Cataloguing mutations in cancer genomes

18 December 2009

Earlier this year, researchers from the Genome Centre at Washington University were the first to sequence the genome from a cancer cell (see previous news). They used high-throughput parallel sequencing to identify single nucleotide variants (SNVs – including SNPs and indels) in tumour cells from a patient with acute myeloid leukaemia [Ley TJ  et al. Nature (2008) 456: 66-71]. Two further articles published this week in the journal Nature, describe the employment of a similar technique in order to catalogue all mutations in the genome of two cancers (see press release). Both studies used next generation sequencing technologies to compare DNA from cancer cells with that from healthy tissue in order to identify all variants unique to these particular cancer cells. In addition, they were also able to catalogue these variants as either driver mutations or passenger mutations. Driver mutations are those that are causally implicated in development of the cancer and are typically found in cancer genes. Passenger mutations are caused by a mutagenic environment (e.g. cigarette smoke), but do not influence the development of cancer. However, as they are passed on to daughter cancer cells, studying these mutations can give insights into the development and pathogenesis of the cancer.

Pleasance et al. compared the genome of a small-cell lung cancer cell line with that of a normal lymphoblastoid cell line, both of which had been derived from a 55 year old male with small-cell lung carcinoma (SCLC) [Pleasance et al. (2009) Nature doi10.1038/nature08629]. They identified 22, 910 substitutions, 65 indels, 334 copy number variations and 58 structural variants. Tobacco a major risk factor for lung cancer contains many chemical that act as carcinogens by binding to DNA and chemically modifying it in a characteristic fashion, thereby leaving particular mutation signatures. Mutations caused by carcinogens in tobacco can be identified by looking for these signatures; in this study the majority of the observed mutations had a profile that would be expected if tobacco was the carcinogen. The sequencing of the genome from a cell line derived from a 43 year old male with melanoma also yielded similar findings [Pleasance et al. (2009) Nature doi10.1038/nature08658]. 33, 345 somatic base substitutions, 66 indels and 37 rearrangements were identified. They dominant mutational signature reflected damage caused by ultraviolet light exposure. The researchers were also able to identify areas where DNA repair processes had been attempted.

Comment: Human cancer cells typically exhibit numerous genetic aberrations, ranging from point mutations through to complete chromosome duplications. The systematic identification of these mutations can give insights into the mutational processes that lead to cancer. This endeavour has been helped by developments in sequencing technologies. Although work still needs to be done to identify the causative mutations from all those identified, cataloguing cancer genomes in such a way may ultimately lead to better prevention and treatment.

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