Abstract LB-192: A single catastrophic genomic event is required for the development of osteosarcoma

Abstract

Abstract Over sixty years ago, the groundbreaking works by Nordling1, Armitage and Doll2 found a deep connection between the age dependent incidence rates of cancer with elementary mutational processes in cancer. However, their method to estimate the number of driver mutations from the characteristic increase of adult cancer risk with patient age implicitly assumes tissue homeostasis. It can therefore not be used for developmental cancers emerging from growing tissues. Osteosarcoma (OS), a bone cancer most frequently occurring during adolescence, is one prominent example. Here we combine a model of bone growth and maintenance with somatic mutation theory. Based on age dependent stature3` and morphometric data, we find that our model accurately reproduces epidemiological OS incidence rates4`. We conclude that the OS risk can be explained by the cell cycle rate in the osteoblast lineage. Other risk factors, such as endocrine and paracrine signaling have only a weak, if any, impact. The strict association with the cell cycle rate, as opposed to wall clock time, suggests that environmental factors play no dominant role either. In other words, with few exceptions such as genetic syndromes or unusually strong environmental factors such as radiation in cancer treatment, the OS risk is dominated by pure chance. We find that the OS incidence rate is strictly proportional to the age dependent cell cycle rate. This result implies that there is only a single rate limiting factor in the etiology of the disease. This result is a remarkable as it suggests that the disease is not necessarily initiated within a stem cell because the Hayflick limit set by telomere shortening can not suppress single-hit-malignancies. Our results are not only important for a better understanding of the disease and the design of future sequencing efforts. But they also inform development of treatment strategies to reduce the mortality caused by this still deadly disease. 1. Nordling, C. O. C. A New Theory on the Cancer-inducing Mechanism. Br. J. Cancer 7, 68¨C72 (1953). 2. Armitage, P. & Doll, R. The age distribution of cancer and a multi-stage theory of carcinogenesis. Br. J. Cancer VIII, 1¨C12 (1954). 3. CDC Height Data. at 4. Cancer incidence in five continents, vol. I to VIII. CancerBase No. 7. (Lyon: IARC). at Citation Format: Sven Bilke, Paul Meltzer. A single catastrophic genomic event is required for the development of osteosarcoma. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr LB-192. doi:10.1158/1538-7445.AM2015-LB-192