ABSTRACT
Introduction 17 Molecular basis of cancer 17 Hereditary cancer 17 Retinoblastoma 18 Route to discovering cancer genes 18 Cancer-predisposing syndromes 19 Familial adenomatous polyposis 19 Other autosomal dominant tumour syndromes 20 Common cancer non-‘syndromic’ cancer predisposition 21
Breast/ovarian cancer 21 Panel gene testing 22 Colorectal cancer 22 Other common cancers 22 Genetic polymorphisms and cancer 23 Where are the remaining genes? 23 Conclusion 23 References 23
From epidemiological and genetic segregation work on retinoblastoma, a rare childhood malignancy of the eye, it became the model for much of our current knowledge of tumour suppressor genes. is oen newborn or infancy eye malignancy was recognized as having a familial component as early as the nineteenth century. Approximately 50% of cases are due to inheritance of a mutation/deletion in one copy of the retinoblastoma gene (RB) (Table 2.1), and >90% of individuals who carry a mutation will develop retinoblastoma, usually bilaterally and oen multifocally in the same retina. In 1971, Knudson proposed that the condition was caused by mutational events in both copies of the RB gene [1,3]. ose children that inherited a mutated copy required only one further mutational event in the other copy of RB and were far more likely to develop the malignancy, causing it to occur at a younger age and usually bilaterally. Sporadic cases required two mutations (‘hits’) in a retinal cell, as opposed to one in the familial situation (Figure 2.1), and thus bilateral tumours are incredibly unlikely to occur
and the unilateral tumours present later. is hypothesis, which has since been validated in a number of other conditions including type 2 neurobromatosis [4] and BRCA1 [5]-related breast and ovarian cancer, now bears the conceiver’s name: the Knudson ‘two-hit’ hypothesis.
