Speeding discovery of the 'human cancer genome'

June 28, 2006

Two gene discoveries announced in separate reports in the June 30, 2006 issue of Cell highlight one way to speed through the human genome in search of those genes most important for spawning cancer. Both groups say that a critical element in the enterprise to efficiently characterize the "human cancer genome" --a comprehensive collection of the genetic alterations responsible for major cancers--is the strategic comparison of human tumors with those of mice. As a demonstration of the value of such strategic comparisons between species, the researchers report promising finds: one of the research teams identified two genes that can--in some circumstances--conspire to produce liver cancer, while the second uncovered a gene important to the spread of melanoma, the most serious form of skin cancer. Such functionally important genes, and the larger genetic pathways of which they are a part, are also those with the most promise as potential targets for cancer drugs, according to the researchers.

"With improvements in genome technology, we've found that human cancer is noisy," said Howard Hughes Medical Institute investigator Scott Lowe of Cold Spring Harbor Laboratory. "There are lots of alterations, only some of which causally contribute to the disease."

"Genetically engineered mice, by definition, develop more defined cancers than humans," he said. "Mice can therefore be used as a filter to help reduce that noise, and as a tool to determine, in areas of chromosomal alteration, what changes are functionally relevant."

The difficulty stems from the fact that studies that scan the genomes of human tumors for differences typically find hundreds to thousands of genes that distinguish cancer and noncancer.

Some of those differences are at the root of the cancer, while others are what Lowe refers to as "evolutionary byproducts." In other words, they are genes that simply came along for the ride with those that actually contribute to the cancerous cells' ability for unchecked proliferation or spread.

Simply sorting through those differences one by one takes time and money, said Lynda Chin of the Dana-Farber Cancer Institute and Harvard Medical School.

"There has to be a way to prioritize the effort," she said.

Chin's and Lowe's groups already relied on large-scale structural changes to chromosomes as a way of identifying areas of the genome with potential importance for cancer. Such chromosomal rearrangements often lead to the amplification of cancer-causing genes or the loss of genes that normally suppress tumor formation.

But as genome technology continues to improve, providing ever-increasing resolution, researchers have found more than they had expected, Chin said.

In human melanoma, for example, more than 100 genomic regions exhibit recurring structural changes, not all of which appear to be important, she said. One way to narrow down the number of regions is to look for chromosomal alterations found in both humans and in the complementary, or syntenic, regions of the mouse genome.

"If you are seeing the same event in different species, it becomes more likely that a common biological pressure is responsible--more likely that it is an important event," Chin said.

Using that strategy in the current study, Chin's group examined genetically engineered mice with melanoma that had developed an increased potential to spread, a process known as metastasis. Metastasis is a multistep process that requires and selects for tumor cells capable of escaping their normal microenvironment, traversing into and out of lymphatic or blood vessels, and proliferating in new "soil," the researchers said.

Metastasis is particularly important in skin cancer, Chin added, as the primary tumor is almost always curable. Once the cancer spreads from the skin to other parts of the body, however, it can be difficult to treat and deadly.

The metastatic cancers of mice developed a chromosomal amplification--a region of the genome expressed in an unusually large number of copies--that corresponded to a much larger amplified region in the metastatic human melanomas, they found. Further study of that common region in mouse melanomas that independently developed their invasive ability revealed just one consistently elevated protein, called Nedd9.

To find out whether Nedd9 could play a role in skin cancer's spread, the researchers blocked the protein in both mouse and human metastatic melanoma cells. Cancer cells without active Nedd9 lost their ability to invade. Similarly, primary melanomas, when made to express too much Nedd9, became invasive, identifying Nedd9 as a "bona fide melanoma metastasis gene." Nedd9's role appears to result from its interaction with another enzyme known to be important for cell's ability to migrate and take root.

As further evidence, they also found that the Nedd9 gene was frequently expressed at higher levels in metastatic human melanomas compared to primary melanomas.

Drugs aimed at Nedd9 might therefore prevent the skin cancer's spread, Chin said. Measurement of Nedd9 levels in primary melanomas might also provide an indication of the cancer's likelihood of spreading, although "any prognostic significance would require rigorous investigation and validation in appropriately designed prospective clinical trials."

Taking a similar approach, Lowe's team identified two genes that can work together to encourage one form of liver cancer, called hepatocellular carcinoma.

Hepatocellular carcinoma is the fifth most frequent form of cancer worldwide but, owing to the lack of effective treatment options, represents the third leading cause of death, Lowe said. The only curative treatments involve surgery or transplantation as chemotherapies are ineffective, and no existing drug regimen prolongs survival.

While a handful of genes have been linked to liver cancer, "how specific lesions interact to produce its aggressive characteristics remains poorly understood."

Lowe's team relied on mice with specific pathological changes known to play a role in some liver cancers. They then searched for other spontaneous mutations in the animals' tumors and compared them to recurrent alterations observed in the human disease.

That comparison narrowed the field to two genes that appear to "drive" liver tumors in both species: a gene called cIAP1, known to inhibit cell death, and a transcription factor called Yap. Both are required to sustain rapid growth of the tumors, they showed.

As the chromosomal region under study is found in five to ten percent of human tumor types, including lung, ovarian, esophageal, and liver carcinomas, the findings suggest the overall contribution of cIAP1 and Yap to human cancer may be substantial, the researchers said.

Their new mouse model now offers an "excellent setting" for preclinical tests of the potential of cIAP1 and Yap as targets for new cancer therapies, they added.

Taken together, the papers demonstrate a general principle with real importance for cancer patients, Chin said.

"Robust, stringent and biologically relevant systems for filtering, annotating, and prioritizing the efforts of cancer geneticists and biologists will be essential to facilitate and accelerate the translation of our genomic knowledge into cancer drugs that will impact patient survival," she wrote.
(Zender et al.)

The researchers include Lars Zender, Mona S. Spector, Wen Xue, Michael Wigler, David Mu, Robert Lucito, and Scott Powers of Cold Spring Harbor Laboratory in Cold Spring Harbor, NY; Peer Flemming of Hannover Medical School in Hannover, Germany and General Hospital Celle in Celle, Germany; Carlos Cordon-Cardo of Memorial Sloan-Kettering Cancer Center in New York, NY; John Silke of The Walter and Eliza Hall Institute of Medical Research in Parkville and La Trobe University in Melbourne, Victoria, Australia; Sheung-Tat Fan and John M. Luk of University of Hong Kong in Hong Kong, China; Gregory J. Hannon and Scott W. Lowe of Howard Hughes Medical Institute and Cold Spring Harbor Laboratory in Cold Spring Harbor, NY.

This work was generously supported by the German Research Foundation; Alan and Edith Seligson; the Miracle Foundation; the Breast Cancer Research Foundation; Long Islanders Against Breast Cancer; the West Islip Breast Cancer Foundation; Long Island Breast Cancer (1 in 9); an Elizabeth McFarland Breast Cancer Research Grant; Breast Cancer Help Inc.; and grants CA078544, CA13106, CA87497, and CA105388 from the National Institutes of Health. M.W. is an American Cancer Society Research Professor. G.J.H. and S.W.L. are Howard Hughes Medical Institute investigators.

(Kim et al.)

The researchers include Minjung Kim, Joseph D. Gans, Audrey Wang, Ji-Hye Paik, and Bin Feng of Dana-Farber Cancer Institute in Boston, MA; Cristina Nogueira of Dana-Farber Cancer Institute in Boston, MA and University of Porto (IPATIMUP) in Porto, Portugal; Cameron Brennan and Carlos Cordon-Cardo of Memorial Sloan-Kettering Cancer Center in New York, NY; William C. Hahn of Dana-Farber Cancer Institute in Boston, MA and the Broad Institute of Harvard and MIT in Cambridge, MA; Stephen N. Wagner of the Medical University of Vienna and Center of Molecular Medicine, Austrian Academy of Sciences in Vienna, Austria; Thomas J. Flotte and Lyn M. Duncan of Massachusetts General Hospital and Harvard Medical School in Boston, MA; Scott R. Granter of Brigham and Women's Hospital in Boston, MA; Lynda Chin of Dana-Farber Cancer Institute and Harvard Medical School in Boston, MA.

This work was supported by R01 CA93947, U01 CA84313, and P50 CA93683 to L.C. W.C.H. is supported by U01 CA105423 and P50 CA112962. S.N.W. is supported by the Austrian National Bank (No.11062). J-H.P. is a Damon Runyon Fellow.

Kim et al.: "Comparative Oncogenomics Identifies NEDD9 as a Melanoma Metastasis Gene."

Zender et al.: "Identification and validation of oncogenes in liver cancer using an integrative oncogenomic approach."

Related Preview by Peeper et al.: "Cross-species Oncogenomics in Cancer Gene Identification."

Cell Press

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