RESUMEN

PURPOSE: Due to the high recurrence risk of nonmuscle invasive urothelial carcinoma it is crucial to distinguish patients at high risk from those with indolent disease. In this study we used a machine learning algorithm to identify the genes in patients with nonmuscle invasive urothelial carcinoma at initial presentation that were most predictive of recurrence. We used the genes in a molecular signature to predict recurrence risk within 5 years after transurethral resection of bladder tumor. MATERIALS AND METHODS: Whole genome profiling was performed on 112 frozen nonmuscle invasive urothelial carcinoma specimens obtained at first presentation on Human WG-6 BeadChips (Illumina®). A genetic programming algorithm was applied to evolve classifier mathematical models for outcome prediction. Cross-validation based resampling and gene use frequencies were used to identify the most prognostic genes, which were combined into rules used in a voting algorithm to predict the sample target class. Key genes were validated by quantitative polymerase chain reaction. RESULTS: The classifier set included 21 genes that predicted recurrence. Quantitative polymerase chain reaction was done for these genes in a subset of 100 patients. A 5-gene combined rule incorporating a voting algorithm yielded 77% sensitivity and 85% specificity to predict recurrence in the training set, and 69% and 62%, respectively, in the test set. A singular 3-gene rule was constructed that predicted recurrence with 80% sensitivity and 90% specificity in the training set, and 71% and 67%, respectively, in the test set. CONCLUSIONS: Using primary nonmuscle invasive urothelial carcinoma from initial occurrences genetic programming identified transcripts in reproducible fashion, which were predictive of recurrence. These findings could potentially impact nonmuscle invasive urothelial carcinoma management.

Asunto(s)

Inteligencia Artificial , Carcinoma de Células Transicionales/patología , Perfilación de la Expresión Génica , Invasividad Neoplásica/patología , Neoplasias de la Vejiga Urinaria/patología , Anciano , Algoritmos , Biopsia , Carcinoma de Células Transicionales/cirugía , Femenino , Humanos , Aprendizaje Automático , Masculino , Estadificación de Neoplasias , Reacción en Cadena de la Polimerasa , Valor Predictivo de las Pruebas , Pronóstico , Medición de Riesgo , Sensibilidad y Especificidad , Neoplasias de la Vejiga Urinaria/cirugía

RESUMEN

UNLABELLED: Rhabdomyosarcoma is the most common soft tissue sarcoma in children. Metastatic rhabdomyosarcoma in children has a 5-year event-free survival rate of <30%, and a recent clinical trial with irinotecan, a topoisomerase I inhibitor, failed to improve outcome. Therefore, it was surmised that failure of irinotecan may be the result of overexpression of the DNA repair enzyme tyrosyl-DNA phosphodiesterase (TDP1), which processes topoisomerase I-DNA complexes resulting from topoisomerase I inhibitor treatment. Using human tissue microarrays and gene expression arrays, a marked overexpression of TDP1 protein and mRNA in RMS tumors was observed. Critically, knockdown of TDP1 or inhibition of poly(ADP-ribose) polymerase-1 (PARP-1), an enzyme in the same complex as TDP1, sensitized rhabdomyosarcoma cell lines to analogues of irinotecan. Interestingly, BRCA1/2 mutations or altered expression was not detectable in rhabdomyosarcoma cells; however, TDP1 knockdown and PARP-1 inhibition alone were cytotoxic to a subset of rhabdomyosarcoma cells, suggesting that they harbor genetic lesions in DNA repair components that have synthetic lethal interactions with loss of TDP1 or PARP1 function. Furthermore, culturing embryonal rhabdomyosarcoma cells in serum/nutrient-restricted medium increased cellular cytotoxicity upon PARP-1 inhibition and was intrinsically cytotoxic to alveolar, though not embryonal rhabdomyosarcoma cells. The results of these studies suggest a compensatory role for TDP1 in rhabdomyosarcoma after topoisomerase-I based therapy and further demonstrate that TDP1 knockdown, PARP-1 inhibition, and dietary restriction have therapeutic validity. IMPLICATIONS: Selective targeting of TDP1 and/or PARP-1 in rhabdomyosarcoma induces cytotoxicity and sensitizes to DNA damaging agents.

Asunto(s)

Hidrolasas Diéster Fosfóricas/genética , Hidrolasas Diéster Fosfóricas/metabolismo , Poli(ADP-Ribosa) Polimerasas/genética , Poli(ADP-Ribosa) Polimerasas/metabolismo , Rabdomiosarcoma/genética , Antineoplásicos/farmacología , Proteína BRCA1/genética , Proteína BRCA2/genética , Camptotecina/análogos & derivados , Camptotecina/farmacología , Línea Celular Tumoral , Niño , Reparación del ADN , Perfilación de la Expresión Génica , Técnicas de Inactivación de Genes , Glucosa/metabolismo , Humanos , Mutación , Mioblastos Esqueléticos/fisiología , Poli(ADP-Ribosa) Polimerasa-1 , Inhibidores de Poli(ADP-Ribosa) Polimerasas , Rabdomiosarcoma/metabolismo , Rabdomiosarcoma/patología , Suero/metabolismo , Análisis de Matrices Tisulares

RESUMEN

Long non-coding RNAs (ncRNAs) have been shown to regulate important biological processes that support normal cellular functions. Aberrant regulation of these essential functions can promote tumor development. In this review, we underscore the importance of the regulatory role played by this distinct class of ncRNAs in cancer-associated pathways that govern mechanisms such as cell growth, invasion, and metastasis. We also highlight the possibility of using these unique RNAs as diagnostic and prognostic biomarkers in malignancies.