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  • Author: Antonio M Lerario x
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Maria Candida B V Fragoso, Madson Queiroz Almeida, Tania L Mazzuco, Beatriz M P Mariani, Luciana P Brito, Talita Cardoso Gonçalves, Guilherme A Alencar, Lorena de O Lima, Andre M Faria, Isabelle Bourdeau, Antonio M Lucon, Daniel S Freire, Ana Claudia Latronico, Berenice B Mendonca, Andre Lacroix and Antonio M Lerario


A recent microarray study identified a set of genes whose combined expression patterns were predictive of poor outcome in a cohort of adult adrenocortical tumors (ACTs). The difference between the expression values measured by qRT-PCR of DLGAP5 and PINK1 genes was the best molecular predictor of recurrence and malignancy. Among the adrenocortical carcinomas, the combined expression of BUB1B and PINK1 genes was the most reliable predictor of overall survival. The prognostic and molecular heterogeneity of ACTs raises the need to study the applicability of these molecular markers in other cohorts.


To validate the combined expression of BUB1B, DLGAP5, and PINK1 as outcome predictor in ACTs from a Brazilian cohort of adult and pediatric patients.

Patients and methods

BUB1B, DLGAP5, and PINK1 expression was assessed by quantitative PCR in 53 ACTs from 52 patients – 24 pediatric and 28 adults (one pediatric patient presented a bilateral asynchronous ACT).


DLGAP5–PINK1 and BUB1B–PINK1 were strong predictors of disease-free survival and overall survival, respectively, among adult patients with ACT. In the pediatric cohort, these molecular predictors were only marginally associated with disease-free survival but not with overall survival.


This study confirms the prognostic value of the combined expression of BUB1B, DLGAP5, and PINK1 genes in a Brazilian group of adult ACTs. Among pediatric ACTs, other molecular predictors of outcome are required.

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Rafael A Carvalho, Betsaida Urtremari, Alexander A L Jorge, Lucas S Santana, Elisangela P S Quedas, Tomoko Sekiya, Viviane C Longuini, Fabio L M Montenegro, Antonio M Lerario, Sergio P A Toledo, Stephen J Marx, Rodrigo A Toledo and Delmar M Lourenço Jr


Loss-of-function germline MEN1 gene mutations account for 75–95% of patients with multiple endocrine neoplasia type 1 (MEN1). It has been postulated that mutations in non-coding regions of MEN1 might occur in some of the remaining patients; however, this hypothesis has not yet been fully investigated.


To sequence for the entire MEN1 including promoter, exons and introns in a large MEN1 cohort and determine the mutation profile.

Methods and patients

A target next-generation sequencing (tNGS) assay comprising 7.2 kb of the full MEN1 was developed to investigate germline mutations in 76 unrelated MEN1 probands (49 familial, 27 sporadic). tNGS results were validated by Sanger sequencing (SS), and multiplex ligation-dependent probe amplification (MLPA) assay was applied when no mutations were identifiable by both tNGS and SS.


Germline MEN1 variants were verified in coding region and splicing sites of 57/76 patients (74%) by both tNGS and SS (100% reproducibility). Thirty-eight different pathogenic or likely pathogenic variants were identified, including 13 new and six recurrent variants. Three large deletions were detected by MLPA only. No mutation was detected in 16 patients. In untranslated, regulatory or in deep intronic MEN1 regions of the 76 MEN1 cases, no point or short indel pathogenic variants were found in untranslated, although 33 benign/likely benign and three new VUS variants were detected.


Our study documents that point or short indel mutations in non-coding regions of MEN1 are very rare events. Also, tNGS proved to be a highly effective technology for routine genetic MEN1 testing.