Inactivation of both APC alleles in an early stage of colon adenomas in a patient with familial adenomatous polyposis (FAP)

Abstract

To examine whether the dosage effect of germ-line mutations in patients with familial adenomatous polyposis (FAP) is sufficient to cause colorectal adenomas, or an additional somatic mutation of the normal allele is required as well, we have investigated somatic mutations of the APC gene in multiple adenomas developed in one FAP patient. In addition to a 5-bp deletion of one allele present constitutionally in this patient, the normal APC allele had been lost in five of seven DNA samples extracted from small adenomas (< 3 mm in diameter) with mild or moderate atypia. This result indicates that the inactivation of both alleles of the APC gene is probably essential for the development of an early-stage adenoma, in agreement with the two-hit mutational model underlying the concept of tumor suppressor genes.

Li-Fraumeni syndrome – a molecular and clinical review

“…Tumour-suppressor genes such as BRCAJ , RBI (Cavenee et al, 1983), BRCA2 (Gudmundsson et al, 1995), APC (Ichii et al, 1992) and VHL (Tory et al, 1989) have been studied in many families in which there is a germline mutation to those genes, and loss of the wild-type allele has been seen at high frequency in the tumours of patients carrying the mutation. All these genes therefore fulfil the criteria expected of tumoursuppressor genes, namely obeying Knudson's 'two-hit' hypothesis (Knudson, 1971), whereby one defective allele is inherited and the second is inactivated by loss of part or all of the wild-type chromosome (Ponder, 1988).…”

Familial adenomatous polyposis is associated with a marked decrease in alkaline sphingomyelinase activity: A key factor to the unrestrained cell proliferation?

“…The APC gene has been proposed as 'the gatekeeper gene' in the colorectal mucosa, and has recently been suggested to be implicated in cell signal transduction affecting processes like cell growth inhibition (Baeg et al, 1995), apoptosis (Browne et al, 1994) and migration (Wong et al, 1996). Studies in humans with FAP, as well as in mice with analogous mutations, have suggested that the rate-limiting step in the tumour initiation is a somatic mutation of the wild-type APC allele inherited from the unaffected parent (Icii et al, 1992;Luongo et al, 1994). APC mutations have also been found in humans in the earliest neoplastic lesions, the dysplastic aberrant crypt foci (Jen et al, 1994).…”

A detailed study of loss of heterozygosity on chromosome 17 in tumours from Li – Fraumeni patients carrying a mutation to the TP53 gene

“…LOH at a particular locus/gene is considered to indicate the presence of a tumour suppressor at that locus (Ponder, 1988), with the LOH event unmasking the recessive mutation. A number of known tumour suppressor genes such as BRCA1 , RB1 (Cavenee et al, 1983), BRCA2 (Gudmundsson et al, 1995), APC (Ichii et al, 1992) and VHL (Tory et al, 1989) have been studied in families in which there is a germline mutation to those genes, and loss of the wild-type allele has been seen at high frequency in the tumours of patients carrying the mutation. All these genes therefore ful®l the criteria expected of tumour suppressor genes, namely obeying Knudson's`two hit' hypothesis (Knudson, 1971), whereby one defective allele is inherited, and the second is inactivated by loss of part or all of the wild-type chromosome (Ponder, 1988).…”