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.
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.
Authors: Joanie C Neumann; Garvin L Chandler; Vanessa A Damoulis; Nicholas J Fustino; Katherine Lillard; Leendert Looijenga; Linda Margraf; Dinesh Rakheja; James F Amatruda Journal: Proc Natl Acad Sci U S A Date: 2011-07-20 Impact factor: 11.205
Authors: John T Lafin; Alexander P Kenigsberg; Xiaosong Meng; Dreaux Abe; Anna Savelyeva; Nirmish Singla; Solomon L Woldu; Yair Lotan; Ryan J Mauck; Cheryl M Lewis; Vitaly Margulis; Daniel Wong; Liwei Jia; Payal Kapur; Lin Xu; Ryan W Speir; Gregory T Chesnut; A Lindsay Frazier; Douglas W Strand; Nicholas Coleman; Matthew J Murray; James F Amatruda; Aditya Bagrodia Journal: Eur Urol Open Sci Date: 2021-03-05
Authors: Stefan Schönberger; Cornelius van Beekum; Barbara Götz; Daniel Nettersheim; Hubert Schorle; Dominik T Schneider; Anna Casati; Rogerio B Craveiro; Gabriele Calaminus; Dagmar Dilloo Journal: J Cell Mol Med Date: 2017-09-22 Impact factor: 5.310
Authors: Sigrid Marie Kraggerud; Christina E Hoei-Hansen; Sharmini Alagaratnam; Rolf I Skotheim; Vera M Abeler; Ewa Rajpert-De Meyts; Ragnhild A Lothe Journal: Endocr Rev Date: 2013-04-10 Impact factor: 19.871
Authors: Lindsay A Williams; Lauren Mills; Anthony J Hooten; Erica Langer; Michelle Roesler; A Lindsay Frazier; Mark Krailo; Heather H Nelson; Jessica Bestrashniy; James F Amatruda; Jenny N Poynter Journal: Br J Cancer Date: 2018-10-05 Impact factor: 7.640