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‣ Patients with a high polygenic risk of breast cancer do not have an increased risk of radiotherapy toxicity; Overdiagnosis by polygenic risk

Dorling, Leila; Barnett, Gillian C.; Michailidou, Kyriaki; Coles, Charlotte E.; Burnet, Neil G.; Yarnold, John R.; Elliott, Rebecca M.; Dunning, Alison M.; Pharoah, Paul D. P.; West, Catharine M. L.
Fonte: American association for Cancer Research Publicador: American association for Cancer Research
Tipo: Article; accepted version
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This is the author accepted manuscript. The final version is available from American association for Cancer Research via http://dx.doi.org/10.1158/1078-0432.CCR-15-1080; PURPOSE: This study aims to quantify the probability of overdiagnosis of prostate cancer by polygenic risk. METHODS: We calculated the polygenic risk score based on 66 known prostate cancer susceptibility variants for 17,012 men aged 50-69 years (9,404 men identified with prostate cancer and 7,608 with no cancer) derived from three UK-based ongoing studies. We derived the probabilities of overdiagnosis by quartiles of polygenic risk considering that the observed prevalence of screen-detected prostate cancer is a combination of underlying incidence, mean sojourn time (MST), test sensitivity, and overdiagnosis. RESULTS: Polygenic risk quartiles one to four had 9%, 18%, 25% and 48% of the cases respectively. For a PSA test sensitivity of 80% and MST of nine years, 43%, 30%, 25% and 19% of the prevalent screen-detected cancers in quartiles one to four, respectively, were likely to be overdiagnosed cancers. Overdiagnosis decreased with increasing polygenic risk, with 56% drop between the lowest and the highest polygenic risk quartiles. CONCLUSION: Targeting screening to men at higher polygenic risk could reduce the problem of overdiagnosis and lead to a better benefit to harm balance in screening for prostate cancer.; NP is Cancer Research UK Clinician Scientist Fellow. The COGS project was funded through a European Commission's Seventh Framework Programme grant (agreement number 223175 - HEALTH-F2-2009-223175)...

‣ Multistage carcinogenesis and lung cancer mortality in three cohorts

Hazelton, William D; Clements, Mark; Moolgavkar, Suresh
Fonte: American Association for Cancer Research Publicador: American Association for Cancer Research
Tipo: Artigo de Revista Científica
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Experimental evidence indicates that tobacco smoke acts both as an initiator and a promoter in lung carcinogenesis. We used the two-stage clonal expansion model incorporating the ideas of initiation, promotion, and malignant conversion to analyze lung cancer mortality in three large cohorts, the British Doctors' cohort and the two American Cancer Society cohorts, to determine how smoking habits influence age-specific lung cancer rates via these mechanisms. Likelihood ratio tests indicate that smoking-related promotion is the dominant model mechanism associated with lung cancer mortality in all cohorts. Smoking-related initiation is less important than promotion but interacts synergistically with it. Although no information on ex-smokers is available in these data, the model with estimated variables can be used to project risks among ex-smokers. These projected risks are in good agreement with the risk among ex-smokers derived from other studies. We present 10-year projected risks for current and former smokers adjusted for competing causes of mortality. The importance of smoking duration on lung cancer risk in these cohorts is a direct consequence of promotion. Intervention and treatment strategies should focus on promotion as the primary etiologic mechanism in lung carcinogenesis.