ESPE Abstracts (2019) 92 FC11.4

ESPE2019 Free Communications Pituitary, Neuroendocrinology and Puberty Session 2 (6 abstracts)

Whole Exome Sequencing in a Familial Case of Adamantinomatous Craniopharyngioma Revealed Two Hits Affecting Wnt-Signaling Pathway

Alexander Gorelyshev 1 , Nadezhda Mazerkina 2 , Evgeny Vasilyev 1 , Vasily Petrov 1 , Marina Ryzhova 2 , Sergey Gorelyshev 2 & Anatoly Tiulpakov 1

1Endocrinology Research Centre, Moscow, Russian Federation. 2NN Burdenko Neurosurgical Institute, Moscow, Russian Federation

Background: Craniopharyngiomas (CPs) are benign brain tumours that intimately involve pituitary and, often, hypothalamus. Here, primary clinical conundrum is choosing between gross total resection and preserving endocrine functions. Robust predictors of recurrence are much needed, but require a deeper understanding of the molecular basis of CPs. Multiple studies show that CTNNB1 (β-catenin) somatic mutations drive the adamantinomatous subtype (adaCP). However, many adaCPs feature intact CTNNB1, suggesting that these tumours may also arise from other defects in the Wnt signaling pathway. In this study, we present a familial case of adaCP revealing a second-hit somatic mutation in APC---a widely recognized regulator of the Wnt-signaling pathway, where β-catenin is the primary effector.

Subjects & Methods: We studied a family with two maternal half-sisters (current age, 19 and 26 years) who underwent surgery for CP at the age of 14 and 15 years, respectively. We obtained blood samples from both siblings, their mother and father of the younger child (proband), as well as fresh frozen tumor samples from the proband. Whole exome sequencing of these samples was performed on Illumina NextSeq platform. The regions with mutations of interest were additionally analyzed by Sanger sequencing.

Results: Three family members (both siblings and their mother) share a novel heterozygous germline c.7455_7458delTCCT:p.S2487FfsX28 variant in APC gene. This variant is predicted to disrupt C-terminal domains binding microtubule-associated proteins EB1 and DLG. In proband, whole exome sequencing of the tumor sample showed intact CTNNB1; however, we discovered another variant in APC gene (c.904C>T:p.R302X). R302X variant is reportedly associated with familial adenomatous polyposis (FAP) and results in a loss of all APC domains required for β-catenin inactivation. Additional studies using TA cloning and Sanger sequencing of GRCh37/hg19_chr5:112151102-112154104 region encompassing c.904C position and polymorphic variant rs12656359 confirmed that the somatic mutation occurred on paternal allele. Histological evaluation of FFPE specimens confirmed adaCP in both children.

Conclusion: To our knowledge, this is the first evidence to show that mutations in APC may recapitulate classic clinical and histological features of an adaCP in the presence of intact CTNNB1 gene.

Volume 92

58th Annual ESPE

Vienna, Austria
19 Sep 2019 - 21 Sep 2019

European Society for Paediatric Endocrinology 

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