SUN-218 Analysis of ATRX and ZNRF3 Expression and Copy Number Variation in a Pediatric and Adult Cohort with Adrenocortical Tumors
Authors: Brondani Vânia Balderrama , Montenegro Luciana Ribeiro , Mariani Beatriz Marinho , Nishi Mirian Yumie , Zerbini Maria Claudia N , Lacombe Amanda Meneses Ferreira , Tanno Fabio Y , Srougi Victor , Chambo Jose L , Denes Francisco T , Mendonca Berenice B , Almeida Madson Q , Villares Fragoso Maria Candida Barisson 
Published: May 2020

Abstract
Introduction: Adrenocortical carcinoma (ACC) is a rare malignancy with an incidence of 1 to 2 cases per million/year in adults and with a global survival rate of less than 40% in 5 years. ACC diagnosis was based on Weiss criteria for adult patients. Pediatric patients with adrenocortical tumors (PAT), in general, are associated with better survival in most cases, and the malignant disease is established when local or distant metastases are found. The integrated and extensive genomic-molecular characterization of ACC has resulted in a better understanding of its pathophysiology. Some studies have demonstrated the involvement of ATRX and ZNRF3 genes in adrenal tumorigenesis in pediatric and adult patients with PAT and ACC, respectively. However, these data have not been validated in a Brazilian cohort with a high prevalence of the TP53 germline R337H mutation. Objectives: We aimed to evaluate the ATRX and ZNRF3 expression and copy number variation in a Brazilian cohort of patients with PAT and adults with ACC from a tertiary center. Patients and Methods: 34 adults (19 women - 56%) with median age 49 years old (range 18-83) and twelve pediatric patients (7 girls - 58%) with median age three years old (0.8-15 years old) were included in this study. The epidemiological data, clinical presentation, hormonal data, radiological imaging, and genetic background for TP53 were retrospectively evaluated. MLPA and RT-PCR were employed to evaluate the copy number variation and the gene expression, respectively, of ATRX and ZNRF3 in tumor tissues. Results: Adult group: Seven patients out of 27 (25.9%) presented the pathogenic germline mutation pR337H onTP53. 20 patients (58.8%) presented metastasis, and 19 (55%) had a fatal outcome. The median global survival was 17.23 months (0.6-185.8 m). Pediatric group: 10 patients (83.3%) presented the pathogenic germline mutation p.R337H on TP53. Four patients presented metastasis and only two had a fatal outcome. The median global survival was 42.4months (6.63-125.5m). All tumors were functional. Molecular results: Three out of 33 adult patients (9%), and 2 out of 12 (16.6%) pediatric patients presented deletion on ATRX. Four out of 25 adults (16%) and 2 out of 12 pediatric (16.6%) patients showed deletion on ZNRF3. There was no correlation between ATRX and ZNRF3 expressions or deletions with the overall survival rate (p&gt;0.05). The decrease in the ATRX expression was associated with the presence of TP53 germline mutation in pediatric and adult cohorts (p 0.028). Conclusion: We confirmed the presence of alterations on ATRX and ZNRF3 genes in both cohort (adult and pediatric tumors). These results differ from the previous studies, which demonstrated ATRX and ZNRF3 alterations were present in pediatric and adult tumors, respectively. However, prospective studies with larger cohorts are necessary to confirm the prognostic value of ATRX and ZNRF3 genes in PAT and adults with ACC.