Background: The sonic hedgehog pathway (SHH) regulates CNS development and mutations or abnormal expression of the SHH pathway genes have been identified in epithelial tumors. SHH pathway interacts with Wnt/β-catenin signalling. To date, CTNNB1/β-catenin mutations are the sole molecular abnormality found in adamantinomatous craniopharyngiomas (ACPs).
Objective and Hypotheses: To analyze the expression pattern of SHH pathway genes in ACPs and its association with CTNNB1 mutations and clinical outcome in patients with ACPs.
Method: Eighteen patients (ten females) with ACPs were analyzed. Mean age at diagnosis was 16.4 years (630). Control tissues included seven normal anterior pituitaries. The mRNA expression of SHH pathway components SHH, PTCH1, SMO, GLI1, GLI2, GLI3 and SUFU was evaluated by qPCR in tumoral and control tissues. Immunohistochemistry (IHC) evaluated SMO, GLI1, GLI3, SUFU, β-catenin and Ki67 expression in ACPs. CTNNB1 gene was directed sequenced on tumoral DNA.
Results: Somatic CTNNB1/β-catenin mutations were found in eight ACPs. Compared to normal pituitary, ACPs presented higher mRNA expression of SHH (+400-fold change-FC; P<0.01), GLI1 (+102 FC; P< 0.001) and GLI3 (+5.1 FC; P<0.01). Interestingly, ACPs harboring CTNNB1/β-catenin mutations presented higher expression of GLI1 (+10.2 FC; P=0.03) and SMO (+4.3 FC; P=0.02) than WT tumors. Higher expression of SMO mRNA associated with disease progression (P<0.01) while lower SMO mRNA expression was associated with longer disease free survival (P<0.01; HR=0.14, 95%CI=0.030.54). Moreover, GLI1 staining was detected in the typical palisade ACPs cells and co-localized with Ki67 staining, which is a marker of cell proliferation.
Conclusion: These results show that the deregulation of the SHH signalling may be an important pathogenic event in ACPs, being associated with disease progression. These abnormalities appear to be more prominent in CTNNB1/β-catenin mutated ACPs. Therefore, inhibition of the SHH pathway may be a novel potential target in adjuvant therapy for ACPs patients.
20 - 22 Sep 2014
European Society for Paediatric Endocrinology