Adrenocortical Carcinoma, Hereditary
A number sign (#) is used with this entry because of evidence that one form of adrenocortical carcinoma is caused by heterozygous mutation in the TP53 gene (191170) on chromosome 17p13.
DescriptionAdrenocortical carcinoma (ADCC) is a rare but aggressive childhood tumor, representing about 0.4% of childhood tumors, with a high incidence of associated tumors. ADCC occurs with increased frequency in patients with the Beckwith-Wiedemann syndrome (130650) and is a component tumor in Li-Fraumeni syndrome (LFS; 151623).
InheritanceAutosomal dominant inheritance of ADCC has been reported (e.g., by Longui et al., 2004).
Autosomal recessive inheritance is supported by the occurrence of ADCC in sibs and in children of consanguineous parents. Fraumeni and Miller (1967) mentioned affected sibs. Mahloudji et al. (1971) observed affected brother and sister who were products of a consanguineous union. Nichols (1968) also described affected brother and sister.
MappingOne form of ADCC is caused by mutation in the TP53 gene, which maps to chromosome 17p13.
Associations Pending Confirmation
Henry et al. (1987) described 2 brothers who developed ADCC with signs of virilism. Studies with 11p markers indicated loss of heterozygosity (LOH) in the tumor cells of both brothers; furthermore, the chromosome 11 region that remained in the tumor was the same and was inherited from the same parent. Henry et al. (1987, 1989) interpreted this as indicating the existence of a recessive oncogene responsible for hereditary ADCC on 11p, probably 11p15.5.
Gicquel et al. (1997) evaluated the frequency and distribution of 11p15 LOH and IGF2 gene (147470) overexpression in a series of 82 sporadic adrenocortical tumors. They screened for pathologic functional imprinting of the 11p15 region in tumors not exhibiting LOH and evaluated the expression of the H19 gene (103280) in these tumors. Abnormalities of the 11p15 region, including LOH with the loss of the maternal allele and duplication of the paternal allele and/or IGF2 gene overexpression, are frequent features of the malignant state; these abnormalities were found in 27 of 29 (93%) of the malignant tumors but in only 3 of 35 (9%) of the benign tumors. Tumors without abnormality of the 11p15 region, mainly benign tumors, did not exhibit pathologic functional imprinting. The authors concluded that dysregulation of the 11p15 region occurs in late steps of adrenocortical tumorigenesis and suggested that LOH and IGF2 overexpression are new molecular markers for better diagnostic and prognostic evaluations of adrenocortical tumors.
Figueiredo et al. (1999) noted that in southern Brazil, the incidence of ADCC is high, ranging from 3.4 to 4.2 per million children. They used comparative genomic hybridization to screen for DNA sequence copy number changes in 9 nonfamilial ADCC (6 carcinomas and 3 adenomas) from unrelated patients from this region. Chromosomes and chromosomal regions 1q, 5p, 5q, 6p, 6q, 8p, 8q, 9q, 10p, 11q, 12q, 13q, 14q, 15q, 16, 18q, 19, and 20q demonstrated gains, whereas 2q, 3, 4, 9p, 11, 13q, 18, 20p and Xq showed losses. The most striking finding was consistent copy number gain of chromosomal region 9q34 in 8 of the 9 tumors. They concluded that both benign and malignant ADCC from southern Brazil showed multiple genetic aberrations, including a consistent gain of chromosomal region 9q34.
Molecular GeneticsVarley (2003) found that over 80% of a cohort of children with ADCC unselected for family history had a germline TP53 (191170) mutation; in addition, all 12 LFS or LFS-like families that they studied in which there was a case of ADCC had a germline TP53 mutation.
Longui et al. (2004) investigated the INHA gene (147380) in 46 Brazilian children with ADCC, 39 of whom were heterozygous carriers of the R337H TP53 mutation (191170.0035). 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.
In a male infant who developed an adrenocortical carcinoma and a choroid plexus carcinoma (see 260500) by age 1.5 years, Russell-Swetek et al. (2008) identified a heterozygous de novo mutation in the TP53 gene (E285V; 191170.0040). Immunohistochemical analysis showed strong positive staining for p53 in the nuclei of both types of cancer cell, consistent with the tumors expressing the mutant p53 protein. Functional analyses of E285V revealed significant defects in its ability to regulate promoter activity, suppress tumor cell growth, and trigger apoptosis. The mutant protein also functioned efficiently as a dominant-negative regulator that neutralized wildtype p53 activity.
Animal ModelConstitutive activation of beta-catenin (CTNNB1; 116806) is the most frequent alteration in benign and malignant adrenocortical tumors in humans. Berthon et al. (2010) showed that constitutive activation of beta-catenin in the adrenal cortex of transgenic mice resulted in progressive steroidogenic and undifferentiated spindle-shaped cell hyperplasia as well as dysplasia of the cortex and medulla. Over 17 months, transgenic adrenals developed malignant characteristics such as uncontrolled neovascularization and loco-regional metastatic invasion. These oncogenic events were accompanied by ectopic differentiation of glomerulosa at the expense of fasciculata cells, which caused primary hyperaldosteronism. Berthon et al. (2010) concluded that constitutively active beta-catenin is an adrenal oncogene, which may trigger benign aldosterone-secreting tumor development and promote malignancy.