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Sequencing Tumors to Target Treatment

The mutations that trigger cancer progression suggest that a shift is needed in drug development.
October 7, 2009

Scientists have sequenced the genomes of two tumors from the same breast cancer patient–a primary tumor and a metastatic tumor that occurred nine years later–illuminating some of the genetic changes that trigger the progression of cancer. The initial findings suggest that both primary cancers and the process of metastasis–the spread of cancer cells–are more complicated and more variable than expected, which means that successful cancer treatment might ultimately require a combination of drugs targeted to different mutations.

Cancer sequence: Scientists have identified genetic mutations in the tumor tissue of a breast cancer patient, shown here.

The project is also a testament to how easy it has become to sequence a human genome. The researchers, from the British Columbia Cancer Agency, in Vancouver, now plan to sequence the tumor genomes of more than 250 additional patients over the next year. “We are sequencing dozens of tumors a week now,” says Samuel Aparicio, the scientist who led the study. Oncologists hope eventually to be able to profile every patient’s tumor this way, using the results to tailor treatment. Scientists sequenced a tumor for the first time last year–the current study is the first to compare the sequencing of two types of tumors.

Cancer develops when a number of mutations accumulate in a cell, disrupting the cell’s normal protective mechanisms and causing it to divide uncontrollably. Scientists have identified a number of genes involved in this process, such as BRCA1 and BRCA2, that predispose women to developing breast cancer. Some drugs, such as herceptin, specifically target molecular differences in cancer cells. But a broader understanding of the genetic triggers that enable both cancer development and metastasis would aid the development of new treatments. For example, women with triple-negative breast cancer, an aggressive subtype of cancer that often strikes younger women, tend to be resistant to existing drugs.

Using sequencing technology from San Diego-based Illumina, Aparicio and colleagues sequenced the genome of metastatic tissue from a breast cancer patient 43 times–to make sure that the sequence was accurate and that it covered every part of the genome–allowing them to identify the rare spots where the tumor genome differed from the patient’s normal genome. By comparing the genome sequence in noncancerous and metastatic tissue, scientists found 32 protein-altering mutations unique to the secondary tumor. “This paper is a remarkable tour de force in how thoroughly they examined this tumor,” says Leif Ellisen, a physician and scientist at Massachusetts General Hospital, in Boston, who was not involved in the study. The research was published today in the journal Nature.

The number of mutations in cancerous tissue was greater than some scientists had expected, making it challenging to determine which mutations enhance a cancer’s ability to spread, and which are the so-called “carrier mutations” that have no effect. “Many metastatic mutations occur in the patient as the tumor evolves into a more aggressive form,” says Arul Chinnaiyan, director of the Michigan Center for Translational Pathology, in Ann Arbor, who was not involved in the study. “In order to find mutations that trigger the formation of cancer from a benign cell, it will be important to focus on the sequence of early forms of the tumor rather than metastatic tumors.”

One of the major questions in cancer metastasis is whether tumors start out with the ability to spread, or they evolve that capacity over time. So the researchers looked for mutations found in both the metastatic tissue and in the primary tumor, to try to understand what made it eventually spread. Nineteen of the metastatic mutations were completely absent from the primary tumor, suggesting that they arose after the cancer spread. And six mutations appeared to be present in only a subset of the cells in the primary tumor, suggesting that the cells carrying these mutations may have been selected for as the cancer progressed, eclipsing other cells.

That suggests that even low-grade and medium-grade tumors can be genetically heterogeneous, which could be problematic for molecularly targeted drugs. “We think this points to the need to shift the way we develop and apply cancer treatments–we need to think about multiple mutations from the outset,” says Aparicio. “We are going to end up with recurrence of cancers unless we address the fact that there are cells that do not respond to the drug.”

Some diseases, such as malaria and HIV, have already been shown to require this strategy. “You need to use a cocktail of three different drugs, which target different bits of the pathology,” says Aparicio. “If you only have one or two, eventually you end up with resistance to the drugs. This may be going on in cancer as well, so we have to adapt our strategies accordingly.”

In the primary tumor, the researchers identified some proteins thought to play a role in cancer, such as PALB2, which is known to interact with the breast cancer risk factor BRCA2, as well as new mutations such as HAUS3, which plays a role in cell division.

The study also suggests that the mutations underlying different women’s cancers appear to be highly variable. Genetically screening other breast tumor tissue samples revealed that none shared the exact mutations identified in the original patient, although some samples contained mutations in the same gene. “A number of mutations were present in less than 1 percent frequency, so we need to look quite hard to find them,” says Aparicio.

The researchers are now sequencing tumors from women with triple-negative breast cancers in hope of identifying mutations that would suggest new drug targets for these cancers. They are also sequencing tumors of women in a clinical trial for an experimental cancer drug, in order to identify genetic markers that predict who will respond best to the drug.

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