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Sanger Team Sequences, Catalogs Somatic Mutations in Two Cancer Genomes

NEW YORK (GenomeWeb News) – In a pair of papers appearing online in Nature today, researchers from the Wellcome Trust Sanger Institute and elsewhere reported that they have sequenced the genomes of two cancers — a skin cancer and a lung cancer — and attempted to catalog the complete set of somatic mutations in each.

The team used SOLiD and Illumina sequencing, respectively, to sequence the small cell lung cancer and malignant melanoma genomes. They then analyzed the sequences, coming up with a full set of somatic mutations in both the coding and non-coding parts of each genome. In the process, the researchers identified more than 34,000 mutations in the melanoma genome and some 23,000 mutations in the lung cancer genome.

"This is the sum total of what is in [each] genome," co-senior author Andrew Futreal, joint head of the Sanger Institute's Cancer Genome Project, told GenomeWeb Daily News. "It is the full catalog."

Cancer genome sequencing studies have become increasingly common since a University of Washington-led team published the results from the first cancer genome just over a year ago. But so far the analyses of these genomes have focused heavily on coding regions, Futreal explained.

For the current study, the team attempted to compile a list of mutations found over the entire genomes of a small cell lung cancer and a malignant melanoma — two cancers linked to known environmental exposures: cigarette smoke and ultraviolet light.

These cancers are also advantageous because some gene mutation and DNA damage patterns have already been identified, Futreal added, giving the researchers a chance to compare their whole genome approach with previous findings.

Using Illumina Genome Analyzer IIs, the researchers sequenced a malignant melanoma cell line called COLO-829, developed from a 43-year-old man's melanoma, and a matched lymphoblastoid line from the same individual.

On average, the team got more than 40 times coverage of the melanoma genome and 32 times coverage of the matched control genome.

When they compared the melanoma genome with the matched control, the team found 33,345 somatic base substitutions, including 187 non-synonymous changes affecting protein-coding sequences. The researchers also confirmed that the cancer genome contained 66 small insertions or deletions, and 37 somatic rearrangements.

Some mutations affected known melanoma-related genes, while others point to genes not previously implicated in the disease, including the ETS transcription factor gene SPDEF and the metalloproteinase gene MMP28.

In general, the team noted, the melanoma genome contained a preponderance of substitutions previously observed in DNA exposed to UV light — a mutation signature consistent with the role of UV light in skin cancer risk.

For the second study, the team used the ABI SOLiD to sequence the genomes of a small cell lung cancer cell line called NCI-H209, created from a metastatic lung cancer tumor isolated from the bone marrow of a 55-year-old man, and a lymphoblastoid cell line created from the same individual.

Using mate-pair shotgun sequencing with short reads, the team generated about 39 times coverage of the tumor genome and 31 times coverage of the matched normal genome.

Even though the team knew a bit about the sorts of mutations that occur in lung cancer, the whole genome data was sobering, Futreal said. The researchers detected 22,910 somatic substitutions in the lung cancer genome, including 134 affecting coding exons. They also found 65 small insertions and deletions, 334 copy number changes, and 58 structural rearrangements.

Some of the mutations affected previously identified lung cancer genes, including TP53 and RB1. But other mutations pointed to new possible lung cancer genes, such as CHD7, which codes for a helicase protein thought to be involved in chromatin remodeling. The lung cancer genome contained duplications affecting exons 3-8 of CHD7. And the team found that the gene was also rearranged in three other small cell lung cancer lines tested.

Just as they had detected signs of UV damage in the melanoma genome, the team detected mutation signatures in the lung cancer genome that appeared to reflect the 60 or more carcinogens found in cigarette smoke.

In addition, by looking at the types of mutations and their distribution and context, Futreal explained, the team found evidence of past DNA repair in both the melanoma and lung cancer genomes.

"We can also see the desperate attempts of our genome to defend itself against the damage wreaked by the chemicals in cigarette smoke or the damage from ultraviolet radiation," co-senior author Michael Stratton, joint head of the Sanger Institute's Cancer Genome Project, said in a statement. "Our cells fight back furiously to repair the damage, but frequently lose that fight."

The current study marks some of the first steps in a much larger effort to characterize complete cancer genomes: members of the International Cancer Genome Consortium plan to sequence about 500 cases each for several different cancer types — a scale expected to turn up mutations occurring with five percent or greater prevalence in each cancer type.

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