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Knudson hypothesisThe Knudson hypothesis is the hypothesisthat canceris the result of accumulated mutationsto a cell's DNA. It was first formulated by Alfred G. Knudsonin 1971, and led indirectly to the identification of cancer-related genes. Knudson won the 1998 Albert Lasker Medical Research Awardfor this work. Knudson performed a statistical analysis on cases of retinoblastoma, a tumour of the retinawhich occurred both on childrenas a hereditary diseaseand in adults in a sporadic fashion. In addition, the children often developed the tumour in both eyes, suggesting an underlying predisposition. The findings were that multiple "hits" to DNA were necessary to cause cancer. In the children with retinoblastoma, the first insult was congenital, and any second insult would rapidly lead to cancer. In adult cases, two "hits" had to take place before a tumour could develop, explaining the age difference. It was later found that carcinogenesis(the development of malignancy) depended both on the activation of oncogenes(genes that stimulate cell proliferation) and tumor suppressor genes(genes that keep proliferation in check). A first "hit" in an oncogene would not necessarily lead to cancer, as normally functioning tumor suppressor genes would still counterbalance this impetus; only damage to TSGs would lead to unchecked proliferation. Conversely, a damaged TSG (such as the Rb1 gene in retinoblastoma) would not lead to cancer unless there is a growth impetus from an activated oncogene. Field cancerisationmay be an extended form of the Knudson hypothesis. This is the phenomenon of various primary tumours developing in one particular area of the body, suggesting that an earlier "hit" predisposed the whole area for malignancy. Reference
Categories: Oncology
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