Details

Autor(en) / Beteiligte

• Bueno, Ana Carolina
• da Silva-Júnior, Rui Milton Patrício
• Stecchini, Monica Freire
• Gutiérrez, Junier Marrero
• Cardinalli, Izilda Aparecida
• Scrideli, Carlos Alberto
• Molina, Carlos Augusto Fernandes
• Ramalho, Fernando Silva
• Tucci, Silvio
• Coeli-Lacchini, Fernanda Borchers
• Moreira, Ayrton Custodio
• Ramalho, Leandra Naira Zambelli
• Brandalise, Silvia Regina
• Yunes, Jose Andres
• De Castro, Margaret
• Vencio, Ricardo Zorzetto Nicoliello
• Antonini, Sonir Roberto Rauber

Titel

Tumor DNA Methylation Profiling Is a Robust and Independent Prognostic Marker for Pediatric Patients With Adrenocortical Tumors

Ist Teil von

• Journal of the Endocrine Society, 2021-05, Vol.5 (Supplement_1), p.A99-A100

Erscheinungsjahr

2021

Quelle

EZB Electronic Journals Library

Beschreibungen/Notizen

• Abstract Pediatric adrenocortical tumors (pACTs) display complex genomic background and lack robust prognostic biomarkers. However, pACT methylation profiling was recently associated with patient prognosis. In order to evaluate whether tumor DNA methylation is associated with patient prognosis, we studied a Brazilian cohort of pACT in which most of the patients were carriers of the germline P53 p.R337H mutation (86%). We analyzed the DNA methylation profile of 57 tumor samples (MethylationEPIC BeadChip Array, Illumina) and the respective patients’ clinicopathological features associated with outcome and overall survival. Median age at diagnosis of the 40 girls and 17 boys was 2.1 years (range: 0.2–16.6). Reduced overall survival was observed in patients diagnosed after 4 years of age (n=43, HR=26.5, p<0.0001, 5-year survival (5ys)=43%), in those presenting with Cushing’s syndrome (n=7, HR=12.5, p<0.0001, 5ys=28%), advanced/non localized disease (IPACTR stages III and IV; n=11, HR=12.9, p<0.0001, 5ys=33%) or carcinomas (n=10, HR=4.9, p=0.04 5ys=56%). Unsupervised analysis of methylation data (Euclidean distance and Ward’s method; Pvclust package, R, version 4.0.3) included all 766,031 probes filtered in by the quality control step, and revealed two groups with distinct methylation signatures with a bootstrap support of 99%, namely pACT1 and pACT2. The overall variance of differentially methylated probes (DMPs; FDR p-values <10–6 and, simultaneously, median M-value difference >2) between the groups was 0.084% (n=642 probes). Tumors from pACT1 were enriched for hypomethylation in genes’ body region and for hypermethylation in promoter regions (p<0.0001). Gene set analysis showed that DMPs were mostly enriched in gene sets involved in nervous system differentiation and development, mRNA binding, and peptide secretion and related to pathways in cancer, cell adhesion, and calcium signaling. Methylation was not associated with germline P53 p.R337H mutation (p=0.57). Compared to pACT2, pACT1 group comprised patients older at diagnosis (p=0.0004) and higher frequencies of patients diagnosed after 4 years of age (80 vs 13%; p<0.0001), presenting with Cushing syndrome (40 vs. 4%; p=0.01), non-localized/advanced disease (70 vs 8%; p=0.0001), carcinomas (71 vs 17%. p=0.009), who needed adjuvant chemotherapy (90 vs. 9%; p<0.0001), and who experienced post-surgery recurrence or metastasis (90 vs 6%; p<0.0001). pACT1 methylation signature was associated with reduced overall survival from the disease (HR=51, p=0.0001, 5ys: 20 vs 98%), and remained associated after adjusting for prognostic features. Interestingly, different tumor methylation signatures were associated with pACT clinical presentation and evolution, regardless the presence of the P53 p.R337H mutation. Our data supports the analysis of methylation profiling as a robust and independent prognostic biomarker for pACT.