Study of gene enhancers sheds light on how some cancers form and spread

Examination of nearly 9,000 tumor samples across 33 cancer types reveals enhancers as key regulators of therapy targets, including PD-L1

MD Anderson News Release April 05, 2018

At the heart of any cancer diagnosis or treatment are cells. If one thinks of the cell components controlling gene activation as a Russian nesting-doll of gene regulatory layers, within those increasingly smaller tiers are short pieces of non-coding DNA called enhancers. A study at The University of Texas MD Anderson Cancer Center reveals enhancers as a significant area of research for diagnosing and/or treating many cancers.

Cancer researchers have been interested in enhancers due to their ability to turn genes off or on. Tens of thousands of enhancers can reside in a single cell, but in-depth understanding of how they work has eluded investigators. Findings from the study, which provides significant new knowledge about these cell components, were published in the April 5, 2018 online issue of Cell.

“Although the role of enhancers in cancer development has increasingly been recognized, genome-wide studies on enhancer activity over large patient cohorts have not been done,” said Han Liang, Ph.D., study lead and associate professor of Bioinformatics & Computational Biology at The University of Texas MD Anderson Cancer Center. “Our study was able to illustrate, for the first time, the enhancer expression ‘landscape’ in a broad range of cancers.”

In cancer cells, regulatory networks are often “rewired,” leading to cancer; however, understanding of how this occurs has been limited. Liang’s team revealed enhancers as a missing piece of the puzzle, indicating, among several key findings, their role as key regulators of therapeutic targets, including programmed death ligand-1 (PD-L1).

PD-L1, a protein that suppresses the immune system allowing cancer to form and grow, is an important target for many existing and emerging immunotherapies. Using RNA-sequencing data from The Cancer Genome Atlas (TCGA), Liang’s team conducted a genome-wide analysis of 8,928 tumor samples across 33 cancer types, and identified a considerable number of enhancers in addition to PD-L1.

The study is part of the PanCancer Atlas, which aims to answer big overarching questions about cancer by examining the full set of tumors available via The Cancer Genome Atlas (TCGA), a joint effort of the National Cancer Institute (NCI) and the National Human Genome Research Institute (NHGRI). This study is one of several that conclude the PanCancer Atlas and TCGA missions of mapping key genomic changes in an array of cancer types, and providing a community resource that accelerates our understanding of the molecular basis of cancer.

“Our study provided a systematic view of enhancer activity in diverse tumors, suggesting a conceptually novel strategy to inhibit key therapeutic targets,” said Liang.

The team also demonstrated how enhancers can serve as biomarkers, through examination of an enhancer that targets spleen tyrosine kinase (SYK), often linked to multiple types of late-stage cancer. In looking at patient survival times, the enhancer proved to be a marker of poor prognosis in several cancer types.

Based on their TCGA analyses, Liang’s team additionally proposed a model in which chromatin – the “packaging” around DNA – could be a vital contributor to certain enhancer activation processes, which provides insights into how genetic mutation and cloning evolve into some cancers.

“Variations in chromatin organization in a single tumor progenitor cell could create striking differences among tumors if the variations occur over many generations of cell growth,” said Liang. “Chromatin organization could be substantially remodeled by histone gene mutations, which are frequently seen in cancers.”

The team’s observation of enhancers’ unique abilities to be both “on” and “off” switches throughout the cancer genome provided new data about tumor clonal evolution – the step-by-step cellular process by which cancer forms, and revealed a number of enhancers associated with genes tied to cancer. Liang adds that further efforts are required to investigate the potential of enhancers in clinical applications.

MD Anderson study team members included Han Chen, Ph.D.; Chunyan Li, Ph.D.; Xinxin Peng, Ph.D.; Zhicheng Zhou, Ph.D.; and John Weinstein, M.D., Ph.D., all of the Department of Bioinformatics & Computational Biology. The study was part of TCGA Program, a joint effort of the National Cancer Institute and the National Human Genome Research Institute.

Funding came from the National Institutes of Health (CA175486, CA209851 and CA016672) and the Cancer Prevention and Research Institute of Texas (RP140462).