SAT-155 High Prevalence Alterations on DNA Mismatch Repair Genes Related to Lynch Syndrome in Pediatric Patients with Adrenocortical Tumor Carried of the Germline Mutation on TP53
Authors: Brondani Vânia Balderrama , Montenegro Luciana Ribeiro , Lacombe Amanda Meneses Ferreira , Nishi Mirian Yumie , Funari Mariana Ferreira de Assis , Narcizo Amanda de Moraes , Cardoso Laís , Zerbini Maria Claudia , Denes Francisco , Latronico Ana Claudia , Mendonca Berenice Bilharinho , Almeida Madson Q , Lerario Antonio , Soares Ibere , Vilares Candida 
Published: May 2020

Abstract
Background: Adrenocortical cancer (ACC) is a rare malignant neoplasia associated with a variable clinical presentation. Pediatric patients generally have a better prognosis when compared to adults. In addition, unlike in adults where ACC which is usually sporadic, 50-80% of pediatric ACC is associated with genetic disorders such as Beckwith-Wiedemann and Li-Fraumeni syndromes. Recently, was showed that 3-5% of adult patients with ACC presented germline variants in DNA mismatch repair genes such as MSH2 and MSH6, the cause of Lynch syndrome (LS). The prevalence of these alterations in pediatric ACC is unknown. We aimed to investigate the prevalence of germline alterations in DNA mismatch repair genes among pediatric and adult patients with adrenocortical tumors (benign and malignant) carriers of the germline TP53 p.R337H mutation. Methods: 35 patients selected (30 pediatric and 5 adult) with functional tumors. ACC was diagnosed in 4 pediatric and in all adult patients. NGS was performed in 35 DNA blood samples by HNPCC MASTR Plus for the identification of SNV in 4 genes (MLH1, MSH2, MSH6, and PMS2) and 3’ UTR of EPCAM. Copy number variation (CNV) analyses were done by Copy Number Targeted Resequencing Analysis (CONTRA) and MLPA. The variants were classified, according to ACMG (American College Medical Genome) by Varsome platform. The protein expression was evaluated by Immunohistochemistry (IHC): MLH1 (clone ES05), MSH2 (FE11), MSH6 (EP49), and PMS2 (EP51). All patients were evaluated for variants in TP53. Results: NGS: 2 children presented 2 pathogenic allelic variants associated with LS (2/30, 6.6%), both patients with benign outcome and follow up of 4 years: 1 deletion in MLH1 (c.1500_1502del) and 1 nonsense in the MSH6 gene (c.328C&gt;T p.Arg110X. CNV: MLPA specific for MLH1/MSH2 showed a normal copy number. ICH: the loss of expression in MLH1/PMS2 was identified in only one case without allelic variants. Discussion: Although our cohort is small, we observed 2 allelic pathogenic variants associated with LS among pediatric with adrenocortical tumors. It is higher than the prevalence of colorectal and endometrial cancer (3.2%) in LS. A personal and family history of LS tumors should be strongly considered for genetic risk assessment in pediatric patients with ACT. If the association with TP53 alteration can influence the tumor’s behavior with early clinical presentation, as seen in hereditary nonpolyposis colorectal cancer, it needs to be investigated. The patients with both alterations must be followed with surveillance, according to the US Multi-Society task force guideline for Lynch syndrome and for Li-Fraumeni syndrome.