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Analysis of the adenomatous polyposis coli (APC) gene in childhood and adolescent germ cell tumors
Author(s) -
Okpanyi Vera,
Schneider Dominik T.,
Zahn Susanne,
Sievers Sonja,
Calaminus Gabriele,
Nicholson James C.,
Palmer Roger D.,
Leuschner Ivo,
Borkhardt Arndt,
Schönberger Stefan
Publication year - 2011
Publication title -
pediatric blood and cancer
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.116
H-Index - 105
eISSN - 1545-5017
pISSN - 1545-5009
DOI - 10.1002/pbc.22669
Subject(s) - wnt signaling pathway , adenomatous polyposis coli , cancer research , biology , epigenetics , methylation , loss of heterozygosity , yolk sac , familial adenomatous polyposis , dna methylation , genetics , cancer , gene , colorectal cancer , gene expression , allele , embryo
Background Aberrant Wnt signaling due to deregulation of Wnt regulators is implicated in the development and progression of numerous embryonal tumors. This study addresses the questions if activation of Wnt signaling in germ cell tumors (GCTs) arising during childhood and adolescence is associated with aberrations of the tumor suppressor adenomatous polyposis coli (APC), and whether APC aberrations might be responsible for progression from benign teratoma to malignant yolk sac tumor (YST). Procedure Forty‐eight GCTs were analyzed, including mature (n = 5) and immature (n = 7) teratomas, mixed malignant GCTs (n = 10), YSTs (n = 17) as well as dysgerminomas (n = 9). To screen APC for genetic aberrations, we conducted direct sequencing of the mutation cluster region (MCR), loss of heterozygosity analyses (LOH) and protein truncation test. Epigenetic analyses included methylation specific PCR and bisulfite genomic sequencing of the APC 1a promoter. Gene expression was determined by quantitative real‐time PCR. Results Aberrant promoter methylation was detected in YSTs, teratomas and mixed malignant GCTs, with a pronounced hypermethylation exclusively in YSTs (11/13) while dysgerminomas were not methylated (0/9). Teratomas (2/2) and YSTs (4/5) show LOH at the APC locus. However, neither mutations within the MCR nor truncated protein were detected. APC expression did not significantly vary between the different histological subgroups. Conclusions Methylation of APC and LOH 5q21‐22 in YSTs and teratomas provide evidence for involvement of APC in the accumulation of β‐catenin and activation of the WNT pathway. Our additional analyses suggest that APC is unlikely to be solely responsible for the formation and progression of childhood GCTs. Pediatr Blood Cancer 2011;56:384–391. © 2010 Wiley‐Liss, Inc.