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

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

JOURNAL=Frontiers in Oncology

VOLUME=13

YEAR=2023

URL=https://www.frontiersin.org/journals/oncology/articles/10.3389/fonc.2023.1237170

DOI=10.3389/fonc.2023.1237170

ISSN=2234-943X

ABSTRACT=<sec><title>Purpose</title><p>Medulloblastomas are the most common primary malignant brain tumors in children. They are divided into molecular subgroups: WNT-activated, SHH-Activated, <italic>TP53</italic> mutant or wild type, and non-WNT/non-SHH (Groups 3 and 4). WNT-activated medulloblastomas are usually caused by mutations in the <italic>CTNNB1</italic> gene (85%–90%), and most remaining cases <italic>of CTNNB1</italic> wild type are thought to be caused by germline mutations in <italic>APC</italic>. So far, the frequencies of <italic>CTNNB1</italic> have been reported mainly in North American and European populations. The aim of this study was to report the frequency of <italic>CTNNB1</italic> mutations in WNT-activated medulloblastomas in a Latin-Iberian population and correlate with their clinicopathological characteristics.</p></sec><sec><title>Methods</title><p>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 <italic>CTNNB1</italic> mutation analysis were performed by nCounter and Sanger sequencing, respectively.</p></sec><sec><title>Results</title><p>WNT-activated medulloblastomas accounted for 15% (40/266) of the series. We observed that 73% of WNT-activated medulloblastomas harbored <italic>CTNNB1</italic> mutations. <italic>CTNNB1</italic> wild-type cases (27%) were more prevalent in female individuals and suggested to be associated with a worse outcome. Among the <italic>CTNNB1</italic> wild-type cases, the available analysis of family history revealed two cases with familiar adenomatous polyposis, harboring <italic>APC</italic> germline variants.</p></sec><sec><title>Conclusion</title><p>We observed a lower incidence of <italic>CTNNB1</italic> mutations in WNT-activated medulloblastomas in our Latin-Iberian cohort compared to frequencies previously described in other populations. Considering that <italic>CTNNB1</italic> wild-type cases may exhibit <italic>APC</italic> germline mutations, our study suggests a higher incidence (~30%) of hereditary WNT-activated medulloblastomas in the Latin-Iberian population.</p></sec>