Common beliefs and bias in retinoblastoma

The ''two hit'' hypothesis, formulated by Knudson in 1971, has represented the first attempt of unitary explanation of the differences usually found in the clinical expression of the disease. The theory, by highlighting the role and distribution in time of two mutational events, has not only given a substantial contribution to the comprehension of the clinical differences between unilateral and bilateral, familial and sporadic disease, but it has also allowed the discovery of an entirely new category of genes (tumour suppressor genes) normally involved in the control of cell proliferation. However, after 16 years from its formulation, a more accurate analysis of epidemiological, biological and molecular data concerning retinoblastoma reveals a number of discrepancies between the theory, its clinical consequences, and the different aspects of the disease. Common beliefs, biases and misinterpretations have largely contributed to this substantially incorrect approach to the unitary explanation of the disease. The aim of the present paper is to contribute to a new and methodologically correct approach to the interpretation of clinical, biological and molecular aspects of tile disease, by demonstrating inconsistencies, drawbacks and pitfalls contained in the ''two hit'' hypothesis formulation.