RESUMEN
Sézary syndrome (SS) is a leukemic variant of cutaneous T-cell lymphoma (CTCL) and represents an ideal model for study of T-cell transformation. We describe whole-exome and single-nucleotide polymorphism array-based copy number analyses of CD4(+) tumor cells from untreated patients at diagnosis and targeted resequencing of 101 SS cases. A total of 824 somatic nonsynonymous gene variants were identified including indels, stop-gain/loss, splice variants, and recurrent gene variants indicative of considerable molecular heterogeneity. Driver genes identified using MutSigCV include POT1, which has not been previously reported in CTCL; and TP53 and DNMT3A, which were also identified consistent with previous reports. Mutations in PLCG1 were detected in 11% of tumors including novel variants not previously described in SS. This study is also the first to show BRCA2 defects in a significant proportion (14%) of SS tumors. Aberrations in PRKCQ were found to occur in 20% of tumors highlighting selection for activation of T-cell receptor/NF-κB signaling. A complex but consistent pattern of copy number variants (CNVs) was detected and many CNVs involved genes identified as putative drivers. Frequent defects involving the POT1 and ATM genes responsible for telomere maintenance were detected and may contribute to genomic instability in SS. Genomic aberrations identified were enriched for genes implicated in cell survival and fate, specifically PDGFR, ERK, JAK STAT, MAPK, and TCR/NF-κB signaling; epigenetic regulation (DNMT3A, ASLX3, TET1-3); and homologous recombination (RAD51C, BRCA2, POLD1). This study now provides the basis for a detailed functional analysis of malignant transformation of mature T cells and improved patient stratification and treatment.
Asunto(s)
Reparación del ADN , Genoma Humano , Inestabilidad Genómica , Síndrome de Sézary/genética , Supervivencia Celular/genética , Epigénesis Genética , Femenino , Regulación Neoplásica de la Expresión Génica , Humanos , Masculino , Proteínas de Neoplasias/genética , Proteínas de Neoplasias/metabolismo , Síndrome de Sézary/metabolismo , Transducción de Señal/genéticaRESUMEN
OBJECTIVES: To identify prognostic factors influencing cervical cancer survival for patients referred to a tertiary care center in Kentucky. METHODS: A cohort study was performed to assess predictive survival factors of cervical cancer patients referred to the University of Kentucky from January 2001 to May 2010. Eligibility criteria included those at least 18 years-old, cervical cancer history, and no prior malignancy. Descriptive statistics were compiled and univariable and multivariable Cox proportional hazard analysis were performed. RESULTS: 381 patients met entry criteria. 95% were Caucasian (N=347) and 66% (N=243) lived in Appalachian Kentucky. The following covariates showed no evidence of a statistical association with survival: race, body mass index, residence, insurance status, months between last normal cervical cytology and diagnosis, histology, tumor grade, and location of primary radiation treatment. After controlling for identified significant variables, stage of disease was a significant predictor of overall survival, with estimated relative hazards comparing stages II, III, and IV to stage I of 3.09 (95% CI: 1.30, 7.33), 18.11 (95% CI: 7.44, 44.06), and 53.03(95% CI: 18.16, 154.87), respectively. The presence of more than two comorbid risk factors and unemployment was also correlated with overall survival [HR 4.25 (95% CI: 1.00, 18.13); HR 2.64 (95% CI 1.29, 5.42), respectively]. CONCLUSIONS: Residence and location of treatment center are not an important factor in cervical cancer survival when a tertiary cancer center can oversee and coordinate care; however, comorbid risk factors influence survival and further exploration of disease comorbidity related to cervical cancer survival is warranted.