RESUMEN
Molecular features of gynecologic cancers have been investigated in comprehensive studies, but correlation of these molecular signatures with clinical significance for precision medicine is yet to be established. Towards this end, we evaluated 95 gynecologic cancer cases submitted for testing using The JAX ActionSeq™ NGS panel. Molecular profiles were studied and compared to TCGA datasets to identify similarities and distinguishing features among subtypes. We identified 146 unique clinically significant variants (Tier I and II) across 45 of the 212 genes (21%), in 87% (83/95) of cases. TP53, PTEN, ARID1A, PIK3CA and ATM were the most commonly mutated genes; CCNE1 and ERBB2 amplifications were the most frequently detected copy-number alterations. PARP inhibitors were among the most commonly reported drug class with clinical trials, consistent with the frequency of DNA damage-response pathway mutations in our cohort. Overall, our study provides additional insight into the molecular profiles of gynecologic cancers, highlighting regulatory pathways involved, raising the potential implications for targeted therapeutic options currently available.
Asunto(s)
Neoplasias de los Genitales Femeninos/genética , Mutación , Guías de Práctica Clínica como Asunto , Transcriptoma , Adulto , Anciano , Anciano de 80 o más Años , Antineoplásicos/uso terapéutico , Ciclo Celular/genética , Estudios de Cohortes , Variaciones en el Número de Copia de ADN , Reparación del ADN/genética , ADN de Neoplasias/genética , Conjuntos de Datos como Asunto , Femenino , Amplificación de Genes , Frecuencia de los Genes , Genes Relacionados con las Neoplasias , Neoplasias de los Genitales Femeninos/tratamiento farmacológico , Neoplasias de los Genitales Femeninos/patología , Adhesión a Directriz , Humanos , Persona de Mediana Edad , Inhibidores de Poli(ADP-Ribosa) Polimerasas/uso terapéutico , Medicina de Precisión/métodos , Estudios RetrospectivosRESUMEN
The World Health Organization (WHO) has defined more than 130 distinct central nervous system (CNS) tumor entities, of which glioblastoma is the most fatal primary brain tumor. However, the correlation of the molecular signatures of glioblastoma with clinical significance for precision medicine is not well-known. How, and to what extent these variants may affect clinical decision making remains uncertain. Here, we evaluate 48 glioblastomas submitted for testing using the JAX ActionSeq™ Next-generation sequencing (NGS) panel. We identified 131 clinically significant variants (Tier I and II) across 30 of the 212 genes (14%). TP53, EGFR, PTEN, IDH1 were the most commonly mutated genes; EGFR, CDK4 amplifications, and CDKN2A deletion were the most frequently detected copy-number alterations. CDK4/6 and PI3K inhibitors were among the most commonly reported drug class with FDA approved therapies and investigational therapies, which is consistent with the frequencies of these genes in our cohort. Overall, our study established the molecular profiles of glioblastoma based on the 2017 joint consensus guidelines by AMP/ASCO/CAP and provides the potential implications for targeted therapeutic options currently available.
Asunto(s)
Neoplasias del Sistema Nervioso Central/genética , Glioblastoma/genética , Medicina de Precisión/métodos , Estudios de Cohortes , Femenino , Secuenciación de Nucleótidos de Alto Rendimiento , Humanos , Mutación , Estudios RetrospectivosRESUMEN
OBJECTIVE: The study aimed to retrospectively evaluate the positive yield rate of a custom 212-gene next-generation sequencing (NGS) panel, the JAX ActionSeq™ assay, used in molecular profiling of solid tumors for precision medicine. METHODS: We evaluated 261 cases tested over a 24-month period including cancers across 24 primary tissue types and report on the mutation yield in these cases. RESULTS: Thirty-three of the 261 cases (13%) had no detectable clinically significant variants. In the remaining 228 cases (87%), we identified 550 clinically significant variants in 88 of the 212 genes, with four of fewer clinically significant variants being detected in 62 of 88 genes (70%). TP53 had the highest number of variants (125), followed by APC (47), KRAS (47), ARID1A (20), PIK3CA (20) and EGFR (18). There were 38 tier I and 512 tier II variants, with two genes having only a tier I variant, seven genes having both a tier I and tier II variant, and 79 genes having at least one tier II variant. Overall, the ActionSeq™ assay detected clinically significant variants in 42% of the genes included in the panel (88/212), 68% of which (60/88) were detected in more than one tumor type. CONCLUSIONS: This study demonstrates that of the genes with documented involvement in cancer, only a limited number are currently clinically significant from a therapeutic, diagnostic and/or prognostic perspective.