At a glance:
- New computational tool reveals that having too few or too many copies of certain chromosomes or parts of chromosomes, a state known as aneuploidy, drives cancer progression.
- The work — led by researchers at Harvard Medical School, the Broad Institute of MIT and Harvard, and Dana-Farber Cancer Institute — answers a long-standing question about whether aneuploidy promotes cancer growth or is simply a side effect of it.
- Findings point to new ways of guiding cancer treatment and developing targeted drugs.
Having too few or too many copies of certain chromosomes or parts of chromosomes — a state known as aneuploidy — drives cancer progression, researchers at Harvard Medical School, the Broad Institute of MIT and Harvard, and the Dana-Farber Cancer Institute have found using a computational tool they developed.
The findings, published June 28 in Nature, could lead to new ways of guiding cancer treatment or developing targeted drugs.
The vast majority of cancer cells exhibit aneuploidy, but for decades, researchers have debated whether aneuploidy promotes the growth of cancers or is simply a side effect of cancer cells’ fast growth. Such large-scale changes in DNA have been difficult to study.
Using the new tool, the multi-institutional team compared large chromosome changes in tumor cells from nearly 11,000 cancer patients and identified key chromosome regions that, when duplicated or deleted, were harmful or beneficial to tumor cells.
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The work also revealed a new role for a known cancer gene called WRN. The team said this result shows how this type of analysis can reveal new insights into cancer biology.
“This study provides a computational answer, by directly using tumor samples from patients, to that age-old question of whether these large-scale events are really driving cancer or are just along for the ride,” said oncologist and co-senior author Rameen Beroukhim, HMS associate professor of medicine at Dana-Farber and associate member in the Cancer Program at the Broad Institute.
“We found that these aneuploidies are being directly selected for or against depending on their impact on cancer cells,” he said.
A common problem
Most human cells contain 23 pairs of chromosomes. In the late 19th century, scientists noticed that tumors often had cells with abnormal numbers of chromosomes.
More recently, studies have shown that aneuploidies — which also include duplications or deletions of entire arms of chromosomes — are present in almost 90 percent of human cancers, often appear early in cancer, and are associated with worse clinical outcomes.
Some researchers suspected that aneuploidies appeared because of the severe dysregulation of cancer cells and didn’t have any real impact on the cancer. Since the deleted or duplicated DNA regions involved in an aneuploidy can include hundreds or thousands of genes, pinning down any molecular mechanism by which an aneuploidy impacts tumor growth has been difficult.
“We’ve known for more than a century that these aneuploidies were really prominent in cancer genomes, but we didn’t have great methods to study them,” said co-senior author Alison Taylor, former postdoctoral fellow in the lab of co-author Matthew Meyerson at Dana-Farber and the Broad Institute, who is now assistant professor of pathology and cell biology at Columbia University Medical Center.
To study aneuploidy in cancer, Beroukhim and Taylor, in collaboration with first author Juliann Shih and other colleagues, wondered whether they could take advantage of other, shorter types of chromosome changes in cancer cells and tease out which sections of chromosomes might play a role in tumor growth and survival.
“There are large-scale changes that don’t quite fit the typical definition of an aneuploidy but are still impacting a large part of a chromosome arm,” said Shih, former associate computational biologist at the Broad Institute and now an internal medicine resident at the Kirk Kerkorian School of Medicine at the University of Nevada, Las Vegas.
“We began to think that these shorter events could give us signals about whether cancer cells were selecting for certain chromosome changes.”
The long and the short
The team developed a method, dubbed BISCUT for Breakpoint Identification of Significant Cancer Undiscovered Targets, to analyze where large changes were most likely to begin or end in each chromosome.
If the beginning and endpoints were in completely random spots, that would suggest that the aneuploidy had no direct impact on cancer cell survival.
However, if a particular region were often included in a large-scale chromosome change, that would hint that the aneuploidy encompassing this area was helping cancer cells survive.
Conversely, if a region were often excluded, that would suggest that the aneuploidy encompassing this area killed cancer cells or stunted their growth.
The researchers used BISCUT to analyze 10,872 tumor samples from 33 cancer types using data from The Cancer Genome Atlas.
The analysis revealed 193 regions within or near aneuploidies that cancer cells seemed to be selecting for or against. Less than half included known cancer genes.
Beroukhim’s group also discovered that the frequencies of aneuploidies on different chromosomes were correlated with the predicted selection pressure on regions within the aneuploidies.
“That was a pretty clear way of showing that selection seems to be the major driver of patterns of aneuploidies, and therefore that aneuploidies are having an impact on cancer cell survival,” Beroukhim said.
Toward treatments
In nearly one-third of all cancers in The Cancer Genome Atlas, one arm of chromosome 8 is missing, but researchers had never been sure why this aneuploidy is so common.
The study showed that deletions on chromosome 8 were more likely to include the cancer gene WRN than other areas of DNA, suggesting that it has a particularly large impact.
Certain cancer types are known to rely on WRN, and drugs are already under development to block the gene. However, the new study showed a different role in up to one third of cancers, where a partial loss of the gene appears to help cancer cells survive.
This observation could lead to new treatment approaches that selectively kill cancer cells harboring WRN loss. It could also lead to ways of identifying patients who will most likely benefit from these types of treatments.
This kind of finding is one example of the dozens of insights that Beroukhim, Taylor, and Shih think their dataset will eventually lead to.
Separate studies can delve into the mechanism behind each chromosome region identified by BISCUT, they said. Many of the regions, they suspect, will point toward new drug targets or ways of screening cancer patients for the most effective treatments.
“Our ability to address a centuries-old question is an example of how cancer research can make big leaps even in areas where it had seemed hopelessly stymied,” Beroukhim said.
Authorship, funding, disclosures
Additional authors are Shahab Sarmashghi, Nadja Zhakula-Kostadinova, Shu Zhang, Yohanna Georgis, Stephanie H. Hoyt, Michael S. Cuoco, Galen F. Gao, Liam F. Spurr, Ashton C. Berger, Gavin Ha, Veronica Rendo, Hui Shen, Matthew Meyerson, and Andrew D. Cherniack.
Support for the study was provided in part by the National Institutes of Health (National Cancer Institute and National Institute of General Medical Sciences), Fund for Innovation in Cancer Informatics, Gray Matters Brain Cancer Foundation, Pediatric Brain Tumor Foundation, The Brain Tumour Charity, and St. Baldrick’s Foundation.
Gao, Berger, Cherniack, and Meyerson receive or received research support from Bayer AG. Meyerson and Taylor received research support from Ono Pharmaceutical. Meyerson is an equity holder of, consultant for, and scientific advisory board chair for OrigiMed. Meyerson additionally receives research support from Novo Nordisk and Janssen Pharmaceuticals, consults for Interline Therapeutics, and is an inventor of a patent for EGFR mutation diagnosis in lung cancer, licensed to Labcorp. Beroukhim consults for and owns equity in Scorpion Therapeutics and receives research support from Novartis. The other authors declare no competing interests.
Adapted from a Broad Institute blog post.
