Adrenocortical carcinoma causes

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Raviteja Guddeti, M.B.B.S. [2] Ahmad Al Maradni, M.D. [3] Mohammed Abdelwahed M.D[4]

Overview

There are no established causes for adrenocortical carcinoma. The relatively increased incidence in childhood is mainly explained by germline TP53 mutations, which are the underlying genetic cause of ACC in more than 50% to 80% of children.

Causes

• There are no established causes for adrenocortical carcinoma.
• The relatively increased incidence in childhood is mainly explained by germline TP53 mutations, which are the underlying genetic cause of ACC in >50% to 80% of children.

Genetics

The genetic dissection of ACC has revealed genomic aberrations that contribute to neoplastic transformation of adrenocortical cells:

1. Clonality

• ACCs initiate from monoclonal cell populations, suggesting that mutation events lead to clonal expansion and ultimate progression to cancer.
• Flow cytometry revealed aneuploidy in ACC. aneuploidy was observed in 75% of ACC.
• Assessment of aneuploidy with histopathological criteria in 7 of 9 adrenal tumors revealed a high correlation with Weiss score >3 (indicative of malignancy).
• No significant difference in overall survival was observed in patients with ACC exhibiting aneuploidy vs patients with ACC exhibiting diploid neoplasms.

2. Gene expression arrays

• An initial study identified elevated expression of genes involved in cell proliferation in ACC, such as IGF2, compared with increased expression of steroidogenic genes in ACA.

• Giordano et al identified unique transcriptionally activated (12q and 5q) and repressed (11q, 1p, and 17p) chromosomal regions in 33 ACCs vs 22 ACAs in a microarray study.

• Giordano et al (192) determined that ACC with high histological grade exhibited overexpression of cell cycle and functional aneuploidy genes and leading to the decreased survival of patients.

• Expression levels of BUB1B, PINK1, and DLG7 are identified in ACC.

3. MicroRNAs

• MicroRNAs are RNAs that are important in the regulation of gene expression.
• Numerous miRNAs have been identified in the regulation of various cellular processes such as proliferation, apoptosis, and differentiation.
• Dysregulation of miRNAs, such as overexpression or deletion, plays an important role in diseases.
• Mistargeting of the miRNAs, resulting in inhibition or activation of various oncogenes, tumor suppressors, and other factors important in tumor angiogenesis.
• The investigation identified 14 upregulated miRNAs and 9 downregulated miRNAs unique to ACC.
• Upregulated miRNAs in ACCs included miR-184, miR-210, and miR-503.
• Downregulated miRNAs included miR-214, miR-375, and miR-511.
• Levels of miR-184, miR-503, and miR-511 are able to distinguish benign from malignant adrenal tumors.^[16]
• MiR-483 was found to be significantly upregulated in pediatric ACCs.
• MiR-99a and miR-100 are bioinformatically predicted to target the 3- untranslated regions of IGF1R, RPTOR, and FRAP1 and were experimentally confirmed to target several components of the IGF-1 signaling pathway.^[17]

4. Gene mutations

• Targeted genetic analyses have identified somatic genetic changes in TP53, MEN1, IGF2, IGF2R, and p16.^[18]

• TP53 located on 17p13 is the most commonly mutated gene in ACC, present in at least one-third of ACCs.^[19]
• LOH in the gene encoding p16ink/ p14arf, CDKN2A is observed in a subset of ACCs. The tumor suppressor function of this gene has been established in multiple cancers. LOH of 11q13 has been identified in 83% of samples.^[20]
• MEN1 somatic mutations are unusual in sporadic ACC.^[21]
• The canonical Wnt pathway, the catenin gene, and CTNNB1 have been identified as activating point mutations in over 25% of both ACAs and ACCs in children and adults.^[22]

5. Chromosomal aberrations

• Comparative genomic hybridization(CGH) can identify structural chromosomal abnormalities within ACCs.^[23]

• ACCs showed complex chromosomal alterations. ACCs contained multiple chromosomal gains or losses with a mean of 10 events.

• The newest study confirmed increased alterations in ACC (44%) compared with ACAs (10%).

• In ACCs, the frequently observed chromosomal gains at 5, 7, 12, 16, 19, and 20 and losses at 13 and 22 were confirmed.

• The group identified genes within these regions with potential tumorigenic potential including fibroblast growth factor 4 (FGF4), cyclin-dependent kinase 4 (CDK4), and cyclin E1(CCNE1). The study confirmed the diagnostic utility of 6 loci (5q, 7p, 11p, 13q, 16q, and 22q) in the differentiation of ACA and ACC.

• Genomic aberration at chromosomes 5, 12, and 17 are predicted to illustrate genes that initiate or maintain neoplastic transformation. Chromosome 17, specifically at 17p13, contains the well-known tumor suppressor gene TP53.

6. Epigenetic

• DNA methylation involves the addition of a methyl group to the cytosine pyrimidine ring or adenine purine ring.^[24]
• Dysregulation in this process is observed in tumor cells.
• A recent study revealed hypermethylation of promoters in ACC with correlation to poor survival and identified H19, PLAGL1, G0S2, and NDRG2 as silenced genes also provided evidence about the role of methylation in ACC tumorigenesis, particularly in the 11p15 locus containing IGF2 and H19.

Hereditary syndromes associated with adrenocortical carcinoma are:

• Lynch syndrome

• Beckwith-Wiedemann syndrome
• Carney complex
• Neurofibromatosis type 1
• MEN1

Associated conditions	Gene mutations	Clinical picture
Lynch syndrome	MSH2, MSH6, MLH1, PMS2	Colorectal cancer Endometrial cancer Sebaceous neoplasms Ovarian cancer Pancreatic cancer Brain cancer
Neurofibromatosis type 1	NF1	Malignant peripheral nerve sheet tumor Pheochromocytoma Café au lait spots Neurofibroma Optic glioma Lisch nodule Skeletal abnormalities
MEN1	MENIN	Foregut neuroendocrine tumors Pituitary tumors Parathyroid hyperplasia Collagenoma Angiofibroma Adrenal adenoma/hyperplasia
Carney complex	PRKAR1A	Adrenal disease Sertoli cell tumors Thyroid adenoma Myxoma Somatotroph pituitary adenoma
BWS	IGF2, CDKN1C, H19	Wilm’s tumor Hepatoblastoma Macrosomia Adrenocortical cytomegaly Adrenal adenoma Adrenal cyst Hemihypertrophy Macroglossia Omphalocele