ENDOCRINE TUMORS: BRAF V600E mutations in papillary craniopharyngioma

Brastianos, Priscilla K.; Santagata, Sandro

doi:10.1530/eje-15-0957

Cited by 70 publications

(61 citation statements)

References 58 publications

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“…We also found for the first time to our knowledge that these rare “ciliated craniopharyngioma” cases were positive for the BRAF V600E mutation by genotyping and immunohistochemistry, confirming that these cases are likely more closely related to papillary craniopharyngioma than Rathke’s cleft cysts with extensive squamous metaplasia (22), and that they may also respond favorably to pharmacologic inhibition of MAPK signaling as has been shown in two patients with papillary craniopharyngioma (31,32,47). Given the robust preservation of ciliated epithelium in a recurrent lesion after an extended period of time, it remains unclear whether “ciliated papillary craniopharyngiomas” may represent “transitional lesions”, or a distinct stable phenotype of papillary craniopharyngioma.…”

Section: Discussionsupporting

confidence: 81%

Distinct patterns of primary and motile cilia in Rathke's cleft cysts and craniopharyngioma subtypes

Coy

Sheu

et al. 2016

Modern Pathology

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Cilia are highly conserved organelles which serve critical roles in development and physiology. Motile cilia are expressed in a limited range of tissues, where they principally regulate local extracellular fluid dynamics. In contrast, primary cilia are expressed by many vertebrate cell types during interphase, and are intimately involved in the cell cycle and signal transduction. Notably, primary cilia are essential for vertebrate hedgehog pathway activity. Improved detection of motile cilia may assist in the diagnosis of some pathologic entities such as Rathke’s cleft cysts while characterizing primary cilia in neoplastic tissues may implicate cilia-dependent signaling pathways as critical for tumorigenesis. We show that immunohistochemistry for the nuclear transcription factor FOXJ1, a master regulator of motile ciliogenesis, robustly labels the motile ciliated epithelium of Rathke’s cleft cysts. FOXJ1 expression discriminates Rathke’s cleft cysts from entities in the sellar/suprasellar region with overlapping histologic features such as craniopharyngiomas. Co-immunohistochemistry for FOXJ1 and markers that highlight motile cilia such as acetylated tubulin (TUBA4A) and the small GTPase ARL13B further enhance the ability to identify diagnostic epithelial cells. In addition to highlighting motile cilia, ARL13B immunohistochemistry also robustly highlights primary cilia in formalin-fixed paraffin-embedded sections. Primary cilia are present throughout the neoplastic epithelium of adamantinomatous craniopharyngioma, but are limited to basally oriented cells near the fibrovascular stroma in papillary craniopharyngioma. Consistent with this differing pattern of primary ciliation, adamantinomatous craniopharyngiomas express significantly higher levels of SHH, and downstream targets such as PTCH1 and GLI2, compared to papillary craniopharyngiomas. In conclusion, motile ciliated epithelium can be readily identified using immunohistochemistry for FOXJ1, TUBA4A and ARL13B, facilitating the diagnosis of Rathke’s cleft cyst. Primary cilia can be identified by ARL13B immunohistochemistry in routine pathology specimens. The widespread presence of primary cilia in adamantinomatous craniopharyngioma implicates cilia-dependent hedgehog signaling in the pathogenesis of adamantinomatous craniopharyngioma.

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Section: Discussionsupporting

confidence: 81%

Distinct patterns of primary and motile cilia in Rathke's cleft cysts and craniopharyngioma subtypes

Coy

Sheu

et al. 2016

Modern Pathology

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“…9,28 In the most detailed study to date, CTNNB1 mutation was identified in 95% of ACP specimens, using massively parallel sequencing and targeted genotyping. 5 In the same study, Brastianos and Santagata determined that CTNNB1 mutation was not present in PCP. 5 Other groups have identified CTNNB1 mutation in 70%-80% of ACP specimens.…”

Section: Ctnnb1 Mutationmentioning

confidence: 92%

“…5 In the same study, Brastianos and Santagata determined that CTNNB1 mutation was not present in PCP. 5 Other groups have identified CTNNB1 mutation in 70%-80% of ACP specimens. 9,12,19,31 Sampling error or the significant intratumoral heterogeneity present in these tumors, which often have scant neoplastic epithelium, may explain the variability in the frequency with which CTNNB1 mutation is detected.…”

Section: Ctnnb1 Mutationmentioning

confidence: 92%

“…As such, a multi-institutional trial of combined BRAF and MEK inhibition for patients with PCP is forthcoming. 5 In addition to offering therapeutic potential, the high prevalence of the BRAF v600e mutation in PCP may simplify diagnosis of these tumors. A mutation-specific antibody (clone VE1) recognizes the BRAF v600e mutant protein but not the wild-type protein.…”

Section: Brafmentioning

confidence: 99%

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Potential evolution of neurosurgical treatment paradigms for craniopharyngioma based on genomic and transcriptomic characteristics

Robinson

Santagata

Hankinson

2016

FOC

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The recent genomic and transcriptomic characterization of human craniopharyngiomas has provided important insights into the pathogenesis of these tumors and supports that these tumor types are distinct entities. Critically, the insights provided by these data offer the potential for the introduction of novel therapies and surgical treatment paradigms for these tumors, which are associated with high morbidity rates and morbid conditions. Mutations in the CTNNB1 gene are primary drivers of adamantinomatous craniopharyngioma (ACP) and lead to the accumulation of β-catenin protein in a subset of the nuclei within the neoplastic epithelium of these tumors. Dysregulation of epidermal growth factor receptor (EGFR) and of sonic hedgehog (SHH) signaling in ACP suggest that paracrine oncogenic mechanisms may underlie ACP growth and implicate these signaling pathways as potential targets for therapeutic intervention using directed therapies. Recent work shows that ACP cells have primary cilia, further supporting the potential importance of SHH signaling in the pathogenesis of these tumors. While further preclinical data are needed, directed therapies could defer, or replace, the need for radiation therapy and/or allow for less aggressive surgical interventions. Furthermore, the prospect for reliable control of cystic disease without the need for surgery now exists. Studies of papillary craniopharyngioma (PCP) are more clinically advanced than those for ACP. The vast majority of PCPs harbor the BRAFv600e mutation. There are now 2 reports of patients with PCP that had dramatic therapeutic responses to targeted agents. Ongoing clinical and research studies promise to not only advance our understanding of these challenging tumors but to offer new approaches for patient management.

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“…By contrast, pCP has recently been reported to be characterized by BRAF mutations, all of which are the V600E (Val 600 Glu) mutation . BRAF is a critical component of the mitogen‐activated protein kinase (MAPK) signaling pathway and has been reported in various cancers .…”

Section: Introductionmentioning

confidence: 99%

High‐resolution melting and immunohistochemical analysis efficiently detects mutually exclusive genetic alterations of adamantinomatous and papillary craniopharyngiomas

et al. 2017

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Craniopharyngioma consists of adamantinomatous and papillary subtypes. Recent genetic analysis has demonstrated that the two subtypes are different, not only in clinicopathological features, but also in molecular oncogenesis. Papillary craniopharyngioma (pCP) is characterized by a BRAF mutation, the V600E (Val 600 Glu) mutation. Adamantinomatous craniopharyngioma (aCP) can be distinguished by frequent β-catenin gene (CTNNB1) mutations. Although these genetic alterations can be a diagnostic molecular marker, the precise frequency of these mutations in clinical specimens remains unknown. In this study, we first evaluated BRAF V600E and CTNNB1 mutations in four and 14 cases of pCP and aCP, respectively, using high-resolution melting analysis followed by Sanger sequencing. The results showed that 100% (4/4) of pCP cases had BRAF V600E mutations, while 78% (11/14) of the aCP cases had CTNNB1 mutations, with these genetic alterations being subtype-specific and mutually exclusive. Second, we evaluated BRAF V600E and CTNNB1 mutations by immunohistochemical analysis (IHC). All pCP cases showed positive cytoplasmic staining with the BRAF V600E-mutant antibody (VE-1), whereas 86% (12/14) of aCP cases showed positive cytoplasmic and nuclear staining for CTNNB1, suggesting a CTNNB1 mutation. Only one case of wild-type CTNNB1 on the DNA analysis showed immunopositivity on IHC. We did not detect a coexistence of BRAF V600E and CTNNB1 mutations in any single tumor, which indicated that these genetic alterations were mutually exclusive. We also report our modified IHC protocol for VE-1 staining, and present the possibility that BRAF V600E mutations can be used as a diagnostic marker of pCP in the differentiation of Rathke cleft cyst with squamous metaplasia.

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ENDOCRINE TUMORS: BRAF V600E mutations in papillary craniopharyngioma

Cited by 70 publications

References 58 publications

Distinct patterns of primary and motile cilia in Rathke's cleft cysts and craniopharyngioma subtypes

Distinct patterns of primary and motile cilia in Rathke's cleft cysts and craniopharyngioma subtypes

Potential evolution of neurosurgical treatment paradigms for craniopharyngioma based on genomic and transcriptomic characteristics

High‐resolution melting and immunohistochemical analysis efficiently detects mutually exclusive genetic alterations of adamantinomatous and papillary craniopharyngiomas

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