ESPE2021 Free Communications Adrenal (6 abstracts)
Tumor DNA methylation profiling as a prognostic marker for pediatric patients with adrenocortical tumors
Ana Carolina Bueno 1 , Rui M P da Silva 1 , Mônica F. Stecchini 1 , Junier M Gutiérrez 1 , Izilda A Cardinalli 2 , Carlos A Scrideli 1 , Thais Junqueira 2 , Carlos A F Molina 1 , Fernando S Ramalho 1 , Silvio Tucci 1 , Fernanda B Coeli-Lacchini 1 , Ayrton C Moreira 1 , Leandra N Z Ramalho 1 , Silvia R Brandalise 2 , José A Yunes 2 , Margaret de Castro 1 , Ricardo Z N Vêncio 3 & Sonir R Antonini 1
1Ribeirao Preto Medical School, University of Sao Paulo, Ribeirao Preto, Brazil.;2Boldrini Children’s Center, State University of Campinas, Campinas, Brazil.;3Faculty of Philosophy, Sciences and Letters at Ribeirao Preto, University of Sao Paulo, Ribeirao Preto, Brazil
Abnormal DNA methylation contributes to tumor progression and is emerging as a prognostic marker in several types of cancers. To investigate whether DNA methylation is associated with pediatric adrenocortical tumor (pACT) presentation and patient prognosis, we analyzed the methylation profile of 57 tumors (MethylationEPIC BeadChip Array-Illumina) and patients’ clinicopathological features and outcome. The study comprehended 40 girls and 17 boys, with median age at diagnosis of 2.1 years (0.2-16.6). Reduced overall survival was observed in patients older than 4 years of age (n = 43, P < 0.0001, 5-year survival [5ys]=43%), in those presenting with Cushing’s syndrome (n = 7, P < 0.0001, 5ys=28%), advanced/non localized disease (IPACTR stages III and IV; n = 11, P < 0.0001, 5ys=33%) or carcinomas (n = 10, P = 0.04, 5ys=56%). Unsupervised analysis of methylation data (M-values; Euclidean distance and Ward’s D method; Pvclust, R, version 4.0.3) included all 766,031 probes filtered in after quality control, and revealed two groups with distinct methylation signatures with a bootstrap support of 99%, namely pACT-1 and pACT-2. The overall variance of differentially methylated probes (DMPs; Wilcoxon rank-sum test FDR p-values <10-6 and, simultaneously, median M-value difference >2) between the groups was 0.084% (n = 642 probes). Further ranking of DMPs excluded those with sample individual M-value invasion (I>0, n = 561; 0.074%) between groups, and identified the DMPs that most distinguished them (I=0, n = 81; 0.01%). pACT-1 presented 51 hypomethylated and 30 hypermethylated DMPs, being enriched for hypomethylation in genes’ body region and for hypermethylation in promoter regions (P = 0.0006). pACT-1 was significantly hypermethylated in CpG islands (P=0.007) and hypomethylated in non-CpG islands (P=0.0008) than pACT-2. DMPs analysis yielded 23 hypomethylated and 15 hypermethylated genes in pACT-1. Patients in pACT-1 were older at diagnosis (P = 0.0004) and were more likely to be diagnosed after 4 years of age (80 vs 13%; P < 0.0001), to present with Cushing syndrome (40 vs. 4%; P = 0.01), non-localized/advanced disease (70 vs 8%; P = 0.0001) or carcinomas (71 vs 17%. P = 0.009), to require adjuvant chemotherapy (90 vs. 9%; P < 0.0001), and to experience post-surgery recurrence/metastasis (90 vs 6%; P < 0.0001). Hence, patients in pACT-1 had reduced disease-free (P < 0.0001, 5ys: 11 vs 91%) and overall survival from the disease (P = 0.0001, 5ys: 20 vs 98%) than those in pACT-2, even after stratifying for the aforementioned prognostic features. Tumor methylation profiles were not associated with P53 p.R337H (P = 0.57) or CTNNB1 (P = 0.6) activating mutations. Our data supports tumor methylation profile as a robust and independent prognostic biomarker for pACT and suggests a feasible list of candidate genes for further validation.
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