High Prevalence of Alterations in DNA Mismatch Repair Genes of Lynch Syndrome in Pediatric Patients with Adrenocortical Tumors Carrying a Germline Mutation on TP53.

Vania Balderrama Brondani,Luciana Montenegro,Antonio Marcondes Lerario,Breno Marchiori Magalhães,Maria Claudia Nogueira Zerbini,Ibere Cauduro Soares,Ana Claudia Latronico,Maria Candida Barisson Villares Fragoso,Amanda Meneses Ferreira Lacombe,Berenice Bilharinho Mendonca,Lais Cavalca Cardoso,Mariana Ferreira De Assis Funari,Amanda De Moraes Narcizo,Sheila Aparecida Coelho Siqueira,Francisco Tibor Denes,Mirian Yumie Nishi,Madson Queiroz Almeida

doi:10.3390/cancers12030621

Abstract

Adrenocortical cancer is a rare malignant neoplasm associated with a dismal prognosis. Identification of the molecular pathways involved in adrenal tumorigenesis is essential for a better understanding of the disease mechanism and improvement of its treatment. The aim of this study is to define the prevalence of alterations in DNA mismatch repair (MMR) genes in Lynch syndrome among pediatric patients with adrenocortical neoplasia from southern Brazil, where the prevalence of a specific TP53 germline mutation (p.Arg337His) is quite high. Thirty-six pediatric patients were retrospectively evaluated. Immunohistochemistry (IHC) for the MMR enzymes MLH1, MSH2, MSH6, and PMS2, as well as next-generation sequencing (NGS) were performed. For IHC, 36 pediatric tumors were tested. In all of them, the expression of all evaluated MMR proteins was well-preserved. For NGS, 35 patients with pediatric tumor were tested. Three patients (8.57%) with the TP53 p.Arg337His germline mutation presented pathogenic and likely pathogenic variants in the MMR genes (two in MLH1 and one in MSH6). The prevalence of altered MMR genes among pediatric patients was elevated (8.57%) and higher than in colorectal and endometrial cancer cohorts. Pediatric patients with adrenocortical tumors should, thus, be strongly considered as at genetic risk for Lynch syndrome.

Highlights

Adrenocortical cancer (ACC) is a rare malignant neoplasm, presenting a general incidence of one to two cases/million/year [1,2] and an overall age-adjusted incidence of 0.72 cases/million/year in the United States [3]
Twenty-eight patients had their tumor tissue studied by IHC/Tissue microarray (TMA) and eight cases were studied by IHC/Formalin-fixed and paraffin-embedded tumor sections (FFPE)
Germline mutations in mismatch repair (MMR) genes cause loss of function of the encoded protein, which results in microsatellite instability (MSI) and, facilitates a hypermutated status [30]

Summary

Introduction

Adrenocortical cancer (ACC) is a rare malignant neoplasm, presenting a general incidence of one to two cases/million/year [1,2] and an overall age-adjusted incidence of 0.72 cases/million/year in the United States [3]. The incidence of pediatric adrenocortical tumors in Southern Brazil has been estimated to be 3.4–4.2 cases/million children/year [6], which represents a rate that is ten to fifteen times higher than the global incidence rate. This notorious difference is due to the high prevalence of the germline mutation TP53 p.Arg337His in this region of Brazil [6,9,10,11,12]. Germline mutations are responsible for most cases and TP53 mutations are present in 50–90% of cases [5,11]; this differs from the adult

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