Signatures of Mutational Processes in Human Cancer
The Center for Theoretical Biological Physics PRESENTS Seminar Speaker Ludmil B. Alexandrov Oppenheimer Fellow Center for Nonlinear Studies Los Alamos National Laboratory Abstract: All cancers are caused by somatic mutations. These mutations may be the consequence of the intrinsic slight infidelity of the DNA replication machinery, exogenous or endogenous mutagen exposures, enzymatic modification of DNA, or defective DNA repair. In some cancer types, a substantial proportion of somatic mutations are known to be generated by exogenous carcinogens, for example, tobacco smoking in lung cancers and ultraviolet light in skin cancers, or by abnormalities of DNA maintenance, for example, defective DNA mismatch repair in some colorectal cancers. Each biological process causing mutations leaves a characteristic imprint on the genome of a cancer cell, termed, mutational signature. In this talk, I will present mutational signatures analyses encompassing 12, 023 cancer genomes across 40 distinct types of human cancer revealing more than 30 different signatures of mutational processes. Some signatures are present in many cancer types, notably a signature attributed to the APOBEC family of cytidine deaminases, whereas others are confined to a single cancer class. Certain signatures are associated with age of the patient at cancer diagnosis, known mutagenic exposures or defects in DNA maintenance, but many are of cryptic origin. The results reveal the diversity of mutational processes underlying the development of cancer, with potential implications for understanding of cancer etiology, prevention and therapy. Bio: Ludmil Alexandrov is an Oppenheimer Fellow in the Theoretical Biology and Biophysics Group and the Center for Nonlinear Studies at Los Alamos National Laboratory. He earned his Bachelor of Science degree in Computer Science from Neumont University and received his Master’s of Philosophy in Computational Biology as well as his Ph.D. in Cancer Genetics from the University of Cambridge. Ludmil’s research has been focused on understanding mutational processes in human cancer through the use of mutational signatures. In 2013, he developed the first comprehensive map of the signatures of the mutational process that cause somatic mutations in human cancer. This work was published in several well-regarded scientific journals and highlighted by the American Society of Clinical Oncology as a milestone in the fight against cancer. More recently, Ludmil mapped the signatures of clock-like mutational processes operative in normal somatic cells, demonstrated that mutational signatures have the potential to be used for targeted cancer therapy, and identified the mutational signatures associated with tobacco smoking.
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