Department of Integrative Biology and Physiology, University of California, Los Angeles, Los Angeles, CA, 90095, USA.
Bioinformatics Interdepartmental Program, University of California, Los Angeles, Los Angeles, CA, 90095, USA.
Commun Biol. 2020 Aug 3;3(1):422. doi: 10.1038/s42003-020-01146-2.
Bulk tissue DNA methylation profiling has been used to examine epigenetic mechanisms and biomarkers of complex diseases such as cancer. However, heterogeneity of cellular content in tissues complicates result interpretation and utility. In silico deconvolution of cellular fractions from bulk tissue data offers a fast and inexpensive alternative to experimentally measuring such fractions. In this study, we report the design, implementation, and benchmarking of MethylResolver, a Least Trimmed Squares regression-based method for inferring leukocyte subset fractions from methylation profiles of tumor admixtures. Compared to previous approaches MethylResolver is more accurate as unknown cellular content in the mixture increases and is able to resolve tumor purity-scaled immune cell-type fractions without a cancer-specific signature. We also present a pan-cancer deconvolution of TCGA, recapitulating that high eosinophil fraction predicts improved cervical carcinoma survival and identifying elevated B cell fraction as a previously unreported predictor of poor survival for papillary renal cell carcinoma.
批量组织 DNA 甲基化分析已被用于研究癌症等复杂疾病的表观遗传机制和生物标志物。然而，组织中细胞成分的异质性使得结果解释和应用变得复杂。从批量组织数据中进行细胞分数的计算是一种快速且廉价的替代方法，无需进行此类分数的实验测量。在这项研究中，我们报告了 MethylResolver 的设计、实现和基准测试，这是一种基于最小二乘回归的方法，用于从肿瘤混合物的甲基化谱中推断白细胞亚群分数。与之前的方法相比，MethylResolver 在混合物中未知细胞含量增加时更准确，并且能够在没有癌症特异性特征的情况下解析与肿瘤纯度成比例的免疫细胞类型分数。我们还对 TCGA 进行了泛癌症去卷积，结果表明高嗜酸性粒细胞分数预示着宫颈癌生存率的提高，并确定了升高的 B 细胞分数是乳头状肾细胞癌中以前未报道的生存率不良的预测因子。
