Wednesday 16 October 2013 at 12:00pm

Title: Dissecting sources of genome instability in cancer

Speaker: Stephen A. Roberts, Ph.D.
IRTA Postdoctoral Fellow, National Institute of Environmental Health Sciences

Abstract: Frequency, location and timing are key parameters determining biological outcomes of mutations. Recent sequencing of human tumors has enabled us to address how these parameters contribute to a cancer mutator phenotype. While inactivation of DNA repair can lead to persistent, high mutation rates, few such examples are reported in cancers. Transient acquisition of multiple mutations in one or a few cell generations is an alternative and could produce synergistic or compensatory changes leading to rapid establishment of a growth advantage. Using a combination of experimental model studies and bioinformatics analysis of clinical mutation databases, I have shown that chronic DNA damage can generate clusters of simultaneous multiple mutations via transient mutagenesis. Genome sequencing of methyl methanesulfonate-treated yeast revealed mutation clusters composed of “strand-coordinated” changes originating from lesions occurring exclusively on one DNA strand, indicating the mutations were likely induced in the same generation. Mutation patterns and genetic controls suggested these mutations resulted from alkylations in long single-strand (ss)DNA formed during double-strand break repair and replication. Analogous simultaneous clustered mutations also occur in human cancers. Using a bioinformatics approach, I identified clusters among mutations that occurred in 41 human cancer genomes. Similar to MMS-induced clusters in yeast, clustered mutations in these cancers were highly strand-coordinated. One unusual class was composed entirely of mutated cytosines and resided near chromosome rearrangement breakpoints. Surprisingly, nearly all of these mutations occurred in a trinucleotide motif, TpCpW (W=A or T), targeted by APOBEC family cytosine-deaminases. Thus these highly regulated enzymes, normally involved in RNA editing and retrotransposon or retrovirus restriction, may inadvertently induce mutations in human malignant tumors. Using the motif specificity defined in APOBEC-induced clusters to characterize 954,247 mutations found in 2,680 exomes of 14 different cancer types, primarily from The Cancer Genome Atlas, I further found that APOBEC signature mutagenesis is pervasive throughout many cancer genomes, reaching 68% of all mutations in some samples. Across cancer types, APOBEC signature mutations readily occurred within genes whose alteration can drive cancer, establishing this form of mutagenesis as one of the most predominate carcinogenic mutagens. I propose that frequent APOBEC-induced mutation is carcinogenic and intend to use a variety of biochemical, genetic, and bioinformatics approaches to further investigate these enzymes, their environmental regulation, and the consequences of their activity on genome instability and cancer progression.

Host: Russell T. Hill, Ph.D.