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Genomic instability and radiation risk in two molecular pathways to colon cancer
Colon cancer is caused by multiple genomic alterations which lead to genomic instability (GI). GI appears in molecular pathways of microsatellite instability (MSI) and chromosomal instability (CIN) with clinically observed case shares of about 15-20% and 80-85%. Radiation enhances the colon cancer risk by inducing GI, but little is known about different outcomes for MSI and CIN.
Computer-based modelling can facilitate the understanding of the phenomena named above. Comprehensive biological models, which combine the two main molecular pathways to colon cancer, are fitted to incidence data of Japanese a-bomb survivors. The preferred model is selected according to statistical criteria and biological plausibility. Imprints of cell-based processes in the succession from adenoma to carcinoma are identified by the model from age dependences and secular trends of the incidence data. Model parameters show remarkable compliance with mutation rates and growth rates for adenoma, which has been reported over the last fifteen years. Possibly driven by a trend of Westernization in the Japanese diet, incidence rates for the CIN pathway increased notably in subsequent birth cohorts, whereas rates pertaining to MSI remained constant. According to the model results, an imbalance between number of CIN and MSI cases began to emerge in the 1980s, whereas in previous decades the number of both types of cases was almost equal. The CIN pathway exhibits a strong radio-sensitivity, probably more intensive in men. Among young birth cohorts of both sexes the excess absolute radiation risk related to CIN is larger by an order of magnitude compared to the MSI-related risk. Observance of pathway-specific risks improves the determination of the probability of causation for radiation-induced colon cancer in individual patients, if their exposure histories are known.
Bedeutung für die Mission des Helmholtz Zentrums München:
The study aims to close the gap between molecular biology and epidemiology by identifying imprints of molecular pathways to colon cancer in the incidence data of a radio-epidemiological cohort. By assigning differential radiation risks to the two molecular pathways it paves the way for a more targeted use of radiation for therapeutic and diagnostic purposes.
The Helmholtz Zentrum München develops the fundamental principles for medicine of the future and a personalized medicine, focused on the causes of the chronic complex diseases diabetes and lung diseases. We are also making important contributions to the mechanisms of neuropsychiatric diseases, cancer, cardiovascular diseases, allergies and infectious diseases. Additionally, we investigate ecological systems with essential significance for human health.
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