Principal Investigator: Dr Alkes Price
Department: Department of Epidemiology
Harvard School of Public Health, Department of Epidemiology, 655 Huntington Avenue, Building 2 Room 211, Boston MA 02115, United StatesTags: 19808, CLL, clonal expansion, featured, leukaemia, leukemia, mosaicism
1a: Genetic variation naturally occurs among the cells of a single individual as a result of somatic mutation. Some somatic mutations proliferate to high frequency within an individual, producing a phenomenon known as clonal mosaicism. Cancer is an extreme example, but mosaicism also exists in cancer-free individuals. We aim to study the distribution of chromosome-scale mosaic aberrations in UK Biobank samples. We then aim to investigate the relationship between these aberrations and diseases of the blood, with a focus on chronic lymphocytic leukaemia (CLL).
1b: This work will improve our understanding of clonal expansions in the blood, a phenomenon present in many aging individuals that is closely related to leukaemia. By investigating mosaicism in a very large prospective cohort, this research may potentially identify signatures of pre-cancerous mosaic events and/or enable earlier diagnoses of leukaemia.
1c: We will analyze allelic intensity data from genotyped blood samples to identify imbalances in the frequencies of maternally and paternally derived chromosomal segments. Such imbalances indicate large-scale chromosomal aberrations (i.e., losses and gains of long segments of DNA) that have proliferated to significant frequency in the blood. We will then compare incidences of these events to data on blood counts and cancer outcomes.
1d: We will analyze the full cohort.
Project Extension approved by UK Biobank 27th January 2017:
“In the process of reviewing the literature on mosaicism as a precursor to cancer, we realized that mosaicism has also been observed to predispose to other adverse health outcomes. In particular, Jaiswal et al. 2014 NEJM observed that mosaic status increases risk of cardiovascular disease. Given that the UK Biobank resource contains data on cardiovascular outcomes, we would like to expand the scope of our study to also investigate the link between mosaicism and cardiovascular disease.
Similarly, Jaiswal et al. 2014 NEJM and Genovese et al. 2014 NEJM observed that mosaic status increases all-cause mortality. We would like to follow up on this finding as well, and we are particularly curious to see whether mosaic status adds information independent of the two-year mortality predictor returned in category 10003.”