Adrenocortical carcinoma (ACC) is part of the Li-Fraumeni tumour syndrome which is due to germline mutations in TP53. Recent studies demonstrate low penetrance mutations leading to later tumour manifestation. Furthermore, in ACC mutations outside the hotspot region have been found. TP53-polymorphisms have also been described to impact on p53 function. We, therefore investigated TP53 sequence alterations in a large cohort of adult patients with ACC.
Methods: Germline DNA of 140 ACC-patients was extracted from leucocytes. Mutation and polymorphism analysis was performed by amplification and sequencing of exons 211 of TP53. Corresponding tumour DNA of mutation carriers was also investigated and LOH analysis was performed.
In 103 evaluable cases 5 TP53 germline mutations were found in 4 patients (4%). Three mutations have not been described previously. Three mutation carriers were diagnosed at young age (<40 years), had a short survival time (<3 years) and 2 had a family history of cancer. One young female was found to have 2 mutations and a family history of ACC (mother and uncle) indicating an adrenal specific phenotype. Furthermore, the brazilian hot spot mutation R337H was found in a male patient diagnosed at high age and with a current survival time of 10 years. LOH of one TP53 allele in the tumour was detected in all cases with loss of the mutated allele in one patient. Analysis of 11 TP53-polymorphisms revealed significantly different distributions for 3 polymorphisms in ACC compared to controls. However, correlation with clinical outcome did not reveal a prognostic impact of these polymorphisms in multivariate analysis.
TP53 germline mutations can also be found in a significant but lower percentage of adult ACC patients and may appear outside the hot spot region (2 of 5 mutations in exon 10). TP53-polymorphisms seem to be of minor relevance in ACC.
30 Apr - 04 May 2011
European Society of Endocrinology