High frequency of WNT-activated medulloblastomas with CTNNB1 wild type suggests a higher proportion of hereditary cases in a Latin-Iberian population

Daniel Antunes Moreno; Murilo Bonatelli; Augusto Perazzolo Antoniazzi; Flávia Escremim de Paula; Leticia Ferro Leal; Felipe Antônio de Oliveira Garcia; André Escremim de Paula; Gustavo Ramos Teixeira; Iara Viana Vidigal Santana; Fabiano Saggioro; Luciano Neder; Elvis Terci Valera; Carlos Alberto Scrideli; João Stavale; Suzana Maria Fleury Malheiros; Matheus Lima; Glaucia Noeli Maroso Hajj; Hernan Garcia-Rivello; Silvia Christiansen; Susana Nunes; Maria João Gil-da-Costa; Jorge Pinheiro; Flavia Delgado Martins; Carlos Almeida Junior; Bruna Minniti Mançano; Rui Manuel Reis

doi:10.3389/fonc.2023.1237170

High frequency of WNT-activated medulloblastomas with CTNNB1 wild type suggests a higher proportion of hereditary cases in a Latin-Iberian population

Front Oncol. 2023 Sep 4:13:1237170. doi: 10.3389/fonc.2023.1237170. eCollection 2023.

Authors

Daniel Antunes Moreno¹, Murilo Bonatelli², Augusto Perazzolo Antoniazzi³, Flávia Escremim de Paula², Leticia Ferro Leal^{1

4}, Felipe Antônio de Oliveira Garcia¹, André Escremim de Paula², Gustavo Ramos Teixeira^{5

4}, Iara Viana Vidigal Santana⁵, Fabiano Saggioro⁶, Luciano Neder⁶, Elvis Terci Valera⁷, Carlos Alberto Scrideli⁷, João Stavale⁸, Suzana Maria Fleury Malheiros⁸, Matheus Lima⁹, Glaucia Noeli Maroso Hajj⁹, Hernan Garcia-Rivello¹⁰, Silvia Christiansen¹⁰, Susana Nunes¹¹, Maria João Gil-da-Costa¹¹, Jorge Pinheiro¹², Flavia Delgado Martins¹³, Carlos Almeida Junior¹⁴, Bruna Minniti Mançano¹⁵, Rui Manuel Reis^{1

2

16

17}

Affiliations

¹ Molecular Oncology Research Center, Barretos Cancer Hospital, Barretos, Brazil.
² Molecular Diagnosis Laboratory, Barretos Cancer Hospital, Barretos, Brazil.
³ Cancer Genetics Department, Barretos Cancer Hospital, Barretos, Brazil.
⁴ Pathology Department, Barretos Cancer Hospital, Barretos, Brazil.
⁵ Barretos School of Health Sciences Dr. Paulo Prata, Barretos Cancer Hospital, Barretos, Brazil.
⁶ Department of Pathology and Forensic Medicine, University of São Paulo, Ribeirão Preto, Brazil.
⁷ Department of Pediatrics of Ribeirão Preto Medical School, University of São Paulo, Ribeirão Preto, Brazil.
⁸ Department of Neurology and Neurosurgery, Federal University of São Paulo (UNIFESP), São Paulo, Brazil.
⁹ Oncology Department, AC Camargo Hospital, São Paulo, Brazil.
¹⁰ Pathology Department, Italian Hospital of Buenos Aires, Buenos Aires, Argentina.
¹¹ Pediatric Oncology Department, Centro Hospitalar Universitário São João, Porto, Portugal.
¹² Department of Pathology, Centro Hospitalar Universitário São João, Porto, Portugal.
¹³ Brasília Children's Hospital, Brasília, Brazil.
¹⁴ Pediatric Neurosurgery Department, Barretos Cancer Hospital, Barretos, Brazil.
¹⁵ Pediatric Oncology Department, Barretos Cancer Hospital, Barretos, Brazil.
¹⁶ ICVS/3B's - PT Government Associate Laboratory, Braga/Guimarães, Portugal.
¹⁷ Life and Health Sciences Research Institute (ICVS), School of Medicine, University of Minho, Braga, Portugal.

Abstract

Purpose: Medulloblastomas are the most common primary malignant brain tumors in children. They are divided into molecular subgroups: WNT-activated, SHH-Activated, TP53 mutant or wild type, and non-WNT/non-SHH (Groups 3 and 4). WNT-activated medulloblastomas are usually caused by mutations in the CTNNB1 gene (85%-90%), and most remaining cases of CTNNB1 wild type are thought to be caused by germline mutations in APC. So far, the frequencies of CTNNB1 have been reported mainly in North American and European populations. The aim of this study was to report the frequency of CTNNB1 mutations in WNT-activated medulloblastomas in a Latin-Iberian population and correlate with their clinicopathological characteristics.

Methods: A total of 266 medulloblastomas from seven different institutions from Brazil (n=211), Portugal (n=38), and Argentina (n=17) were evaluated. Following RNA and DNA isolation from formalin-fixed, paraffin-embedded (FFPE) tumor tissues, the molecular classification and CTNNB1 mutation analysis were performed by nCounter and Sanger sequencing, respectively.

Results: WNT-activated medulloblastomas accounted for 15% (40/266) of the series. We observed that 73% of WNT-activated medulloblastomas harbored CTNNB1 mutations. CTNNB1 wild-type cases (27%) were more prevalent in female individuals and suggested to be associated with a worse outcome. Among the CTNNB1 wild-type cases, the available analysis of family history revealed two cases with familiar adenomatous polyposis, harboring APC germline variants.

Conclusion: We observed a lower incidence of CTNNB1 mutations in WNT-activated medulloblastomas in our Latin-Iberian cohort compared to frequencies previously described in other populations. Considering that CTNNB1 wild-type cases may exhibit APC germline mutations, our study suggests a higher incidence (~30%) of hereditary WNT-activated medulloblastomas in the Latin-Iberian population.

Keywords: APC; CTNNB1; Latin-Iberian; WNT activated; medulloblastomas.

Copyright © 2023 Moreno, Bonatelli, Antoniazzi, de Paula, Leal, Garcia, de Paula, Teixeira, Santana, Saggioro, Neder, Valera, Scrideli, Stavale, Malheiros, Lima, Hajj, Garcia-Rivello, Christiansen, Nunes, Gil-da-Costa, Pinheiro, Martins, Junior, Mançano and Reis.

Grants and funding

This study was funded by the Barretos Cancer Hospital and the Public Ministry of Labor Campinas (Research, Prevention, and Education of Occupational Cancer, Brazil). LL was supported by the Public Ministry of Labor Campinas (Research, Prevention, and Education of Occupational Cancer) in Campinas, Brazil. RMR is a recipient of CNPq Productivity (Brazil). DM is supported by a scholarship from National Oncology Care Support Program (PRONON), Brazil.