículo en Inglés | MEDLINE | ID: mdl-16618716

RESUMEN

Malignant gliomas have a very poor prognosis. The current standard of care for these cancers consists of extended adjuvant treatment with the alkylating agent temozolomide after surgical resection and radiotherapy. Although a statistically significant increase in survival has been reported with this regimen, nearly all gliomas recur and become insensitive to further treatment with this class of agents. We sequenced 500 kb of genomic DNA corresponding to the kinase domains of 518 protein kinases in each of nine gliomas. Large numbers of somatic mutations were observed in two gliomas recurrent after alkylating agent treatment. The pattern of mutations in these cases showed strong similarity to that induced by alkylating agents in experimental systems. Further investigation revealed inactivating somatic mutations of the mismatch repair gene MSH6 in each case. We propose that inactivating somatic mutations of MSH6 confer resistance to alkylating agents in gliomas in vivo and concurrently unleash accelerated mutagenesis in resistant clones as a consequence of continued exposure to alkylating agents in the presence of defective mismatch repair. The evidence therefore suggests that when MSH6 is inactivated in gliomas, alkylating agents convert from induction of tumor cell death to promotion of neoplastic progression. These observations highlight the potential of large scale sequencing for revealing and elucidating mutagenic processes operative in individual human cancers.


Asunto(s)
Antineoplásicos Alquilantes/uso terapéutico , Neoplasias Encefálicas/genética , Proteínas de Unión al ADN/genética , Dacarbazina/análogos & derivados , Glioma/genética , Mutación , Recurrencia Local de Neoplasia/genética , Anciano , Neoplasias Encefálicas/tratamiento farmacológico , Neoplasias Encefálicas/enzimología , Dacarbazina/uso terapéutico , Femenino , Glioma/tratamiento farmacológico , Glioma/enzimología , Humanos , Masculino , Persona de Mediana Edad , Recurrencia Local de Neoplasia/enzimología , Proteínas Quinasas/genética , Temozolomida
4.
Cancer Res ; 65(17): 7591-5, 2005 Sep 01.
Artículo en Inglés | MEDLINE | ID: mdl-16140923

RESUMEN

Protein kinases are frequently mutated in human cancer and inhibitors of mutant protein kinases have proven to be effective anticancer drugs. We screened the coding sequences of 518 protein kinases (approximately 1.3 Mb of DNA per sample) for somatic mutations in 26 primary lung neoplasms and seven lung cancer cell lines. One hundred eighty-eight somatic mutations were detected in 141 genes. Of these, 35 were synonymous (silent) changes. This result indicates that most of the 188 mutations were "passenger" mutations that are not causally implicated in oncogenesis. However, an excess of approximately 40 nonsynonymous substitutions compared with that expected by chance (P = 0.07) suggests that some nonsynonymous mutations have been selected and are contributing to oncogenesis. There was considerable variation between individual lung cancers in the number of mutations observed and no mutations were found in lung carcinoids. The mutational spectra of most lung cancers were characterized by a high proportion of C:G > A:T transversions, compatible with the mutagenic effects of tobacco carcinogens. However, one neuroendocrine cancer cell line had a distinctive mutational spectrum reminiscent of UV-induced DNA damage. The results suggest that several mutated protein kinases may be contributing to lung cancer development, but that mutations in each one are infrequent.


Asunto(s)
Neoplasias Pulmonares/enzimología , Neoplasias Pulmonares/genética , Mutación , Proteínas Quinasas/genética , Adenocarcinoma/enzimología , Adenocarcinoma/genética , Tumor Carcinoide/enzimología , Tumor Carcinoide/genética , Carcinoma de Células Grandes/enzimología , Carcinoma de Células Grandes/genética , Carcinoma de Células Escamosas/enzimología , Carcinoma de Células Escamosas/genética , Línea Celular Tumoral , Análisis Mutacional de ADN , Humanos
5.
Mol Cancer Ther ; 5(11): 2606-12, 2006 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-17088437

RESUMEN

The panel of 60 human cancer cell lines (the NCI-60) assembled by the National Cancer Institute for anticancer drug discovery is a widely used resource. The NCI-60 has been characterized pharmacologically and at the molecular level more extensively than any other set of cell lines. However, no systematic mutation analysis of genes causally implicated in oncogenesis has been reported. This study reports the sequence analysis of 24 known cancer genes in the NCI-60 and an assessment of 4 of the 24 genes for homozygous deletions. One hundred thirty-seven oncogenic mutations were identified in 14 (APC, BRAF, CDKN2, CTNNB1, HRAS, KRAS, NRAS, SMAD4, PIK3CA, PTEN, RB1, STK11, TP53, and VHL) of the 24 genes. All lines have at least one mutation among the cancer genes examined, with most lines (73%) having more than one. Identification of those cancer genes mutated in the NCI-60, in combination with pharmacologic and molecular profiles of the cells, will allow for more informed interpretation of anticancer agent screening and will enhance the use of the NCI-60 cell lines for molecularly targeted screens.


Asunto(s)
Línea Celular Tumoral , Genes Relacionados con las Neoplasias , Mutación , Análisis Mutacional de ADN , Exones , Eliminación de Gen , Perfilación de la Expresión Génica , Homocigoto , Humanos , Sitios de Empalme de ARN
6.
Genes Chromosomes Cancer ; 45(1): 42-6, 2006 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-16175573

RESUMEN

The protein kinase gene family is the most frequently mutated in human cancer. Previous work has documented activating mutations in the KIT receptor tyrosine kinase in testicular germ-cell tumors (TGCT). To investigate further the potential role of mutated protein kinases in the development of TGCT and to characterize the prevalence and patterns of point mutations in these tumors, we have sequenced the coding exons and splice junctions of the annotated protein kinase family of 518 genes in a series of seven seminomas and six nonseminomas. Our results show a remarkably low mutation frequency, with only a single somatic point mutation, a K277E mutation in the STK10 gene, being identified in a total of more than 15 megabases of sequence analyzed. Sequencing of STK10 in an additional 40 TGCTs revealed no further mutations. Comparative genomic hybridization and LOH analysis using SNP arrays demonstrated that the 13 TGCTs mutationally screened through the 518 protein kinase genes were uniformly aneuploid with consistent chromosomal gains on 12p, 8q, 7, and X and losses on 13q, 18q, 11q, and 4q. Our results do not provide evidence for a mutated protein kinase implicated in the development of TGCT other than KIT. Moreover, they demonstrate that the general prevalence of point mutations in TGCT is low, in contrast to the high frequency of copy number changes.


Asunto(s)
Neoplasias de Células Germinales y Embrionarias/genética , Proteínas Quinasas/genética , Proteínas Serina-Treonina Quinasas/genética , Seminoma/genética , Neoplasias Testiculares/genética , Adolescente , Adulto , Aberraciones Cromosómicas , Exones , Dosificación de Gen , Humanos , Masculino , Persona de Mediana Edad , Mutación Puntual
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