RESUMEN
BACKGROUND: Genomic testing to identify driver mutations that enable targeted therapy is emerging for patients with non-small-cell lung cancer (NSCLC). We report the implementation of systematic prospective genotyping for somatic alterations in BRAF, PIK3CA, HER2, and ALK, in addition to EGFR and KRAS, in NSCLC patients at the Dana-Farber Cancer Institute. METHODS: Patients with NSCLC were prospectively referred by their providers for clinical genotyping. Formalin-fixed, paraffin embedded tumor samples were analyzed by Sanger sequencing for mutations in selected exons of EGFR, KRAS, BRAF, PIK3CA, and HER2. ALK rearrangements were detected by fluorescence in situ hybridization or immunohistochemistry. RESULTS: Between July 1, 2009 and August 1, 2010, 427 specimens from 419 patients were referred for genomic characterization; 344 (81%) specimens were successfully genotyped with a median turnaround time of 31 days (range, 9-155). Of the 344 specimens, 185 (54%) had at least one identifiable somatic alteration (KRAS: 24%, EGFR: 17%, ALK: 5%, BRAF: 5%, HER2: 4%, PIK3CA: 2%). As of August 1, 2011, 63 of 288 advanced NSCLC patients (22%) had received molecularly targeted therapy based on their genotypic results, including 34 of 42 patients (81%) with EGFR mutations, 12 of 15 (80%) with ALK rearrangements, and 17 of 95 (18%) with KRAS, BRAF, or HER2 mutations. CONCLUSIONS: Large-scale testing for somatic alterations in EGFR, KRAS, BRAF, PIK3CA, HER2, and ALK is feasible and impacts therapeutic decisions. As the repertoire for personalized therapies expands in lung cancer and other malignancies, there is a need to develop new genomics technologies that can generate a comprehensive genetic profile of tumor specimens in a time- and cost-effective manner.
Asunto(s)
Adenocarcinoma/genética , Biomarcadores de Tumor/genética , Carcinoma de Células Grandes/genética , Carcinoma de Pulmón de Células no Pequeñas/genética , Carcinoma de Células Escamosas/genética , Neoplasias Pulmonares/genética , Recurrencia Local de Neoplasia/genética , Adenocarcinoma/patología , Adulto , Anciano , Anciano de 80 o más Años , Carcinoma de Células Grandes/patología , Carcinoma de Pulmón de Células no Pequeñas/patología , Carcinoma de Células Escamosas/patología , Femenino , Genotipo , Humanos , Hibridación Fluorescente in Situ , Neoplasias Pulmonares/patología , Masculino , Persona de Mediana Edad , Mutación/genética , Recurrencia Local de Neoplasia/patología , Estadificación de Neoplasias , Pronóstico , Estudios Prospectivos , Adulto JovenAsunto(s)
Adenocarcinoma/genética , Carcinoma in Situ/genética , Neoplasias del Colon/genética , Neoplasias Pulmonares/genética , Mutación/genética , Proteínas Proto-Oncogénicas/genética , Proteínas ras/genética , Adenocarcinoma/secundario , Anciano , Carcinoma in Situ/patología , Neoplasias del Colon/patología , ADN de Neoplasias/genética , Femenino , Humanos , Neoplasias Pulmonares/patología , Reacción en Cadena de la Polimerasa , Pronóstico , Proteínas Proto-Oncogénicas p21(ras)RESUMEN
Overexpression of HOXA9 is linked to the molecular pathogenesis of acute myeloid leukaemia (AML) and myelodysplastic syndrome (MDS), conferring a poor prognosis. HOXA9 expression levels were analysed in the diagnostic bone marrow (BM) samples of 13 MDS patients. HOXA9 was expressed by CD34(+) BM cells at median levels 3.1-fold higher than in CD34(-) cells from the same patient and at median levels 4.3-fold higher than in CD34(+) cells from healthy donors. These results indicate that CD34(+) cell selection is required to accurately assess the expression levels of HOXA9 and related genes in the multipotential malignant progenitor cells of MDS patients.
