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]

Overview

There are no established causes for adrenocortical carcinoma.

Causes

  • There are no established causes for Adrenocortical carcinoma
  • The relative increase in 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

2. Gene expression arrays

  • Expression levels of BUB1B, PINK1, and DLG7 are identified in ACC.[12]

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 proliferationapoptosis, and differentiation.[13]
  • 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 oncogenestumor suppressors, and other factors important in tumor angiogenesis.[14]
  • The investigation identified 14 upregulated miRNAs and 9 downregulated miRNAs unique to ACC.[15]
  • Upregulated miRNAs in ACCs included miR-184, miR-210, and miR-503.
  • Downregulated miRNAs included miR-214, miR-375, and miR-511.[16]
  • 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 IGF1RRPTOR, and FRAP1 and were experimentally confirmed to target several components of the IGF-1 signaling pathway.[17]

4. Gene mutations

  • 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 p16inkp14arfCDKN2A 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

  • 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.

6. Epigenetic

Hereditary syndromes associated with adrenocortical carcinoma are:

Differential Diagnosis 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
  • Primary pigmented nodular
  • Adrenal disease
  • Large-cell calcifying Sertoli cell tumors
  • Thyroid adenoma
  • Myxoma
  • Somatotroph pituitary adenoma
BWS 41
  • IGF2, CDKN1C, H19
  • Wilms’ tumor
  • Hepatoblastoma
  • Macrosomia
  • Adrenocortical cytomegaly
  • Adrenal adenoma
  • Adrenal cyst
  • Hemihypertrophy
  • Macroglossia
  • Omphalocele

References

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