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Department of Oncology |
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| University of Cambridge > Department of Oncology > Research > Paul Pharoah |
Paul Pharoah
Genetic epidemiology projects using population based case collections at StrangewaysThe main focus of the group based at the Strangeways Research Laboratories is to identify genetic variants which contribute to the polygenic susceptibility to cancer, and to study the interaction of these variants with each other and with the environment. Where there are known rare, high penetrance susceptibility genes (e.g. BRCA1 and BRCA2 for breast and ovarian cancer), the contribution of these to disease burden will also be assessed. These studies are in collaboration with Doug Easton (Cancer Research UK Genetic Epidemiology Group) and Alison Dunning (CRUK Human Cancer Genetics Group).The success of such studies is critically dependent on large case-control sample collections and with Doug Easton I have been co-ordinating the population based cancer case collections which have now been in progress for 7 years. Our initial focus was on breast cancer with over 4,000 cases recruited so far. We have subsequently started to recruit patients with ovarian, endometrial and colorectal cancer, and we plan to extend the studies to other cancer types over the next 5 years. High penetrance gene analysis An study of the contribution of BRCA1 and BRCA2 to the burden of breast cancer in the population was completed in 2000. The analysis of our ovarian cancer case series for mutations in BRCA1 and BRCA2 has now been started. This will be one of the largest such studies carried out in the world to date. Development of genetic risk models for breast cancer Data from the ABC Study were used to investigate the genetic models that best account for the familial aggregation of breast cancer not due to the high-penetrance BRCA genes (A. Antoniou and D. Easton, CR UK Genetic Epidemiology Group). The model best describing these data was a polygenic model, in which susceptibility to breast cancer is conferred by a large number of alleles. I have used the results of this analysis to examine the potential for prediction of risk based on common genetic variation. The data are compatible with a log-normal distribution of genetic risk in the population, which is sufficiently wide to provide useful discrimination of high- and low-risk groups. These data were published last year. Common gentic variation and clinical outcome in breast cancer:- The genotype data which have been generated in our search for susceptibility genesalso provide the opportunity to study the effects of germline genetic variation on survival. Linkage of our breast cancer cases to the East Anglian Cancer Registry database has enabled us to collect clinical information such as tumour characteristics, treatment and outcome. An analysis of the data for the first 40 polymorphisms genotyped has been carried out by Dr Ellen Goode (from the University of Washington, Seattle and funded by a Wellcome Burroughs travel scholarship) and published. As more genes are analysed, and with additional follow-up, further similar analyses will be carried out. Other studies in progress Dr Douglas Easton (CRC Genetic Epidemiology Group) and I have co-ordinated the collection of data from 15 investigators from around the world who have carried out studies of BRCA1 and BRCA2 mutation carrier frequency in breast and ovarian cancer case series unselected for family history. The main aim of this study is to estimate cancer risks associated with mutations in BRCA1 and BRCA2 that are free from ascertainment bias. I have co-ordinated a collaboration between the UKCCCR National Familial Ovarian Cancer Register and the Gilda Radner Familial Ovarian Cancer Register (Prof A. Whittemore, Stanford University). Combined data from the registers have been used to estimate the effect of the oral contraceptive pill on the ovarian cancer risk conferred by the high penetrance genes BRCA1.
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breast cancer risk and 
ovarian cancer risk