The article by Cristian Tomasetti, Lu Li, and Bert Vogelstein explores the relationship between stem cell divisions and cancer etiology, emphasizing the role of replicative mutations (R) in cancer development. The authors analyzed data from 69 countries to study the correlation between the number of normal stem cell divisions and the risk of 17 cancer types. They found a strong correlation (median = 0.80) between cancer incidence and stem cell divisions, suggesting that R mutations are responsible for a significant portion of cancer cases. This finding is consistent with epidemiological estimates of preventable cancers through environmental changes. The study also highlights the importance of early detection and intervention in reducing deaths from cancers arising from unavoidable R mutations. The authors developed a method to estimate the fractions of cancer-causing mutations due to environmental (E), hereditary (H), and replicative (R) factors, demonstrating that even in cancers with a high environmental or hereditary component, a substantial fraction of mutations are due to R. This research provides a molecular explanation for the unpreventable component of cancer risk and underscores the need for both primary and secondary prevention strategies.The article by Cristian Tomasetti, Lu Li, and Bert Vogelstein explores the relationship between stem cell divisions and cancer etiology, emphasizing the role of replicative mutations (R) in cancer development. The authors analyzed data from 69 countries to study the correlation between the number of normal stem cell divisions and the risk of 17 cancer types. They found a strong correlation (median = 0.80) between cancer incidence and stem cell divisions, suggesting that R mutations are responsible for a significant portion of cancer cases. This finding is consistent with epidemiological estimates of preventable cancers through environmental changes. The study also highlights the importance of early detection and intervention in reducing deaths from cancers arising from unavoidable R mutations. The authors developed a method to estimate the fractions of cancer-causing mutations due to environmental (E), hereditary (H), and replicative (R) factors, demonstrating that even in cancers with a high environmental or hereditary component, a substantial fraction of mutations are due to R. This research provides a molecular explanation for the unpreventable component of cancer risk and underscores the need for both primary and secondary prevention strategies.