近日，加拿大大学健康网络Mathieu Lupien与荷兰癌症研究所Wilbert Zwart等研究人员合作利用顺式组的划分揭示了原发性前列腺癌中主要转录调节因子的体细胞突变和风险变异的汇集。相关论文于2019年11月14日在线发表在《癌细胞》杂志上。

研究人员根据顺式组（cistrome）划分的基因组揭示了前列腺肿瘤中体细胞单核苷酸变异（SNV）的富集，这与包括AR、FOXA1和HOXB13在内的主要转录调节子的相邻正常组织顺式组相反。与这些转录调节因子的肿瘤顺式组相比，这与前列腺癌遗传倾向富集相似，例如在8q24位点，其在上调MYC表达的顺式调节元件中，同时包含了风险变体和体细胞SNV。但是，大规模平行报道者试验显示，很少有SNV可以改变单个顺式调节元件的反式激活潜能。取而代之的是，类似于遗传的风险变体，SNV累积在前列腺癌发展所需的核心转录调节因子的顺式组。

据介绍，成千上万个功能未知的非编码体细胞SNV在肿瘤中被报道。

附：英文原文

Title: Cistrome Partitioning Reveals Convergence of Somatic Mutations and Risk Variants on Master Transcription Regulators in Primary Prostate Tumors

Author: Parisa Mazrooei, Ken J. Kron, Yanyun Zhu, Stanley Zhou, Giacomo Grillo, Tahmid Mehdi, Musaddeque Ahmed, Tesa M. Severson, Paul Guilhamon, Nicholas Sinnott Armstrong, Vincent Huang, Takafumi N. Yamaguchi, Michael Fraser, Theodorus van der Kwast, Paul C. Boutros, Housheng Hansen He, Andries M. Bergman, Robert G. Bristow, Wilbert Zwart, Mathieu Lupien

Issue&Volume: November 14, 2019

Abstract: Thousands of noncoding somatic single-nucleotide variants (SNVs) of unknown functionare reported in tumors. Partitioning the genome according to cistromes reveals theenrichment of somatic SNVs in prostate tumors as opposed to adjacent normal tissuecistromes of master transcription regulators, including AR, FOXA1, and HOXB13. Thisparallels enrichment of prostate cancer genetic predispositions over these transcriptionregulators' tumor cistromes, exemplified at the 8q24 locus harboring both risk variantsand somatic SNVs in cis-regulatory elements upregulating MYC expression. However, Massively Parallel Reporter Assays reveal that few SNVs canalter the transactivation potential of individual cis-regulatory elements. Instead, similar to inherited risk variants, SNVs accumulatein cistromes of master transcription regulators required for prostate cancer development.

DOI: 10.1016/j.ccell.2019.10.005

Source: https://www.cell.com/cancer-cell/fulltext/S1535-6108(19)30479-9