In a special NIEHS seminar Oct. 28, Gad Getz, Ph.D., from the Broad Institute of the Massachusetts Institute of Technology and Harvard University, described how understanding the changes associated with a particular kind of cancer may improve the ways researchers prevent, detect, and treat that cancer.
His Oct. 28 talk, “Mutational Processes in Cancer” was hosted by Dmitry Gordenin, Ph.D., head of the NIEHS Mechanisms of Genome Dynamics Group. Getz directs the Cancer Genome Computational Analysis group at the Broad Institute and is director of Bioinformatics at the Massachusetts General Hospital Cancer Center, as well as the Department of Pathology.
Different cancers have distinct signatures
Cancer is caused by an accumulation of DNA mutations that are generated by multiple processes, Getz explained. Each process has a characteristic combination of mutations, which form a signature. The collection of signatures shown by a particular tumor sheds light on the mixture of processes that occur in it.
Getz said mutational processes may be natural, like aging, or associated with environmental exposures, such as tobacco use. Advances in DNA sequencing technology and computational analysis are helping researchers identify these mutation signatures and learn more about cancer.
Based on analyses of data sets such as The Cancer Genome Atlas (TCGA), which is a collaboration with the National Institutes of Health, researchers are building the Catalogue Of Somatic Mutations In Cancer (COSMIC) database, which so far includes 30 cancer signatures.
Trademark mutations of bladder cancer
According to Getz, one mutational pattern from the COSMIC database, Signature 4, is strongly associated with smoking and occurs predominantly in lung cancers. In contrast, Signature 5 is found in many kinds of cancer, although its source is unclear. Interestingly, bladder cancer, which has been linked with smoking, does not exhibit Signature 4, but does exhibit Signature 5.
To better understand these connections, Getz and colleagues analyzed mutational patterns in bladder tumors. They showed that a DNA repair pathway called nucleotide excision repair is frequently mutated in these tumors, particularly at a gene called ERCC2.
Tumors from patients with a mutation in ERCC2 exhibited a higher level of Signature 5. “That was a big finding, because it suggests that the cause of the Signature 5 mutations might be related to DNA repair,” Getz said in a Broad Institute news story.
The team also reported that tumors from smokers had more Signature 5 mutations, suggesting that tobacco use may play a role in the development of bladder cancer. “This is the first evidence of a molecular process involved in the association between smoking and bladder cancer,” Getz said.
Asymmetry in DNA strand mutations
Getz also discussed another way to look at mutations in cancer — analyzing DNA strand asymmetries, or differences between the two strands of DNA in terms of where mutations originate.
By studying these asymmetries, Getz and his collaborators reported that although mutations associated with smoking and ultraviolet light exposure share one kind of asymmetry, liver cancer exhibits a different asymmetry. This novel finding sheds further light on how DNA transcription and replication processes contribute to mutations involved in cancer.
Getz emphasized that there is still much to learn, especially with regard to epigenetics, or changes that affect DNA expression without altering the DNA bases. This led NIEHS Deputy Director Rick Woychik, Ph.D., to ask about approaches that account for epigenetic changes in genomic studies.
Getz said his team is developing a method to identify patterns in certain epigenetic changes. “The holy grail is to put all these types of data together,” Getz said, referring to all the DNA changes that, when passed down from one cell to its daughter cells, enable a cancer to persist.
Kim J, Mouw KW, Polak P, Braunstein LZ, Kamburov A, Tiao G, Kwiatkowski DJ, Rosenberg JE, Van Allen EM, D'Andrea AD, Getz G. 2016. Somatic ERCC2 mutations are associated with a distinct genomic signature in urothelial tumors. Nat Genet 48(6):600–606.
Haradhvala NJ, Polak P, Stojanov P, Covington KR, Shinbrot E, Hess JM, Rheinbay E, Kim J, Maruvka YE, Braunstein LZ, Kamburov A, Hanawalt PC, Wheeler DA, Koren A, Lawrence MS, Getz G. 2016. Mutational strand asymmetries in cancer genomes reveal mechanisms of DNA damage and repair. Cell 164(3):538–549.
(Samantha Hall is a postbaccalaureate Cancer Research Training Award fellow in the National Cancer Institute Center for Cancer Research Laboratory of Toxicology and Toxicokinetics, housed at NIEHS.)