More than 150 new cancer mutations found

A survey of a single human gene family has revealed more than 150 new mutations that can help trigger cancer, according to a study led by scientists at the Wellcome Trust Sanger Institute that appears today (March 7) in Nature.

The team sequenced all known protein kinase genes in 210 cancer samples, yielding a total of 1,000 mutations, then used statistical analyses to identify 158 cancer-promoting mutations in 119 genes, most of which had never before linked to cancer, said last author Mike Stratton, leader of the Sanger Institute's Cancer Genome Project, during a conference call with reporters this week. The cancer research community has identified a total of about 350 cancer genes, not including the genes discovered in this study, he said.

The results far exceeded the authors' predictions, Andrew Futreal, a senior author of the paper and a researcher at the Cancer Genome Project, said during the call. "The number we expected, particularly in the kinases ... I would have guessed would have been no more than tens" of cancer-triggering mutations.

Kinases have become a popular area of research in the cancer community, due to their ability to "switch" pathways on and off, their involvement in several cancer types, and the effectiveness of several new kinase-targeting drugs, such as Gleevec, which treats chronic myeloid leukemia.

After sequencing all 518 kinases in their cancer samples, the researchers vetted variations against the NIH's Single Nucleotide Polymorphism database and normal DNA from the same donor of each sample.

The team pinpointed a set of 921 single-base changes. Of these, probably only a minority assisted the growth and development of tumor cells, while most were "neutral" mutations, which simply accumulated as the cells multiplied.

Using statistical analyses to distill how many of the identified mutations are involved in cancer, the investigators estimated that the whole set of 921 mutations likely carried around 158 mutations that help cancer grow and survive, and 763 neutral mutations. They did not identify which specific genes are involved in the disease.

Futreal and Stratton were unavailable for interviews with The Scientist.

"The authors did an exceptional job [of comprehensive kinase] sequencing and analysis of complex data, including calculations of significance for mutations identified" as cancer-promoting or neutral, Daniel Haber, director of the Massachusetts General Hospital Cancer Center, told The Scientist in an Email. However, without functional assays, it's too soon to tell if a specific kinase mutation is truly significant, added Haber, who wrote an article accompanying the study.

The study "was a huge effort," noted Haber, but it is "a trial run or pilot" for the NIH's Cancer Genome Atlas, currently in a pilot phase, which would involve "orders of magnitude more sequencing."

"The ultimate validation of all of these would be biochemical studies," said William Pao, an assistant member of the human oncology and pathogenesis program at Memorial Sloan-Kettering Cancer Center, who was not involved in the research. "I think we're still at an early stage in terms of interpreting all the [cancer sequencing] findings coming out."

And since the authors analyzed only a small number of tumors, they may have missed some relatively rare mutations, added Pao. "The task now is to see if these are truly critical for the survival of the specific cancers, and if that's the case, then we can find drugs to target them," said Pao.

Chris Womack
mail@the-scientist.com

Links in this article

C. Greenman, et al. "Patterns of Somatic Mutation in human Cancer Genomes," Nature vol 446, 153-158.
http://www.nature.com/nature/index.html


The Wellcome Trust Sanger Institute
http://www.sanger.ac.uk/

L. Harris, "Kinase screening services probe signaling pathways," The Scientist, May 9, 2005.
http://www.the-scientist.com/article/display/15457/

The Single Nucleotide Polymorphism database
'http://www.ncbi.nlm.nih.gov/projects/SNP/


C. Choi, "'Silent' mutations are not always silent," The Scientist, Dec., 21 2006.
http://www.the-scientist.com/news/display/38329/

D. Haber and J. Settleman, "Drivers and passengers," Nature, Mar. 7, 2007.
http://www.nature.com/nature/index.html

The Cancer Genome Atlas
http://cancergenome.nih.gov