NONCANONICAL AND CANONICAL WNT PATHWAYS ABNORMALITIES IN PEDIATRIC AND ADULT ADRENOCORTICAL TUMORS

Program: Abstracts - Orals, Featured Poster Presentations, and Posters
Session: MON 1-36-Adrenal Incidentaloma & Carcinoma
Clinical
Monday, June 17, 2013: 1:45 PM-3:45 PM
Expo Halls ABC (Moscone Center)

Poster Board MON-17
Livia Mara Mermejo*1, Leticia Ferro Leal1, Leandro Machado Colli1, Maria Candida Barisson Villares Fragoso2, Ana Claudia Latronico3, Luis Gonzaga Tone1, Carlos Scrideli1, Silvio Tucci1, Carlos Eduardo Martinelli1, Jose Andres Yunes4, Maria Jose Mastellaro4, Ana Luiza Seidinger4, Silvia Regina Brandalise4, Ayrton Custodio Moreira1, Leandra Naira Ramalho5, Sonir Roberto Antonini1 and Margaret De Castro1
1School of Medicine of Ribeirao Preto-University of Sao Paulo, Ribeirao Preto-SP, Brazil, 2University of Sao Paulo, Sao Paulo-SP, Brazil, 3Sao Paulo Medical School, Sao Paulo, Brazil, Sao Paulo, Brazil, 4Boldrini Children's Center, Campinas-SP, Brazil, 5School of Medicine of Ribeirao Preto - University of Sao Paulo, Ribeirao Preto-SP, Brazil
Canonical Wnt signaling pathway abnormalities have been described in adrenocortical tumors (ACT), but the role of noncanonical Wnt pathways planar cell polarity (PCP) and calcium-dependent (Wnt/Ca) is still unknown.

Objectives: To investigate the expression of noncanonical (Wnt/PCP and Wnt/Ca) and canonical Wnt-related genes in ACTs and its relationship with clinical outcome, TP53 and CTNNB1 mutations in pediatric and adult ACTs.

Methods: Ninety-one ACTs (66 children; 25 adults) were evaluated. The mRNA levels of 29 canonical and noncanonical Wnt-related genes were assessed by qPCR. Results were compared to 8 normal adrenal tissues. Protein expression was evaluated by immunohistochemistry (IHC).

Results: The p.R337H P53 mutation was more prevalent in children (88% vs. 28%; p<0.0001) and CTNNB1 mutations in adults (32% vs. 6%; p<0.006). Only in adults mortality was higher in p.R337H P53 carriers (87,5% vs. 17,5%; Log-rank test p=0.002). CTNNB1 mutations did not associated with mortality in adults (50% vs. 44%; ns) but did in children (75% vs. 15%; Log-rank test p=0.0003). Pediatric and adult ACTs overexpressed Wnt/Ca ligand WNT5A and Wnt/PCP effector MAPK8. Conversely, Wnt/PCP mediators were downregulated: PRICKLE in pediatric and adult, and VANGL1 in adult ACTs. Overall, the expression pattern of noncanonical Wnt-related genes did not differ between pediatric and adult ACTs. Regarding canonical Wnt pathway, pediatric and adult ACTs presented increased CTNNB1 expression and decreased DKK3, MYC and TCF7 mRNA expression. Whereas decreased SFRP1 and AXIN1 mRNA expression was found only in pediatric ACTs. Pediatric ACTs exhibited lower DKK3 and WNT4 mRNA than adult ACTs. IHC showed cytoplasmic and nuclear β-catenin, nuclear P53 and the noncanonical proteins NFAT and JNK (MAPK8) accumulation in most ACTs. In adults, poor survival was associated with lower expression of TP53 (p=0.02) and Wnt/PCP PRICKLE (p=0.05). In children, higher survival was associated with lower SFRP1 (p=0.0002) and WNT4 mRNA expression (p=0.05).

Conclusions: p.R337H P53 and CTNNB1 mutations correlated with poor prognosis in adults and children, respectively. Adult and pediatric ACTs presented abnormal expression of Wnt canonical genes, irrespectively to CTNNB1 mutations. Overexpression of ligands and effectors of noncanonical Wnt/Ca and Wnt/PCP was found in pediatric and adult ACTs. These original data suggest the involvement of Wnt noncanonical pathways in adrenocortical tumorigenesis.

Nothing to Disclose: LMM, LFL, LMC, MCBVF, ACL, LGT, CS, ST, CEM, JAY, MJM, ALS, SRB, ACM, LNR, SRA, MD

*Please take note of The Endocrine Society's News Embargo Policy at http://www.endo-society.org/endo2013/media.cfm

Sources of Research Support: FAPESP 2008/09276-0