Studies highlight tell-tale signatures of genetic damage due to cigarette smoke and UV light.

Scientists led by a team at the Wellcome Trust’s Sanger Institute report on the first detailed genome-wide sequencing projects to comprehensively catalog the thousands of mutations associated with lung cancer and melanoma. The results, reported in two papers in Nature, identified over 55,000 mutations in the two cancers, and provide stark confirmation of the damaging effects of cigarette smoking and ultraviolet light. They also uncovered previously unidentified cellular mechanisms that fight to prevent cancer from forming.

The lung cancer study, titled “A small-cell lung cancer genome with complex signatures of tobacco exposure,” used massively parallel sequencing technology to sequence a patient-derived small-cell lung cancer (SCLC) cell line, NCI-H209. The results confirmed that the majority of the 23,000 mutations were caused by the plethora of chemicals found in cigarettes.

One gene in particular, CHD7, was found to be mutated in several SCLC samples, implicating this gene as a driver in the formation of lung cancer. The study also highlighted signatures of a previously unknown system of DNA repair.

“On the basis of average estimates, we can say that one mutation is fixed in the genome for every 15 cigarettes smoked,” notes senior author, Peter Campbell, Ph.D., at the Sanger’s Cancer Genome Project.

The melanoma study involved sequencing the genomes of a malignant melanoma and a lymphoblastoid cell line from the same person. The data, reported in a paper titled “A comprehensive catalogue of somatic mutations from a human cancer genome,” showed over 33,000 mutations, and confirmed that the dominant mutational signature did indeed reflect DNA damage due to ultraviolet light exposure. The sequence also showed where genome repair had been attempted, primarily in the coding gene regions.

The results uncover an “archaeology of exposure” according to the Cancer Genome Project’s Michael Stratton, Ph.D. “Written within this code is the history of this cancer—its mutations from UV light and the mutations it acquired when it spread within the patient.”

“Indeed, because of the clarity of the genome data, we can distinguish some of the early, UV-induced mutations from the alter mutations that do not have this signature, presumably occurring after the cancer cells spread from the skin to deeper tissues,” Dr. Campbell adds.

The authors suggest that in future, generating perhaps thousands of comprehensive catalogs of somatic mutations will provide powerful insights into the processes of DNA damage, mutation, repair, and selection that underlie the evolution of all human cancers.

“Nearly ten years on, we are still reaping the benefit from the first human genome sequence and we have much still to do to get to grips with these new disrupted landscapes of cancer genomes,” Dr. Campbell stresses. “But the knowledge we extract over the next few years will have major implications for treatment. By identifying all the cancer genes we will be able to develop new drugs that target the specific mutated genes and work out which patients will benefit from these novel treatments.”

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