Auckland Cancer Society Research Centre seminar: ‘Clues to cancer aetiology and carcinogenic mechanisms derived from DNA adducts and other biomarkers’ Event as iCalendar

05 April 2013

1 - 2pm

Venue: Robb Lecture Theatre, Room 501-B09, Basement Level, Building 501, 85 Park Road, Grafton

DNA adducts in human tissues indicate carcinogen exposure and, in prospective studies, may be indicative of carcinogenic risk and other adverse health outcomes. For example, occupational and environmental exposure to polycyclic aromatic hydrocarbons has been demonstrated by the detection of higher levels of adducts in human tissues. Adducts detected in many tissues of smokers are at higher levels than in non-smokers.

Recently we found that smoking-related DNA adducts were higher in the lungs of lung cancer patients with the TERT-CLPTM1L lung cancer susceptibility variant on chromosome 5p15. In a cohort of children, after adjusting for possible confounders, higher cord adducts were associated with the symptom score of attentional problems between 3.75-6 and anxiety/depression between 6-8 years. Aristolochic acid-DNA adducts in urothelial tissues of Balkan endemic nephropathy patients implicate the compound in the aetiology of this nephropathy and its associated malignancies.

The influence of genetic polymorphisms on DNA adduct levels may also shed light on factors affecting cancer susceptibility. In experimental studies, DNA adduct formation provides clues to mechanisms of activation and malignant transformation. For example benzo[a]pyrene (BaP) affects the cell cycle in vitro and its own activation is cell cycle dependent. Gene expression changes in vitro can be categorised as either resulting from induction of the Ah receptor, or from causation of DNA damage.

In cells that are p53 competent BaP causes accumulation of p53, evident at the protein level but not at the mRNA level. DNA adduct formation by BaP, but not by its ultimately reactive form, BPDE, appears to be p53 dependent, suggesting that loss of p53 affects metabolic activation.

Professor Phillips has been at King’s College London since 2011, with the title of Professor of Environmental Carcinogenesis. Prior to that he was at the Institute of Cancer Research (University of London) for many years. His research interests are in chemically-induced DNA damage – its formation, detection and biological consequences – with particular emphasis on environmental carcinogens and their pathways of metabolic activation. Recently he has become interested in the “exposome” concept, a top-down approach with potential for elucidating environmental causes of disease, and in the development of DNA and protein adduct methods (adductomics) for contributing to this untargeted approach to understanding cancer aetiology. Since 2006, he has chaired the UK government advisory Committee on Carcinogenicity, and has been Editor-in-chief of the journal Mutagenesis since 2002. He was also President of the UK Environmental Mutagen Society 2010-2012.