A simplified approach using Taqman low-density array for medulloblastoma subgrouping

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Veiga Cruzeiro, Gustavo Alencastro ^[1] ; Salomao, Karina Bezerra ^[1] ; Oliveira de Biagi, Jr., Carlos Alberto ^[2] ; Baumgartner, Martin ^[3] ; Sturm, Dominik ^{[4, 5]} ; Peixoto Lira, Regia Caroline ^[1] ; Magalhaes, Taciani de Almeida ^[2] ; Milan, Mirella Baroni ^[2] ; Silveira, Vanessa da Silva ^[2] ; Saggioro, Fabiano Pinto ^[6] ; de Oliveira, Ricardo Santos ^[7] ; dos Santos Klinger, Paulo Henrique ^[1] ; Seidinger, Ana Luiza ^[8] ; Yunes, Jose Andres ^[8] ; de Paula Queiroz, Rosane Gomes ^[1] ; Oba-Shinjo, Sueli Mieko ^[9] ; Scrideli, Carlos Alberto ^[1] ; Kazue Nagahashi, Suely Marie ^[9] ; Tone, Luiz Gonzaga ^[1] ; Valera, Elvis Terci ^[1]

Afiliação do(s) autor(es)

^[1] Univ Sao Paulo, Hosp Clin, Ribeirao Preto Med Sch, Dept Pediat, Ave Bandeirantes 3900, Ribeirao Preto, SP - Brazil

^[2] Univ Sao Paulo, Ribeirao Preto Med Sch, Dept Genet, Ave Bandeirantes 3900, Ribeirao Preto, SP - Brazil

^[3] Univ Childrens Hosp Zurich, Childrens Res Ctr, Neurooncol Grp, Dept Oncol, August Forel Str 1, CH-8008 Zurich - Switzerland

^[4] NCT Heidelberg KiTZ, Hopp Childrens Canc Ctr, Pediat Glioma Res Grp, D-69120 Heidelberg - Germany

^[5] German Canc Res Ctr, D-69120 Heidelberg - Germany

^[6] Univ Sao Paulo, Dept Pathol, Ave Bandeirantes 3900, BR-14049900 Ribeirao Preto, SP - Brazil

^[7] Univ Sao Paulo, Hosp Clin, Ribeirao Preto Med Sch, Div Pediat Neurosurg, Dept Surg & Anat, Ave Bandeirantes 3900, Ribeirao Preto, SP - Brazil

^[8] Univ Campinas UNICAMP, Boldrini Ctr Children, Campinas, SP - Brazil

^[9] Univ Sao Paulo, Dept Neurol, Fac Med, Sao Paulo - Brazil

• Tipo de documento: Artigo Científico
• Fonte: ACTA NEUROPATHOLOGICA COMMUNICATIONS; v. 7, MAR 4 2019.
• Citações Web of Science: 0

Resumo

Next-generation sequencing platforms are routinely used for molecular assignment due to their high impact for risk stratification and prognosis in medulloblastomas. Yet, low and middle-income countries still lack an accurate cost-effective platform to perform this allocation. TaqMan Low Density array (TLDA) assay was performed using a set of 20 genes in 92 medulloblastoma samples. The same methodology was assessed in silico using microarray data for 763 medulloblastoma samples from the GSE85217 study, which performed MB classification by a robust integrative method (Transcriptional, Methylation and cytogenetic profile). Furthermore, we validated in 11 MBs samples our proposed method by Methylation Array 450K to assess methylation profile along with 390MB samples (GSE109381) and copy number variations. TLDA with only 20 genes accurately assigned MB samples into WNT, SHH, Group 3 and Group 4 using Pearson distance with the average-linkage algorithm and showed concordance with molecular assignment provided by Methylation Array 450k. Similarly, we tested this simplified set of gene signatures in 763MB samples and wewere able to recapitulate molecular assignment with an accuracy of 99.1% (SHH), 94.29% (WNT), 92.36% (Group 3) and 95.40% (Group 4), against 97.31, 97.14, 88.89 and 97.24% (respectively) with the Ward.D2 algorithm. t-SNE analysis revealed a high level of concordance (k=4) with minor overlapping features between Group 3 and Group 4. Finally, we condensed the number of genes to 6 without significantly losing accuracy in classifying samples into SHH, WNT and non-SHH/non-WNT subgroups. Additionally, we found a relatively high frequency of WNT subgroup in our cohort, which requires further epidemiological studies. TLDA is a rapid, simple and cost-effective assay for classifying MB in low/middle income countries. A simplified method using six genes and restricting the final stratification into SHH, WNT and non-SHH/non-WNT appears to be a very interesting approach for rapid clinical decision-making. (AU)

• Processo FAPESP: 13/12006-3 - Investigação de novos alvos terapêuticos baseado na classificação dos subgrupos moleculares do meduloblastoma.
• Beneficiário: Gustavo Alencastro Veiga Cruzeiro
• Modalidade de apoio: Bolsas no Brasil - Doutorado
• Processo FAPESP: 14/20341-0 - Interação entre alvos terapêuticos emergentes e vias de desenvolvimento associadas à tumorigênese: ênfase em neoplasias da criança e do adolescente
• Beneficiário: Luiz Gonzaga Tone
• Modalidade de apoio: Auxílio à Pesquisa - Temático
• Processo FAPESP: 14/19976-0 - Caracterização in vitro das diferenças funcionais e moleculares entre os subgrupos de meduloblastoma
• Beneficiário: Gustavo Alencastro Veiga Cruzeiro
• Modalidade de apoio: Bolsas no Exterior - Estágio de Pesquisa - Doutorado
• Processo FAPESP: 04/12133-6 - Procura de marcadores moleculares relacionados ao diagnóstico e prognóstico de tumores do sistema nervoso central
• Beneficiário: Suely Kazue Nagahashi Marie
• Modalidade de apoio: Auxílio à Pesquisa - Temático
• Processo FAPESP: 13/02162-8 - Patogênese molecular e caracterização de doenças monogênicas do desenvolvimento: um caminho para a medicina translacional
• Beneficiário: Berenice Bilharinho de Mendonça
• Modalidade de apoio: Auxílio à Pesquisa - Temático