Are There Low-Penetrance TP53 Alleles? Evidence from Childhood Adrenocortical Tumors

Abstract

We have analyzed a panel of 14 cases of childhood adrenocortical tumors unselected for family history and have identified germline TP53 mutations in >80%, making this the highest known incidence of a germline mutation in a tumor-suppressor gene in any cancer. The spectrum of germline TP53 mutations detected is remarkably limited. Analysis of tumor tissue for loss of constitutional heterozygosity, with respect to the germline mutant allele and the occurrence of other somatic TP53 mutations, indicates complex sequences of genetic events in a number of tumors. None of the families had cancer histories that conformed to the criteria for Li-Fraumeni syndrome, but, in some families, we were able to demonstrate that the mutation had been inherited. In these families there were gene carriers unaffected in their 40s and 50s, and there were others with relatively late-onset cancers. These data provide evidence that certain TP53 alleles confer relatively low penetrance for predisposition to the development of cancer, and they imply that deleterious TP53 mutations may be more frequent in the population than has been estimated previously. Our findings have considerable implications for the clinical management of children with andrenocortical tumors and their parents, in terms of both genetic testing and the early detection and treatment of tumors.

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“…Nonetheless, unaffected carriers were observed and therefore the existence of families with low penetrance cannot ruled out. Varley et al (1999) also observed several unaffected carriers among the relatives of children with adrenocortical tumours not selected on family history. It is noteworthy that the detection of either unaffected carrier parents or de novo mutations in probands is favoured considering the poor prognosis of this disease.…”

“…Germline p53 mutations have also been detected in families presenting tumours outside the spectrum typifying LFS (Malkin et al, 1992;Toguchida et al, 1992). Studies on individuals with typical LFS tumours but not previously selected on family history, have yielded frequencies of germline p53 mutation that vary with age and tumour types (Varley et al, 1999). None of these studies permitted an estimation of cancer risk in mutation carriers, although some unaffected carrier relatives may be found in family studies.…”

A limited role for TP53 mutation in the transformation of follicular lymphoma to diffuse large B-cell lymphoma

“…41 The R213X mutation observed in patient 21 has previously been documented as a low penetrance germline mutation in a child with an adrenocortical tumour, but without a Li-Fraumeni phenotype or significant family history of cancer. 42 In such patients, there is an obligate requirement for additional 'hits' in order for transformation to proceed. In other patients, mutations were identified only at the time of histological transformation supporting a more critical mechanistic role.…”

Immunohistochemical analysis of expression and allelotype of mismatch repair genes (hMLH1 and hMSH2) in bladder cancer

“…PCR amplification was carried out in a 10 µl reaction mix using standard microsatellite analysis PCR method (Varley et al, 1999). Annealing temperature for D3S1611 marker was adjusted at 62˚C rather than 56˚C to eliminate non-specific bands.…”