RESUMEN
OBJECTIVE: van't Veer and colleagues developed a 70-gene prognosis profile known as MammaPrint to identify breast cancer patients who were at low risk of developing metastases. We evaluated the prognostic value of the 70-gene MammaPrint profile in Japanese women with node-negative breast cancer. METHODS: Frozen tumour samples from 102 eligible node-negative breast cancer patients aged 70 or younger were characterized with the MammaPrint array. The patients were treated with breast-conserving therapy or mastectomy with axillary lymph node dissection between December 1998 and August 2001. About 73 percent received adjuvant hormonal therapy and 28 percent received adjuvant chemotherapy. The gene expression profiles obtained by MammaPrint classified the patients as high- or low-genomic risk. The median follow-up was 7.1 years. RESULTS: Among the 102 patients, 20 (20%) were classified as low-genomic risk and 82 (80%) were classified as high-genomic risk. The probability of distant metastasis-free survival at five years was 100% for the low-risk group and 94% for the high-risk group. CONCLUSIONS: The 70-gene MammaPrint prognosis profile accurately identified Japanese breast cancer patients at low risk of developing recurrences. In fact, 100% of the individuals in the low-risk category remained metastasis-free for the duration of the observation period.
Asunto(s)
Neoplasias de la Mama/genética , Perfilación de la Expresión Génica , Análisis de Secuencia por Matrices de Oligonucleótidos , Axila , Neoplasias de la Mama/metabolismo , Neoplasias de la Mama/patología , Supervivencia sin Enfermedad , Femenino , Humanos , Japón , Metástasis Linfática , Persona de Mediana Edad , Metástasis de la Neoplasia , Valor Predictivo de las Pruebas , Receptores de Estrógenos/análisis , Receptores de Progesterona/análisisRESUMEN
The genomic complexity of profound copy number aberrations has prevented effective molecular stratification of ovarian cancers. Here, to decode this complexity, we derived copy number signatures from shallow whole-genome sequencing of 117 high-grade serous ovarian cancer (HGSOC) cases, which were validated on 527 independent cases. We show that HGSOC comprises a continuum of genomes shaped by multiple mutational processes that result in known patterns of genomic aberration. Copy number signature exposures at diagnosis predict both overall survival and the probability of platinum-resistant relapse. Measurement of signature exposures provides a rational framework to choose combination treatments that target multiple mutational processes.
Asunto(s)
Variaciones en el Número de Copia de ADN , Mutación , Neoplasias Ováricas/genética , Adulto , Anciano , Anciano de 80 o más Años , Femenino , Genómica/métodos , Humanos , Persona de Mediana Edad , Recurrencia Local de Neoplasia/genética , Secuenciación Completa del Genoma/métodosRESUMEN
Laryngeal squamous cell carcinoma (LSCC) is the second most common tumour of the head and neck. It is characterized by frequent aberrations in two cell-cycle regulators--CDKN2A and TP53. However, LSCC has been often studied as a part of the group of head and neck cancers and not as an individual entity. In the current study we aimed to examine mutation status of CDKN2A and TP53 genes in 108 LSCC patients. DNA was extracted from fresh-frozen tumour tissues; exons 1-3 of CDKN2A and exons 5-8 of TP53 were screened for mutations by direct sequencing. Genetic aberrations in CDKN2A were found in 16 (14.2%) and those in TP53--in 56/108 (51.9%) tumours. Seven mutations (two insertions, three deletions, one missense and one silent) detected in CDKN2A were not described previously. Also, we found seven novel deletions and a novel indel in TP53. No significant associations with clinical features were found. However, TP53 mutations were predominantly observed in smokers with advanced stage tumours. Screening for genetic aberrations in a defined group of LSCC contributes to the knowledge about laryngeal carcinogenesis. Further investigations are required to confirm the observed trends in associations with clinical features.
Asunto(s)
Carcinoma de Células Escamosas/genética , Inhibidor p16 de la Quinasa Dependiente de Ciclina/genética , Neoplasias Laríngeas/genética , Mutación/genética , Proteína p53 Supresora de Tumor/genética , Carcinoma de Células Escamosas/diagnóstico , ADN de Neoplasias/genética , Femenino , Genes Relacionados con las Neoplasias/genética , Neoplasias de Cabeza y Cuello/genética , Humanos , Neoplasias Laríngeas/diagnóstico , Masculino , Persona de Mediana Edad , Pronóstico , Análisis de Secuencia de ADNRESUMEN
BACKGROUND: Laryngeal squamous cell carcinoma (laryngeal SCC) is a frequently occurring cancer of the head and neck area. Epigenetic changes of tumor-related genes contribute to its genesis and progression. METHODS: We assessed promoter methylation status of the selected genes (CDKN2A, MGMT, MLH1, and DAPK) using methylation-sensitive high resolution melting (MS-HRM) in 100 patients with laryngeal SCC and studied the correlations with clinical characteristics. RESULTS: The prevalence of promoter methylation in MGMT, CDKN2A, MLH1, and DAPK was 59 of 97 (60.8%), 46 of 97 (47.4%), 45 of 97 (46.4%), and 41 of 97 patients (42.3%), respectively. Significantly increased methylation of CDKN2A was observed in heavy smokers. Epigenetic inactivation of CDKN2A and MLH1 were found to be associated with lymph node involvement. An inverse correlation was present between MLH1 methylation and alcohol consumption. CONCLUSION: Our results strongly suggest that deregulation of p16-associated, and MLH1-associated pathways, because of promoter hypermethylation, is associated with increased cancer cell migration, tumor invasiveness, and, thus, aggressive phenotype.
Asunto(s)
Proteínas Adaptadoras Transductoras de Señales/genética , Carcinoma de Células Escamosas/genética , Inhibidor p16 de la Quinasa Dependiente de Ciclina/genética , Metilación de ADN , Metilasas de Modificación del ADN/genética , Enzimas Reparadoras del ADN/genética , Proteínas Quinasas Asociadas a Muerte Celular/genética , Neoplasias Laríngeas/genética , Proteínas Nucleares/genética , Proteínas Supresoras de Tumor/genética , Adulto , Anciano , Bulgaria , Carcinoma de Células Escamosas/patología , Femenino , Humanos , Neoplasias Laríngeas/patología , Masculino , Persona de Mediana Edad , Homólogo 1 de la Proteína MutL , Prevalencia , Regiones Promotoras GenéticasRESUMEN
Multistage carcinogenesis is an important concept in cancer biology. Each new stage is triggered by the acquisition of an additional genetic aberration, leading to clonal expansion of the cancer cell. The resulting tumor mass consists of cancer cells with all genetic aberrations, but may include precursor cells at some point of carcinogenesis. We analyzed six colorectal cancer tissues with APC, K-ras, and p53 mutations. From each sample, 40-50 areas (100x100x40microm) consisting only of cancer cells were microdissected, and genomic DNA was purified. Ratios of mutated and normal alleles were quantitated by the SNaPshot assay, a primer extension assay. In five tumor tissues, we identified cancer cell subpopulations corresponding to putative precursors, i.e., cells with mutations in one or two of the three genes. All samples were likely to be of monoclonal origin, and temporal sequences of the mutations could be deduced from the mutation patterns of putative precursors. The orders of mutation events were variable. However, the two carcinoma tissues accompanying adenoma regions started with the APC mutation, not contradicting the previous studies. The analysis also revealed considerable heterogeneity in allele ratios of one or two of the chromosomes. The current findings are promising to uncover the process of carcinogenesis directly from the tumor tissue of the patient.