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[This corrects the article DOI: 10.1371/journal.pone.0176139.].
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Next year will mark 60 years since Dr. Leslie Foulds outlined his hypothesis that cancer is "a dynamic process advancing through stages that are qualitatively different," leading the way to our view of cancer progression as we know it today. Our understanding of the mechanisms of these stages has been continuously evolving this past half-century, and there has always been an active discussion of the roles of both genetic and epigenetic changes in directing this progression. In this review, we focus on the roles one particular epigenetic mark-DNA methylation-plays in these various "discontinuous" stages of cancer. Understanding these steps not only gives us a better picture of how this fascinating biological process operates, but also opens the doors to new prognostic biomarkers and therapies against these malignancies.
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Metilación de ADN , Epigénesis Genética , Histonas/genética , Recurrencia Local de Neoplasia/genética , Neoplasias/patología , Antimetabolitos Antineoplásicos/uso terapéutico , Biomarcadores de Tumor/genética , Carcinogénesis/genética , Metilasas de Modificación del ADN/antagonistas & inhibidores , Resistencia a Antineoplásicos/genética , Inhibidores Enzimáticos/uso terapéutico , Humanos , Estadificación de Neoplasias , Neoplasias/genética , Neoplasias/terapiaRESUMEN
We present the bottleneck sequencing system (BotSeqS), a next-generation sequencing method that simultaneously quantifies rare somatic point mutations across the mitochondrial and nuclear genomes. BotSeqS combines molecular barcoding with a simple dilution step immediately before library amplification. We use BotSeqS to show age- and tissue-dependent accumulations of rare mutations and demonstrate that somatic mutational burden in normal human tissues can vary by several orders of magnitude, depending on biologic and environmental factors. We further show major differences between the mutational patterns of the mitochondrial and nuclear genomes in normal tissues. Lastly, the mutation spectra of normal tissues were different from each other, but similar to those of the cancers that arose in them. This technology can provide insights into the number and nature of genetic alterations in normal tissues and can be used to address a variety of fundamental questions about the genomes of diseased tissues.
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Genoma Humano/genética , Genómica/métodos , Secuenciación de Nucleótidos de Alto Rendimiento/métodos , Mutación , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Núcleo Celular/genética , Niño , Preescolar , ADN Mitocondrial/química , ADN Mitocondrial/genética , Femenino , Humanos , Masculino , Persona de Mediana Edad , Adulto JovenRESUMEN
UNLABELLED: Pancreatic cancer is projected to become the second leading cause of cancer-related death in the United States by 2020. A familial aggregation of pancreatic cancer has been established, but the cause of this aggregation in most families is unknown. To determine the genetic basis of susceptibility in these families, we sequenced the germline genomes of 638 patients with familial pancreatic cancer and the tumor exomes of 39 familial pancreatic adenocarcinomas. Our analyses support the role of previously identified familial pancreatic cancer susceptibility genes such as BRCA2, CDKN2A, and ATM, and identify novel candidate genes harboring rare, deleterious germline variants for further characterization. We also show how somatic point mutations that occur during hematopoiesis can affect the interpretation of genome-wide studies of hereditary traits. Our observations have important implications for the etiology of pancreatic cancer and for the identification of susceptibility genes in other common cancer types. SIGNIFICANCE: The genetic basis of disease susceptibility in the majority of patients with familial pancreatic cancer is unknown. We whole genome sequenced 638 patients with familial pancreatic cancer and demonstrate that the genetic underpinning of inherited pancreatic cancer is highly heterogeneous. This has significant implications for the management of patients with familial pancreatic cancer.
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Carcinoma/genética , Predisposición Genética a la Enfermedad , Mutación de Línea Germinal , Neoplasias Pancreáticas/genética , Análisis de Secuencia de ADN/métodos , Proteínas de la Ataxia Telangiectasia Mutada/genética , Proteína BRCA2/genética , Inhibidor p16 de la Quinasa Dependiente de Ciclina/genética , Humanos , Mutación PuntualRESUMEN
Cell-free DNA shed by cancer cells has been shown to be a rich source of putative tumor-specific biomarkers. Because cell-free DNA from brain and spinal cord tumors cannot usually be detected in the blood, we studied whether the cerebrospinal fluid (CSF) that bathes the CNS is enriched for tumor DNA, here termed CSF-tDNA. We analyzed 35 primary CNS malignancies and found at least one mutation in each tumor using targeted or genome-wide sequencing. Using these patient-specific mutations as biomarkers, we identified detectable levels of CSF-tDNA in 74% [95% confidence interval (95% CI) = 57-88%] of cases. All medulloblastomas, ependymomas, and high-grade gliomas that abutted a CSF space were detectable (100% of 21 cases; 95% CI = 88-100%), whereas no CSF-tDNA was detected in patients whose tumors were not directly adjacent to a CSF reservoir (P < 0.0001, Fisher's exact test). These results suggest that CSF-tDNA could be useful for the management of patients with primary tumors of the brain or spinal cord.