Nature's Journal Club

Kornelia Polyak

Dana-Farber Cancer Institute and Harvard Medical School, Boston, Massachusetts

A geneticist rebuts criticism of cancer genome projects.

What do you learn if you sequence 13,000 genes in 11 breast and 11 colorectal cancer samples? The question taps into an intense debate about how best to identify genes relevant to human cancer.

Last year, researchers reported the results of a survey such as the one described (T. Sjöblom et al. Science 314, 268–274; 2006). They found that each tumour contains, on average, 90 mutant genes — an unexpectedly high number. They also defined mutation spectra that were specific to colon and breast tumours, including the intriguing observation that the DNA letter sequence CG was swapped for GC at high frequency in breast tumours. This could be due to an uncharacterized DNA repair defect or differential carcinogen exposure.

I consider this report a step towards answering key questions in cancer biology, such as how many genes are mutated in cancer, how many mutations are required for cancer, and whether accumulation of genetic alterations in cancer cells drives tumour progression.

But others disagree. Many labs see large-scale sequencing of cancer genomes as unfocused and expensive fishing experiments. I have been doing genomics experiments since the dawn of this era, and have often faced this criticism.

But just this one study has identified more genes mutated in human cancer than thousands of investigators have found over past decades. And another recent, large-scale sequencing project pinpointed close to 120 mutant kinase enzymes that may have a role in human cancers (C. Greenman et al. Nature 446, 153–158; 2007).

Both cases show that the outcome of unbiased, genome-wide studies may not be what we expect, which is exactly why they’re worth doing.

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