We propose to continue our study of the environmental and inherited determinants of breast cancer in women. Telomere length, measured in peripheral blood white cells, has emerged as a biomarker of ageing, and cancer risk. Telomeres are TTAGGG repeat complexes at the end of chromosomes, that protect against degradation, fusion, and aberrant recombination of chromosomes. As telomeres shorten with each cell replication cycle, they are an indicator of the number of cell divisions a cell has undergone. Shorter telomere length has been associated with risks of head and neck, lung, renal cell and bladder cancers, however, no studies of breast cancer have been published, although telomere length has been shown to shorten in normal breast tissue in older women. Twin studies have shown that telomere length has a substantial heritable component, however, no genetic variants have been linked to telomere length. We propose to (i) Establish whether telomere length in peripheral white blood cells is a predictor of breast cancer risk in premenopausal and postmenopausal breast cancer from the Nurses'Health Studies I and II, and postmenopausal women from the Women's Health Study;(ii) use a multistage design starting with a completed whole genome SNP scan among 2400 postmenopausal women in NHS I to locate the inherited genetic variants associated with rate of telomere shortening;and (iii) examine the environmental and lifestyle predictors of telomere length. Among the novel aspects of this project is that it will be one of the first to apply dense data from a whole genome SNP scan to a continuous quantitative outcome. This project will integrate the genetic and environmental determinants of telomere length for the first time, and should give insight into the biological and modifiable causes of age-related cancers. Telomeres are repeated nucleotide sequences that protect the ends of our chromosomes from degradation. They get shortened during a cell's life and thus represent a marker of aging. We will examine whether shorter telomeres in white blood cells are a marker of a woman's risk of breast cancer, and seek the genetic and lifestyle determinants of shorter telomeres. Understanding the causes of the age-related shortening of telomeres may offer modifiable means of reducing breast cancer risk.
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