November 1, 2018, New York—A multi-institutional study led by Howard Chang, Virginia and D.K. Ludwig Professor of Cancer Genomics at Stanford University, and Stanford geneticist William Greenleaf has surveyed genomes in 410 tumor samples representing 23 types of cancer to produce a sprawling map of DNA sequences that regulate the expression of specific genes in malignancies. By integrating these results—which identify 562,709 such “cis-regulatory elements”—with other genomic, clinical and biochemical information about the same tumors, the researchers also identified such things as new molecular subtypes of cancers and their relationship to patient prognoses, and novel markers of inherited cancer risk.
The study, published in the current issue of Science, provides a sweeping yet granular view of the central role mutations in the non-coding genome—which covers 98% of the whole—play in cancer and the biochemical mechanisms by which they exert their effects. The findings should, further, serve as an invaluable resource for the development of new tools for cancer diagnosis, therapy and prevention.
The DNA within a cell’s nucleus is tightly wound around proteins and packaged into a threadlike structure known as chromatin. As a result, only certain stretches of DNA are accessible to the protein machinery that reads genes. Accessible regions vary to some degree in different types of cells, which permits the reading of unique subsets of genes that create a particular cell type—say a neuron, as opposed to a muscle cell. Little was known, however, about these regions’ vast swaths of noncoding sequences, their regulatory elements or how mutations in these sequences contribute to cancer.
Chang, Greenleaf and colleagues applied a newly developed technique called assay for transposase-accessible chromatin using sequencing, or ATAC-seq, to chart the chromatin available for reading. ATAC-seq, Chang explains, is akin to spray-painting the DNA so that only the accessible chromatin gets painted, giving researchers a fast and easy way to identify those regions.
The researchers not only map these areas but show that mutations in noncoding sequences thousands of bases away from a gene can create a newly accessible stretch that promotes the aberrant expression of that gene. In a bladder tumor, for example, a mutation generates a new binding site for a protein that regulates gene expression, driving the expression of a neighboring gene that influences cell size, motility and shape—all key factors in cancer growth. The findings indicate that unique suites of such mutations may drive different types of cancer.
By juxtaposing their chromatin accessibility map against genome-wide gene expression data for various cancers, the researchers identified tens of thousands of likely interactions between regulatory elements of DNA and genes known to play an important role in cancer and tumor immune evasion. The findings also shed light on how inherited variations in DNA sequence in noncoding DNA can predispose people to cancer.
Chang is also a professor of dermatology and of genetics at Stanford University School of Medicine and a Howard Hughes Medical Institute investigator.