RESUMEN
A large proportion of heritability for prostate cancer risk remains unknown. Transcriptome-wide association study combined with validation comparing overall levels will help to identify candidate genes potentially playing a role in prostate cancer development. Using data from the Genotype-Tissue Expression Project, we built genetic models to predict normal prostate tissue gene expression using the statistical framework PrediXcan, a modified version of the unified test for molecular signatures and Joint-Tissue Imputation. We applied these prediction models to the genetic data of 79 194 prostate cancer cases and 61 112 controls to investigate the associations of genetically determined gene expression with prostate cancer risk. Focusing on associated genes, we compared their expression in prostate tumor vs normal prostate tissue, compared methylation of CpG sites located at these loci in prostate tumor vs normal tissue, and assessed the correlations between the differentiated genes' expression and the methylation of corresponding CpG sites, by analyzing The Cancer Genome Atlas (TCGA) data. We identified 573 genes showing an association with prostate cancer risk at a false discovery rate (FDR) ≤ 0.05, including 451 novel genes and 122 previously reported genes. Of the 573 genes, 152 showed differential expression in prostate tumor vs normal tissue samples. At loci of 57 genes, 151 CpG sites showed differential methylation in prostate tumor vs normal tissue samples. Of these, 20 CpG sites were correlated with expression of 11 corresponding genes. In this TWAS, we identified novel candidate susceptibility genes for prostate cancer risk, providing new insights into prostate cancer genetics and biology.
Asunto(s)
Biomarcadores de Tumor/genética , Epigénesis Genética , Regulación Neoplásica de la Expresión Génica , Predisposición Genética a la Enfermedad , Polimorfismo de Nucleótido Simple , Neoplasias de la Próstata/patología , Transcriptoma , Estudios de Casos y Controles , Metilación de ADN , Estudios de Seguimiento , Estudio de Asociación del Genoma Completo , Humanos , Masculino , Pronóstico , Neoplasias de la Próstata/epidemiología , Neoplasias de la Próstata/genética , Sitios de Carácter Cuantitativo , Estados Unidos/epidemiologíaRESUMEN
In our previous study, we developed a genome-wide DNA methylation model for the diagnosis of prostate cancer, and we pointed out that a considerable average error is associated with the current method for the diagnosis of prostate cancer, which is predicated on pathological assessment of biopsied tissue. In this study, we utilized whole exome and transcriptome RNA-sequencing (RNA-seq) data that were derived from 468 tumor samples and 51 normal samples of prostatic tissue, and we analyzed over 20,000 genes per sample. We were able to develop a mathematical model that classified tumor tissue versus normal tissue with a high accuracy. The overall sensitivity was 97.01%, and the overall specificity was 94.12%. The input variables to the model were the mRNA expression values of the following nine genes: ANGPT1, MED21, AOX1, PLP2, HPN, HPN-AS1, EPHA10, NKX2-3, and LRFN1. The model was validated with unknown samples, with a 10-fold cross-validation, and a leave-one-out cross-validation. We present here a genomic model, based on a whole exome and transcriptome RNA-seq analysis of biopsied prostatic tissue, that could be utilized in the diagnosis of prostate cancer.
RESUMEN
Prostate cancer is the most prevalent and the second most lethal malignancy among males in the United States of America. Its diagnosis is almost entirely predicated upon histopathological analysis of the biopsied tissue, and it is associated with a substantial average error. Using genome-wide DNA methylation data derived from 469 prostatic tumor tissue samples and 50 normal prostatic tissue samples and interrogating over 485 000 CpG sites per sample (spanning across gene promoters, CpG islands, shores, shelves, gene bodies, and intergenic and other areas), we were able to develop a mathematical model that classified with a high accuracy (overall sensitivity = 95.31% and overall specificity = 94.00%) tumor tissue versus normal tissue. The methylation ß values of five CpG sites, corresponding to the genes LINC01091, RPS15, SNORA10, and two unknown DNA areas in chromosome 1, provided the input to the model. The model was validated with unknown samples, as well as with a sixfold cross-validation and a leave-one-out cross-validation. This study presents a novel genomic model based on genome-wide DNA methylation analysis of biopsied prostatic tissue that could aid in the diagnosis of prostate cancer and help advance the transition to genomic medicine.