For Cancer Cells, Chromosome Loss is No Accident

Using a clever combination of new computer algorithms and cell culture techniques, scientists in Columbia University’s Herbert Irving Comprehensive Cancer Center (HICCC) have addressed a question that’s long troubled researchers: why do cancer cells often lose huge chunks of their DNA? The results, published in this week’s issue of the journal Nature, reveal how these losses can help the cells survive, and point toward novel strategies for detecting and attacking tumors.

Cancer cells often develop aneuploidy, losing all or part of one copy of a chromosome. Investigators have known that for decades, but they’ve been unable to get a definitive answer to an obvious question: does aneuploidy provide any advantage to the rogue cells, or is it simply an accident or a byproduct of the other changes that allow them to multiply out of control?

“There haven’t been good systematic ways to study the effects of specific changes, meaning that a specific chromosome or a specific piece of a chromosome gets deleted or gained,” says Alison Taylor, PhD, assistant professor of pathology and cell biology in the HICCC. To address that, Taylor and a multidisciplinary team of collaborators at several other institutions combined a new computational biology algorithm, cutting-edge wet lab experiments, and a massive cancer genome database.

First, the team developed a new algorithm to analyze the patterns of genome breaks in aneuploid cells, then applied it to data from the US National Institutes of Health’s Cancer Genome Atlas. Looking at more than 10,000 unique cancers spanning numerous tissue types, they found that the breaks occurred with different frequencies across different parts of chromosomes. “So it kind of looks like a waterfall, or going down steps,” says Taylor. Those steps, chromosomal regions where the frequency of breaks changes precipitously, suggest that there are some chromosome regions that are important for the cells to keep, and others that they are keen to get rid of.

Taking the results into the lab, the team confirmed that in evolutionary terms the cells are preferentially keeping chromosome segments that give them selective survival advantages anddeleting those that inhibit or halt their growth.

Drilling deeper, Taylor and her colleagues then looked at specific genes inside the affected genome regions. “Many of the genes that we found were genes that were already known [to be involved in cancer],” says Taylor. That provided a reassuring confirmation of the approach. Other genes that they found, however, had never been linked to the disease before, so the new work has significantly expanded the list of likely cancer-driving genes.

Serendipitously, a colleague down the hall from Taylor’s lab works on one of those newly highlighted genes, called WRN. Mutations in both copies of the WRN gene cause a condition called Werner syndrome, characterized by premature aging and an increased risk of cancer. The cells in the Cancer Genome Atlas that had lost WRN, however, had lost only one copy. That finding alone opens an entirely new avenue of inquiry. “What exactly is happening when you’re knocking down 50% of this gene?” says Taylor.

Besides gleaning more details about the biology of individual genes, Taylor hopes the work will spur new clinical research. “I really forsee the day where specific aneuploidy is a biomarker, or it could be a precision medicine target the same way that different mutations are now,” she says.