New method identifies chromosome changes in malignant cells

Combination of computer science and biology could aid cancer research

In a boost to cancer research, Princeton scientists have invented a fast and reliable method for identifying alterations to chromosomes that occur when cells become malignant. The technique helps to show how cells modify their own genetic makeup and may allow cancer treatments to be tailored more precisely to a patient’s disease. Cancer cells are known among biologists for their remarkable ability to disable some genes and overuse others, allowing their unchecked growth into tumors. The most aggressive of these distortions occurs when cells delete or multiply chunks of their own chromosomes. Cells can simply snip strings of genes from the chromosome, or make many extra copies of the string and reinsert it into the chromosome.

Until now, scientists had no routine way to detect these alterations except for very large-scale deletions or additions. Finding small, but critical additions or deletions to chromosomes required painstaking, gene-by-gene searches. Combining computer science and biology, Princeton scientist Olga Troyanskaya, graduate student Chad Myers and other colleagues invented a method for quickly analyzing an entire genome — all the genes contained in a cell — and producing a reliable list of chromosome sections that have been either deleted or added.

“The problem is similar to finding typos in a very large book written in a language you don’t fully understand,” said Troyanskaya, an assistant professor in the Department of Computer Science and the Lewis-Sigler Institute for Integrative Genomics. “All you know are some general rules of grammar and syntax. It would take you years to do by hand, and it’s even very hard with a computer.”

Troyanskaya and Myers started with data from genomics tools that identify thousands of genes at once and show how actively they are being used. They used advanced statistical techniques to analyze this data and accurately detect deletions and additions — some as small as four or five genes — among tens of thousands of genes.

The achievement illustrates the value of the interdisciplinary environment fostered by the Lewis-Sigler Institute for Integrative Genomics, said Troyanskaya. “For this kind of problem you need people who understand computer science, statistics and biology,” she said. “Neither side could do it alone.”

Their findings will be published in an upcoming edition of the journal Bioinformatics and were posted to the journal’s Web site July 29. Troyanskaya and Myers wrote the paper in collaboration with Lewis-Sigler fellow Maitreya Dunham and professor of electrical engineering Sun-Yuan Kung.

The researchers applied their technique to yeast cells as well as human breast cancer cells and found many previously unknown additions and deletions. The results support an idea proposed by some biologists that chromosome additions and deletions are more common than previously believed.

“If a cell really wants to change its behavior drastically — if it is a cancer cell or something has changed in its environment — the fastest way is just to amplify or delete a chunk of chromosome,” said Troyanskaya. “We needed a way to identify these deletions and amplifications very accurately.”

The new method could be particularly important for cancer research because it gives scientists a clearer idea of what is really going wrong in tumors and thus points to possible treatments. The researchers already used their system to identify previously unrecognized immune system genes that are deleted in breast cancer cells, suggesting possible ways in which these aberrant cells avoid being detected and destroyed by the body’s natural defenses.

In some instances, genes that biologists thought were being turned “on” or “off” by normal regulatory chemicals within cells may actually have been added or deleted, said Troyanskaya. When a group of genes appears to be turned on or off together, biologists often look for a master regulator that controls them all at once. “They can write whole papers about how interesting it is that they are regulated together, when in fact what is happening is that the whole chunk of the chromosome containing those genes has just been amplified.”

The work also may help scientists understand the molecular basis of evolution. Additions and deletions within chromosomes are a bold method that cells use to alter their behavior under pressure from changing environments, such as marine organisms whose waters become saltier or bacterial pathogens trying to survive attacks from antibiotic drugs.

Troyanskaya came to Princeton in 2003 after earning a Ph.D. in biomedical informatics from Stanford University. Her work focuses on applying tools of computer science and statistics to questions concerning the regulation and function of genes. In September, Technology Review magazine, which is published by the Massachusetts Institute of Technology, announced that it included Troyanskaya in its annual list of 100 top innovators from around the world. The magazine cited her for creating computing techniques that “allowed her to identify genes involved in a host of diseases, including lymphoma, lung cancer and gastric cancer.”

Troyanskaya and colleagues are continuing their work on chromosome additions and deletions by collaborating with cancer researchers to refine their search for alterations that are involved in tumor growth.