Comparative Genomic Hybridization Analysis of Adrenocortical Tumors

Abstract

Comparative genomic hybridization (CGH) is a molecular cytogenetic technique that allows the entire genome of a tumor to be surveyed for gains and losses of DNA copy sequences. A limited number of studies reporting the use of this technique in adult adrenocortical tumors have yielded conflicting results. In this study we performed CGH analysis on 13 malignant, 18 benign, and 1 tumor of indeterminate malignant potential with the aim of identifying genetic loci consistently implicated in the development and progression of adrenocortical tumors. Tissue samples from 32 patients with histologically proven adrenocortical tumors were available for CGH analysis. CGH changes were seen in all cancers, 11 of 18 (61%) adenomas, and the 1 tumor of indeterminate malignant potential. Of the adrenal cancers, the most common gains were seen on chromosomes 5 (46%), 12 (38%), 19 (31%), and 4 (31%). Losses were most frequently seen at 1p (62%), 17p (54%), 22 (38%), 2q (31%), and 11q (31%). Of the benign adenomas, the most common change was gain of 4q (22%). Mann-Whitney analysis showed a highly significant difference between the cancer group (mean changes, 7.6) and the adenoma group (mean changes, 1.1) for the number of observed CGH changes (P < 0.01). Logistic regression analysis showed that the number of CGH changes was highly predictive of tumor type (P < 0.01). This study has identified several chromosomal loci implicated in adrenocortical tumorigenesis. Activation of a protooncogene(s) on chromosome 4 may be an early event, with progression from adenoma to carcinoma involving activation of oncogenes on chromosomes 5 and 12 and inactivation of tumor suppressor genes on chromosome arms 1p and 17p.

Adrenocortical carcinoma survival rates correlated to genomic copy number variants

“…As reported by Dohna et al, gains and high-level amplifications in chromosomes 7, 14, and 19 were seen only in ACC and not in benign adrenocortical neoplasms, suggesting that these events may be late genetic perturbations in tumorigenesis (16). Deletions have also been found within chromosomes 1p and 17p implicating potential losses of tumor suppressor genes in these regions, marking the progression of benign adrenal adenoma to ACC (17). Similar to other cancers, there is evidence that the number of genetic aberrations increases as a factor of tumor growth and this size progression has been correlated with malignancy (14,18,19).…”

“…Genes within these regions can give insight into the pathways of oncogenesis active within ACC. Among other deleted regions, literature suggests that the loss of chromosomes 1p and 17p are linked to progression from benign to malignant ACC (17). Recent studies have identified a chromodomain helicase DNAbinding protein 5 within 1p36.31 as a tumor suppressor gene (22,23).…”

Meta-analysis of adrenocortical tumour genomics data: novel pathogenic pathways revealed

“…Characteristics of these gene sets are presented in Table 3. Cytogenetic (CGH and FISH) data on adrenocortical tumours were acquired from 10 publications found by literature search (Kjellman et al, 1996;Figueiredo et al, 1999Figueiredo et al, , 2005Russell et al, 1999;Zhao et al, 1999Zhao et al, , 2002Dohna et al, 2000;Sidhu et al, 2002;Bertherat et al, 2003;Stephan et al, 2008). These included 87 ACA and 124 ACC samples (Supplementary Table 3).…”

Tumores adrenocorticais na criança: da abordagem clínica à avaliação molecular

“…A análise do modelo de inativação do cromossomo X em heterozigose em células somáticas femininas demonstrou que carcinomas derivam de células monoclonais enquanto adenomas têm origem tanto monoclonal quanto policlonal (32). Por meio de técnicas de hibridização genômica comparativa (HGC), alterações com ganho nos cromossomos 4, 5, 12, 19 e perdas em 1p, 17p, 22p, 11q, 2q e 11q foram identificadas em 61% dos adenomas e em 62% dos carcinomas (33). Estudos usando marcadores de microssatélites identificaram perda da heterozigose (LOH) em carcinomas nas regiões 11q13 (>90%), 17p13 (>85%) e 2p16 (92%) (28,34).…”