Comparative genomic hybridization analysis of adrenocortical tumors of childhood

Although several genes have been investigated in adrenal tumorigenesis, the genetic background of adrenocortical tumors (ACT) remains poorly character ized. In southern Brazil, the annual incidence of ACT is unusually high, ra nging from 3.4-4.2/million children, compared with a worldwide incidence of 0.3/million children younger than 15 yr. Environmental factors have been i mplicated because the distribution of these tumors follows a regional, rath er than a familial, pattern. However, decreased penetrance of a particular gene defect cannot be excluded. Because linkage or other traditional geneti c analyses would not be appropriate to investigate the defect(s) associated with ACT in this population, we used comparative genomic hybridization (CG H) to screen for DNA sequence copy number changes in 9 nonfamilial ACT (6 c arcinomas and 3 adenomas) from unrelated patients from this region. Six fem ale (aged 10 months to 6 3/4 yr) and 3 male (1 1/12 to 3 1/4 yr) patients w ere studied. Three carcinomas were at stage I, 1 was at stage II, and anoth er was at stage III. Two carcinomas had evidence of invasion of the vena ca ve, and 3 were more than 3 cm in size. All patients underwent surgical exci sion of their turners; chemotherapy was administered to cancer patients. Cu rrently, all patients are alive and in remission, with the exception of 1 p atient with stage III cancer. High mol wt DNA was extracted from tumor tiss ue obtained at surgery and frozen at -70 C. This DNA was labeled and used f or CGH according to standard procedures. Digital image analysis was perform ed to detect chromosomal gains or losses. CGH evaluation revealed extensive genetic aberrations in both adenomas and carcinomas; there were no signifi cant differences relative to age, gender, size, or stage of the tumor (P > 0.1). Chromosomes and chromosomal regions 1q, 5p, 5q, 6p, 6q, 8p, 8q, 9q, 1 0p, 11q, 12q, 13q, 14q, 15q, 16, 18q, 19, and 20q demonstrated gains, where as 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. We conclude that both benign and malignant ACT from southern Brazil show multiple genetic aberrations, including a consistent gain of ch romosomal region 9q34. This genomic area may harbor genetic defects that pr edispose to ACT formation and are shared by the patients who were investiga ted in this study or are accumulated epigenetically under the influence of a common factor, such as an environmental mutagen.