The incidence of pediatric adrenocortical carcinoma (202300) in southern Brazil is 10 to 15 times higher than that of pediatric ADCC worldwide. Because childhood ADCC is associated with Li-Fraumeni syndrome (151623), Ribeiro et al. (2001) examined the cancer history and p53 status of 36 Brazilian patients and their families. Remarkably, 35 of 36 patients had an identical germline point mutation in exon 10 of the p53 gene, a G-to-A transition at nucleotide 1010 encoding an arg337-to-his (R337H) amino acid substitution. Differences within intragenic polymorphic markers demonstrated that at least some mutant alleles arose independently, thus eliminating the possibility of a founder effect. In tumor cells, the wildtype allele was deleted, and mutant p53 protein accumulated within the nuclei. Although these features are consistent with Li-Fraumeni syndrome-associated adrenal tumors, there was no history of increased cancer incidence among family members. Therefore, this inherited R337H p53 mutation represents a low-penetrance p53 allele that contributes in a tissue-specific manner to the development of pediatric ADCC.
DiGiammarino et al. (2002) demonstrated that the mutant tetramerization domain of p53 harboring the R337H mutation adopts a native-like fold but is less stable than the wildtype domain. Furthermore, the stability of the p53 R337H-bearing tetramer is highly sensitive to pH in the physiologic range; this sensitivity correlates with the protonation state of the mutated his337. DiGiammarino et al. (2002) concluded that their results demonstrated a pH-sensitive molecular defect of p53, suggesting that the pH-dependent p53 dysfunction is the molecular basis for these cases of ADCC in Brazilian children.
Latronico et al. (2001) studied this mutation in a larger series of 55 patients (37 adults and 18 children) with benign and malignant sporadic adrenocortical tumors. None of the patients had family cancer histories that conformed to the criteria for Li-Fraumeni syndrome. Among the 19 patients with the R337H mutation, only 1 boy and 3 adults showed fatal evolution or recurrent metastases. This mutation was also identified in heterozygous state in asymptomatic first-degree relatives of the patients, indicating that R337H mutation was inherited in most cases. The authors concluded that the germline R337H mutation of p53 protein is present at a high frequency (approximately 78%) in children with benign or malignant sporadic adrenocortical tumors, but it is not restricted to the pediatric group, since about 14% of adults with adrenocortical tumors also had this mutation. The presence of this mutation was related to unfavorable prognosis in most of the adults but not in the children with adrenocortical tumors.
Longui et al. (2004) investigated the inhibin-alpha (INHA; 147380) gene in 46 Brazilian children with ADCC, 39 of whom were heterozygous carriers of R337H. Six patients were heterozygous for 3 INHA mutations, and Longui et al. (2004) concluded that INHA may be one of the contributing factors needed for adrenocortical tumor formation in pediatric patients with the R337H TP53 mutation.
Figueiredo et al. (2006) identified the R337H mutation in 40 children from southern Brazil with ADCC. The mutation was also identified in 34.5% of relatives tested in parental carrier lines. The penetrance of ADCC among carriers of R337H was estimated at 9.9%.
Pinto et al. (2005) studied deletion mapping of chromosome 17 in 30 adrenocortical tumors from 29 Brazilian patients (15 children and 14 adults). Sixteen patients had the germline R337H mutation. Loss of heterozygosity (LOH) analysis using 6 polymorphic microsatellite markers disclosed loss of the entire chromosome 17 in 18 tumors (10 adenomas and 8 carcinomas) from 17 patients. The R337H mutation was present in 13 of them. The authors demonstrated a high frequency of biallelic inactivation of p53 derived from 2 distinct events occurs, the germline R337H mutation and the acquired loss of the entire chromosome 17. The isolated loss of the entire chromosome 17 did not correlate with aggressive tumor behavior in these patients with adrenocortical tumors.
