title: The cell-type-specificity of inherited predispositions to tumours: review and hypothesis.
abstract: Most hereditary predispositions to tumours affect only one particular cell type of the body but the genes bearing the relevant germ-line mutation are not cell-type-specific. Some predisposition syndromes include increased risks of lesions (developmental or tumourous) of unrelated cell types, in any individual predisposed to the main lesion (e.g. osteosarcoma in patients predisposed to retinoblastoma). Other predispositions to additional lesions occur only in members of some families with the predisposition to the basic lesion (e.g. Gardner's syndrome in some families suffering familial adenomatous polyposis). In yet other predisposition syndromes, different mutations of the same gene are associated with markedly differing family-specific clinical syndromes. In particular, identical germline mutations (e.g. in APC, RET and PTEN genes), have been found associated with differing clinical syndromes in different families. This paper reviews previously suggested mechanisms of the cell-type specificity of inherited predispositions to tumour. Models of tumour formation in predisposition syndromes are discussed, especially those involving a germline mutation (the first 'hit') of a tumour suppressor gene (TSG) and a second (somatic) hit on the second allele of the same TSG. A modified model is suggested, such that the second hit is a co-mutation of the second allele of the TSG and a regulator which is specific for growth and/or differentiation of the cell type which is susceptible to the tumour predisposition. In some cases of tumour, the second hit may be large enough to be associated with a cytogenetically-demonstrable abnormality of the part of the chromosome carrying the TSG, but in other cases, the co-mutation may be of 'sub-cytogenetic' size (i.e. 10(2)-10(5) bases). For the latter, mutational mechanisms of frameshift and impaired fidelity of replication of DNA by DNA polyerases may sometimes be involved. Candidate cell-type-specific regulators may include microRNAs and perhaps transcription factors. It is suggested that searching the introns within 10(5)-10(6) bases either side of known of exonic mutations of TSGs associated with inherited tumour predisposition might reveal microRNA cell-type-specific regulators. Additional investigations may involve fluorescent in situ hybridisations on interphase tumour nuclei.
authors.affiliation: Division of Tissue Pathology, Institute of Medical and Veterinary Science, PO Box 14, Rundle Mall, Adelaide, SA 5001, Australia. leon.bignold@adelaide.edu.au
authors.forename: Leon P
authors.initials: LP
authors.lastname: Bignold
mesh_terms: D000818:Animals; D040461:Gene Components; D023061:Gene Order; D016147:Genes, Tumor Suppressor; D008040:Genetic Linkage; D020022:Genetic Predisposition to Disease / Q000209:etiology*; D023281:Genomics; D018095:Germ-Line Mutation; D006801:Humans; D008957:Models, Genetic; D009369:Neoplasms / Q000151:congenital / Q000235:genetics*