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

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  1 , Murilo Bonatelli  2 , Augusto Perazzolo Antoniazzi  3 , Flávia Escremim de Paula  2 , Leticia Ferro Leal  1   4 , Felipe Antônio de Oliveira Garcia  1 , André Escremim de Paula  2 , Gustavo Ramos Teixeira  5   4 , Iara Viana Vidigal Santana  5 , Fabiano Saggioro  6 , Luciano Neder  6 , Elvis Terci Valera  7 , Carlos Alberto Scrideli  7 , João Stavale  8 , Suzana Maria Fleury Malheiros  8 , Matheus Lima  9 , Glaucia Noeli Maroso Hajj  9 , Hernan Garcia-Rivello  10 , Silvia Christiansen  10 , Susana Nunes  11 , Maria João Gil-da-Costa  11 , Jorge Pinheiro  12 , Flavia Delgado Martins  13 , Carlos Almeida Junior  14 , Bruna Minniti Mançano  15 , Rui Manuel Reis  1   2   16   17
Affiliations

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 et al. Front Oncol. .

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.

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Conflict of interest statement

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Figures

Figure 1
Figure 1
Medulloblastomas molecular subgroups and CTNNB1 mutations in WNT-activated medulloblastomas. (A) Latin-Iberian population (n=266, including patients from Brazil, Portugal, and Argentina). (B) In silico analysis in medulloblastomas from the North American and European populations (n=617).
Figure 2
Figure 2
CTNNB1 variants found in the Latin-Iberian population. (A) Electropherogram of Sanger sequencing of the hotspot region in the exon 3 of CTNNB1 (chr3:41224525 + 41224751), which codes the phosphorylation site of the protein, showing three different CTNNB1 variants: p.(Ser33Tyr), p.(Gly34Val) and p.(Ser45del). (B) Lollipop showing the 25 CTNNB1 variants observed in the WNT-activated medulloblastomas from the Latin-Iberian population.
Figure 3
Figure 3
Kaplan–Meier curves of CTNNB1 mutant and CTNNB1 wild-type WNT-activated medulloblastomas from Latin-Iberian population.
Figure 4
Figure 4
Pedigree of familial adenomatous polyposis showing the occurrence of APC-associated WNT-activated medulloblastomas in siblings. The APC germline mutation was tested, and the “+” indicates APC mutation and “−,” APC wild type.
See this image and copyright information in PMC

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