Seminar by Prof. David Wheeler - “Somatic Mutation: Cancer's Engine and Its Achilles' heel.”

Physics and Biology Unit would like to invite you to the seminar by Profoesor David A. Wheeler.

“Somatic Mutation: Cancer's Engine and Its Achilles' heel.”

Different cancer types exhibit different mutation frequencies with variance in frequency across patients spanning 3 logs.  Typical adult solid tumors have 1-10 mutations per Mb of DNA. Cancers with median frequency of >10 mutations per Mb have disruption of mismatch repair machinery, or some other special mutagenic processes involved such as UV irradiation, or chemical mutagenesis, e.g., cigarette smoke.  These mutatgenic processes lead to recognizable "signatures" in the mutation spectra, which are now well characterized. Tumors with median frequency of >100 mutations per Mb harbor disruption in the replicative machinery in the cell.  Mutation of the replicative machinery, though rare, has led to novel insights into mechanisms of eukaryotic DNA replication. The figure below depicts a putative origin of replication in a human tumor DNA marked by the mutation pattern of POLE exonuclease mutant. POLE mutants preferentially mutate C to A in the base context of 5’ and 3’ flanking T. Mutations of coding sequence increase the anti-tumor immune response, through an increase in the number of epitopes, and leads to better patient prognosis.

Top number line gives the coordinate position on chromosome 17.  Each row of hash marks below the number line corresponds to mutation data from a separate tumor.  Only POLE-specific mutations are shown.  TCT > TAT mutations are in red, AGA> ATA are in blue. Genes in the region are shown in the middle of the figure. At the bottom a cartoon figure interprets the red and blue clusters of mutations based on current theories of eukaryotic DNA replication from origins of replication. Note concordance of red and blue across multiple tumors.

Host: Jonathan Miller, Physics and Biology Unit, OIST