<em>PTCH1</em> mutant small cell glioblastoma in a patient with Gorlin syndrome: A case report

Dorsey,John T.; Mott,Ryan T.; Lack,Christopher M.; Britt,Nicholas; Ramkissoon,Shakti H.; Morris,Bonny B.; Carter,Annette; Detroye,Alisha T.; Chan,Michael; Tatter,Stephen; Lesser,Glenn J.

doi:10.3892/ol.2022.13446

September-2022 Volume 24 Issue 3

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September-2022 Volume 24 Issue 3

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Case Report Open Access

PTCH1 mutant small cell glioblastoma in a patient with Gorlin syndrome: A case report

Authors:
- John T. Dorsey
- Ryan T. Mott
- Christopher M. Lack
- Nicholas Britt
- Shakti H. Ramkissoon
- Bonny B. Morris
- Annette Carter
- Alisha T. Detroye
- Michael Chan
- Stephen Tatter
- Glenn J. Lesser
View Affiliations / Copyright

Affiliations: Department of Hematology‑Oncology, Cone Health Cancer Center, Greensboro, NC 27403, USA, Department of Pathology, Wake Forest School of Medicine, Winston‑Salem, NC 27157, USA, Department of Radiology, Wake Forest School of Medicine, Winston‑Salem, NC 27157, USA, Department of Pathology, Foundation Medicine, Morrisville, NC 27560, USA, Department of Social Sciences and Health Policy, Wake Forest School of Medicine, Winston‑Salem, NC 27157, USA, Department of Internal Medicine, Section on Hematology and Oncology, Wake Forest School of Medicine, Winston‑Salem, NC 27157, USA, Department of Radiation Oncology, Wake Forest School of Medicine, Winston‑Salem, NC 27157, USA, Department of Neurosurgery, Wake Forest School of Medicine, Winston‑Salem, NC 27157, USA

Copyright: © Dorsey et al. This is an open access article distributed under the terms of Creative Commons Attribution License.
Article Number: 326
|
Published online on: July 27, 2022

https://doi.org/10.3892/ol.2022.13446
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Abstract

Gorlin syndrome or nevoid basal cell carcinoma syndrome is a rare genetic disease characterized by predisposition to congenital defects, basal cell carcinomas and medulloblastoma. The syndrome results from a heritable mutation in PATCHED1 (PTCH1), causing constitutive activation of the Hedgehog pathway. The present study described a patient with Gorlin syndrome who presented early in life with characteristic basal cell carcinomas and later developed a small cell glioblastoma (GBM), World Health Organization grade IV, associated with a Patched 1 (PTCH1) N97fs*43 mutation. Comprehensive genomic profiling of GBM tissues also revealed multiple co‑occurring alterations including cyclin‑dependent kinase 4 (CDK4) amplification, receptor tyrosine‑protein kinase 3 (ERBB3) amplification, a fibroblast growth factor receptor 1 and transforming acidic coiled‑coil containing protein 1 (FGFR1‑TACC1) fusion, zinc finger protein (GLI1) amplification, E3 ubiquitin‑protein ligase (MDM2) amplification and spectrin α chain, erythrocytic 1 (SPTA1) T1151fs*24. After the biopsy, imaging revealed extensive leptomeningeal enhancement intracranially and around the cervical spinal cord due to leptomeningeal disease. The patient underwent craniospinal radiation followed by 6 months of adjuvant temozolomide (150 mg/m²) with good response. She was then treated with vismodegib for 11 months, first combined with temozolomide and then with bevacizumab, until disease progression was noted on MRI, with no significant toxicities associated with the combination therapy. She received additional therapies but ultimately succumbed to the disease four months later. The current study presents the first documentation in the literature of a primary (non‑radiation induced) glioblastoma secondary to Gorlin syndrome. Based on this clinical experience, vismodegib should be considered in combination with standard‑of‑care therapies for patients with known Gorlin syndrome‑associated glioblastomas and sonic hedgehog pathway mutations.

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1	Gorlin RJ and Goltz RW: Multiple nevoid basal-cell epithelioma, jaw cysts and bifid rib. A syndrome. N Engl J Med. 262:908–912. 1960. View Article : Google Scholar : PubMed/NCBI
2	Mortimer PS, Geaney DP, Liddell K and Dawber RP: Basal cell naevus syndrome and intracranial meningioma. J Neurol Neurosurg Psychiatry. 47:210–212. 1984. View Article : Google Scholar : PubMed/NCBI
3	Gorlin Syndrome-Genetics Home Reference-NIH, . [11/9/21]. Available from. https://ghr.nlm.nih.gov/condition/gorlin-syndrome
4	Lo Muzio L, Nocini PF, Savoia A, Consolo U, Procaccini M, Zelante L, Pannone G, Bucci P, Dolci M, Bambini F, et al: Nevoid basal cell carcinoma syndrome. Clinical findings in 37 Italian affected individuals. Clin Genet. 55:34–40. 1999. View Article : Google Scholar : PubMed/NCBI
5	Lo Muzio L: Nevoid basal cell carcinoma syndrome (Gorlin syndrome). Orphanet J Rare Dis. 3:322008. View Article : Google Scholar : PubMed/NCBI
6	Gorlin RJ: Nevoid basal cell carcinoma syndrome. Dermatol Clin. 13:113–125. 1995. View Article : Google Scholar : PubMed/NCBI
7	Anderson DE, Taylor WB, Falls HF and Davidson RT: The nevoid basal cell carcinoma syndrome. Am J Hum Genet. 19:12–22. 1967.PubMed/NCBI
8	Smith MJ, Beetz C, Williams SG, Bhaskar SS, O'Sullivan J, Anderson B, Daly SB, Urquhart JE, Bholah Z, Oudit D, et al: Germline mutations in SUFU cause Gorlin syndrome-associated childhood medulloblastoma and redefine the risk associated with PTCH1 mutations. J Clin Oncol. 32:4155–4161. 2014. View Article : Google Scholar : PubMed/NCBI
9	Gururangan S, Robinson G, Ellison DW, Wu G, He X, Lu QR, McLendon R, Grant G, Driscoll T and Neuberg R: Gorlin syndrome and desmoplastic medulloblastoma: Report of 3 cases with unfavorable clinical course and novel mutations. Pediatr Blood Cancer. 62:1855–1858. 2015. View Article : Google Scholar : PubMed/NCBI
10	Evans DG, Ladusans EJ, Rimmer S, Burnell LD, Thakker N and Farndon PA: Complications of the naevoid basal cell carcinoma syndrome: Results of a population based study. J Med Genet. 30:460–464. 1993. View Article : Google Scholar : PubMed/NCBI
11	Choudry Q, Patel HC, Gurusinghe NT and Evans DG: Radiation-induced brain tumours in nevoid basal cell carcinoma syndrome: Implications for treatment and surveillance. Childs Nerv Syst. 23:133–136. 2007. View Article : Google Scholar : PubMed/NCBI
12	Donev K, Scheithauer BW, Rodriguez FJ and Jenkins S: Expression of diagnostic neuronal markers and outcome in glioblastoma. Neuropathol Appl Neurobiol. 36:411–421. 2010. View Article : Google Scholar : PubMed/NCBI
13	Frampton GM, Fichtenholtz A, Otto GA, Wang K, Downing SR, He J, Schnall-Levin M, White J, Sanford EM, An P, et al: Development and validation of a clinical cancer genomic profiling test based on massively parallel DNA sequencing. Nat Biotechnol. 31:1023–1031. 2013. View Article : Google Scholar : PubMed/NCBI
14	Di Stefano AL, Fucci A, Frattini V, Labussiere M, Mokhtari K, Zoppoli P, Marie Y, Bruno A, Boisselier B, Giry M, et al: Detection, Characterization, and Inhibition of FGFR-TACC Fusions in IDH Wild-type Glioma. Clin Cancer Res. 21:3307–3317. 2015. View Article : Google Scholar : PubMed/NCBI
15	Murone M, Rosenthal A and de Sauvage FJ: Hedgehog signal transduction: From flies to vertebrates. Exp Cell Res. 253:25–33. 1999. View Article : Google Scholar : PubMed/NCBI
16	Hahn H, Wicking C, Zaphiropoulous PG, Gailani MR, Shanley S, Chidambaram A, Vorechovsky I, Holmberg E, Unden AB, Gillies S, et al: Mutations of the human homolog of Drosophila patched in the nevoid basal cell carcinoma syndrome. Cell. 85:841–851. 1996. View Article : Google Scholar : PubMed/NCBI
17	Onodera S, Nakamura Y and Azuma T: Gorlin Syndrome: Recent advances in genetic testing and molecular and cellular biological research. Int J Mol Sci. 21:75592020. View Article : Google Scholar : PubMed/NCBI
18	Skoda AM, Simovic D, Karin V, Kardum V, Vranic S and Serman L: The role of the Hedgehog signaling pathway in cancer: A comprehensive review. Bosn J Basic Med Sci. 18:8–20. 2018. View Article : Google Scholar : PubMed/NCBI
19	Sasai N, Toriyama M and Kondo T: Hedgehog signal and genetic disorders. Front Genet. 10:11032019. View Article : Google Scholar : PubMed/NCBI
20	Dessaud E, Yang LL, Hill K, Cox B, Ulloa F, Ribeiro A, Mynett A, Novitch BG and Briscoe J: Interpretation of the sonic hedgehog morphogen gradient by a temporal adaptation mechanism. Nature. 450:717–720. 2007. View Article : Google Scholar : PubMed/NCBI
21	Cohen M, Kicheva A, Ribeiro A, Blassberg R, Page KM, Barnes CP and Briscoe J: Ptch1 and Gli regulate Shh signalling dynamics via multiple mechanisms. Nat Commun. 6:67092015. View Article : Google Scholar : PubMed/NCBI
22	AACR Project GENIE Consortium, . AACR Project GENIE: Powering precision medicine through an International consortium. Cancer Discov. 7:818–831. 2017. View Article : Google Scholar : PubMed/NCBI
23	Chandra V, Das T, Gulati P, Biswas NK, Rote S, Chatterjee U, Ghosh SN, Deb S, Saha SK, Chowdhury AK, et al: Hedgehog signaling pathway is active in GBM with GLI1 mRNA expression showing a single continuous distribution rather than discrete high/low clusters. PLoS One. 10:e01163902015. View Article : Google Scholar : PubMed/NCBI
24	Cerami E, Gao J, Dogrusoz U, Gross BE, Sumer SO, Aksoy BA, Jacobsen A, Byrne CJ, Heuer ML, Larsson E, et al: The cBio cancer genomics portal: An open platform for exploring multidimensional cancer genomics data. Cancer Discov. 2:401–404. 2012. View Article : Google Scholar : PubMed/NCBI
25	Rohner A, Spilker ME, Lam JL, Pascual B, Bartkowski D, Li QJ, Yang AH, Stevens G, Xu M, Wells PA, et al: Effective targeting of Hedgehog signaling in a medulloblastoma model with PF-5274857, a potent and selective Smoothened antagonist that penetrates the blood-brain barrier. Mol Cancer Ther. 11:57–65. 2012. View Article : Google Scholar : PubMed/NCBI
26	Filbin MG, Dabral SK, Pazyra-Murphy MF, Ramkissoon S, Kung AL, Pak E, Chung J, Theisen MA, Sun Y, Franchetti Y, et al: Coordinate activation of Shh and PI3K signaling in PTEN-deficient glioblastoma: New therapeutic opportunities. Nat Med. 19:1518–1523. 2013. View Article : Google Scholar : PubMed/NCBI
27	Gajjar A, Stewart CF, Ellison DW, Kaste S, Kun LE, Packer RJ, Goldman S, Chintagumpala M, Wallace D, Takebe N, et al: Phase I study of vismodegib in children with recurrent or refractory medulloblastoma: A pediatric brain tumor consortium study. Clin Cancer Res. 19:6305–6312. 2013. View Article : Google Scholar : PubMed/NCBI
28	Robinson GW, Orr BA, Wu G, Gururangan S, Lin T, Qaddoumi I, Packer RJ, Goldman S, Prados MD, Desjardins A, et al: Vismodegib exerts targeted efficacy against recurrent sonic hedgehog-subgroup medulloblastoma: Results from phase II pediatric brain tumor consortium studies PBTC-025B and PBTC-032. J Clin Oncol. 33:2646–2654. 2015. View Article : Google Scholar : PubMed/NCBI
29	Sloan AE, Nock CJ, Ye X, Kerstetter A, Supko J, Rich KLN, Miller R, Takebe N, Prados M and Grossman SA: Targeting glioma-initiating cells in GBM: ABTC-0904, a randomized phase 0/II study targeting the Sonic Hedgehog-signaling pathway. J Clin Oncol. 32 (Suppl 15):S20262014. View Article : Google Scholar