Abstract A45: Novel SUFU splice mutation in a child with multiple tumors
Authors: Walsh Michael F. , Harlan Megan , Kennedy Jennifer , Musinsky Jacob , LaQuaglia Michael , Stadler Zsofia , Gilheeney Stephan , Offit Kenneth 
Published: May 2016

Abstract
The heritable basis of medulloblastoma is largely unknown. Genes in DNA stability (BRCA1/2), DNA damage (TP53), Sonic Hedgehog-Patched-Gli signaling (PTCH1, SUFU) and WNT signaling pathways (APC) when mutated predispose to brain tumor development. Identification of syndromic stigmata identified before the evolution of malignancy provides an opportunity for screening and family planning. However, given the rarity of these syndromes, incomplete genotype/phenotype description and variable penetrance, outcome data and recommendations founded on expansive evidence are lacking.
Gorlin syndrome (OMIM: 109400) is a phakomatosis distinguished by multiple jaw keratinocytes, basal cell carcinomas, macrocephaly, bossing of the forehead, coarse facial features, and milia. Other features described include skeletal anomalies, ectopic calcification in the falx, cardiac and ovarian fibromas, and primitive neuroectodermal tumors. Moreover, patients are exquisitely sensitive to radiation and sun exposure. Mutations in PTCH1 and SUFU underpin Gorlin syndrome or Nevoid Basal Cell Carcinoma Syndrome.
Here we describe a 9 year-old female with a history of desmoplastic medulloblastoma, ovarian fibrothecoma and meningioma. The child's treatment to date has included chemotherapy, autologous stem cell transplantation, and intrathecal chemotherapy for her brain tumor and surgical resection of her ovarian tumors. The patient's family history was salient for a paternal aunt diagnosed with a meningioma at 18 years of age and paternal grandfather diagnosed with leukemia in his late 50s. Diagnosis of desmoplastic medulloblastoma at age 3 years and having a family history young onset meningioma, Gorlin syndrome was queried and prompted PTCH1 and SUFU molecular genetic testing.
Testing revealed a novel heterozygous germline SUFU mutation, c.1023-2A&gt;T mutation predicted to lead to aberrant splicing and a heterozygous germline PTCH1, c_6_-4delGGC, pre-coding variant of uncertain significance. The SUFU mutation segregated on the paternal side consistent with the family history. A familial exome analysis is underway in efforts to understand disease penetrance in this family. At present, in the absence of guidelines differentiating screening for individuals with SUFU vs. PTCH1 mutations, family members harboring the SUFU mutation are being surveyed with Gorlin syndrome recommendations and increased neuroimaging. Given limited remaining therapeutic options, if the proband is judged to require adjuvant treatment in the future, targeted molecular agents against smoothened (SMO) with vismodegib which has been shown to be an effective therapeutic intervention for patients with PTCH1 mutations are potential considerations.
In conclusion, utilizing genomic sequencing we have detected a novel SUFU mutation in a child with multiple cancers and family history consistent with mutations in the Sonic Hedgehog-Patched-Gli pathway. In the absence of genotype/phenotype specific guidelines, Gorlin syndrome recommendations including intensive brain MRI are being followed and given the paucity of data related to outcome for targeted therapies in children with pathogenic SUFU mutations further investigations are warranted.
Citation Format: Michael F. Walsh, Megan Harlan, Jennifer Kennedy, Jacob Musinsky, Michael LaQuaglia, Zsofia Stadler, Stephan Gilheeney, Kenneth Offit. Novel SUFU splice mutation in a child with multiple tumors. [abstract]. In: Proceedings of the AACR Special Conference on Advances in Pediatric Cancer Research: From Mechanisms and Models to Treatment and Survivorship; 2015 Nov 9-12; Fort Lauderdale, FL. Philadelphia (PA): AACR; Cancer Res 2016;76(5 Suppl):Abstract nr A45.