Molecular Genetics of Basal Cell Naevus Syndrome

Abstract

Basal cell naevus syndrome (BCNS) is an autosomal‐dominant disorder characterised by a triad of basal cell carcinomas, odontogenic keratocysts and cerebral calcifications. Mutations in multiple genes involved in the prooncogenic hedgehog signalling pathway result in aberrant upregulation of this pathway and a propensity for multiple cancers. Recent advances in genetics have promoted the role of mutation analysis, as mutations in specific genes have a prognostic impact. Moreover, specific treatments targeting ligands of the hedgehog signalling pathway allow for more prolonged suppression of tumour development. Resistance development with these treatments may be halted or delayed by combining multiple modalities that target different parts of the hedgehog signalling pathway. Elucidating the genetics of BCNS has facilitated the tailoring of treatment and surveillance.

Key Concepts

  • Basal cell naevus syndrome is a highly penetrant, autosomal‐dominant disorder that is characterised by a triad of basal cell carcinomas, jaw keratocysts and cerebral calcifications.
  • Patients suffer from a genetic mutation in PTCH1, PTCH2, SMO and/or SUFU that allows for overactivation of the prooncogenic hedgehog signalling pathway.
  • Mutations in PTCH2 and SUFU are associated with milder clinical features and lower penetrance.
  • In particular, loss‐of‐function mutations of SUFU result in the absence of odontogenic keratocysts, development of infundibulocystic keratocysts and higher proclivity for medulloblastomas and meningiomas.
  • Molecular genetic testing methods include single gene testing, multigene panels and genomic testing, with a high specificity and sensitivity.
  • Genetic counselling and prenatal testing should be offered to all patients with basal cell naevus syndrome.
  • Treatment consists of destructive, chemotherapeutic and, more recently, genetic inhibitive modalities.
  • Genetic inhibitors are primarily cyclopamine derivatives, including vismodegib and sonidegib.
  • Resistance commonly develops to cyclopamine derivatives; toxic side effects preclude long‐term use.
  • Combination with other genetic inhibitors, such as azoles and arsenic trioxide, can delay resistance development.

Keywords: basal cell naevus syndrome; Gorlin syndrome; basal cell carcinoma; hedgehog signalling pathway; PTCH1; cyclopamine; vismodegib; sonidegib; itraconazole; resistance

Figure 1. Demonstration of downstream effects of the hedgehog signalling pathway. Ligands (SHH) bind to PTCH1, releasing its inhibition on SMO. SMO in turn disables the inhibitor of Gli transcription factors by SUFU. Gli transcription factors translocate to the cell nucleus and upregulate cell proliferation.
Figure 2. Evidence of multiple basal cell carcinomas on the face of patients with basal cell naevus syndrome.
Figure 3. Healed basal cell carcinoma after surgical manipulation. In basal cell naevus syndrome, cancers tend to develop in locations other than sun‐exposed areas.
Figure 4. Palmar pitting in patients with basal cell naevus syndrome.
close

References

Ahn RS (2016) Not the usual suspect: a case of basal cell naevus syndrome caused by a SMO mutation alone. British Journal of Dermatology 175 (1): 21–22.

Ally MS, Ransohoff K, Sarin K, et al. (2016) Effects of combined treatment with arsenic trioxide and itraconazole in patients with refractory metastatic basal cell carcinoma. JAMA Dermatology 152 (4): 452–456.

Athar M, Li C, Kim AL, Spiegelman VS and Bickers DR (2014) Sonic hedgehog signaling in basal cell nevus syndrome. Cancer Research 74 (18): 4967–4975.

Basset‐Seguin N, Hauschild A, Grob JJ, et al. (2015) Vismodegib in patients with advanced basal cell carcinoma (STEVIE): a pre‐planned interim analysis of an international, open‐label trial. Lancet Oncology 16 (6): 729–736.

Bree AF and Shah MR (2011) Consensus statement from the first international colloquium on basal cell nevus syndrome (BCNS). American Journal of Medical Genetics 155A (9): 2091–2097.

Chang AL, Solomon JA, Hainsworth JD, et al. (2014) Expanded access study of patients with advanced basal cell carcinoma treated with the hedgehog pathway inhibitor, vismodegib. Journal of the American Academy of Dermatology 70 (1): 60–69.

Chen B, Trang V, Lee A, et al. (2016) Posaconazole, a second‐generation triazole antifungal drug, inhibits the hedgehog signaling pathway and progression of basal cell carcinoma. Molecular Cancer Therapeutics 15 (5): 866–876.

Cruz‐Migoni SB and Borycki A‐G (2014) Hedgehog signalling. In: eLS. Chichester: John Wiley & Sons, Ltd., http://www.els.net [doi: 10.1002/9780470015902.a0000806.pub2].

Dreno B, Kunstfeld R, Hauschild A, et al. (2017) Two intermittent vismodegib dosing regimens in patients with multiple basal‐cell carcinomas (MIKIE): a randomised, regimen‐controlled, double‐blind, phase 2 trial. Lancet Oncology 18 (3): 404–412.

Dummer R, Guminski A, Gutzmer R, et al. (2016) The 12‐month analysis from basal cell carcinoma outcomes with LDE225 treatment (BOLT): a phase II, randomized, double‐blind study of sonidegib in patients with advanced basal cell carcinoma. Journal of the American Academy of Dermatology 75 (1): 113–125.

Endo M, Fujii K, Sugita K, et al. (2012) Nationwide survey of nevoid basal cell carcinoma syndrome in Japan revealing the low frequency of basal cell carcinoma. American Journal of Medical Genetics 158A (2): 351–357.

Evans DG, Ramsden RT, Shenton A, et al. (2007) Mosaicism in neurofibromatosis type 2: an update of risk based on uni/bilaterality of vestibular schwannoma at presentation and sensitive mutation analysis including multiple ligation‐dependent probe amplification. Journal of Medical Genetics 44 (7): 424–428.

Evans DG and Farndon PA (2015) Nevoid basal cell carcinoma syndrome. In: Adam MP, Ardinger HH, Pagon RA, et al. (eds) GeneReviews. Seattle, WA: University of Washington. https://www.ncbi.nlm.nih.gov/books/NBK1151/.

Fan Z, Li J, Du J, et al. (2008) A missense mutation in PTCH2 underlies dominantly inherited NBCCS in a Chinese family. Journal of Medical Genetics 45 (5): 303–308.

Fan Q, Gu D, Liu H, et al. (2014) Defective TGF‐beta signaling in bone marrow‐derived cells prevents hedgehog‐induced skin tumors. Cancer Research 74 (2): 471–483.

Fujii K, Ohashi H, Suzuki M, et al. (2013) Frameshift mutation in the PTCH2 gene can cause nevoid basal cell carcinoma syndrome. Familial Cancer 12 (4): 611–614.

Gloude NJ, Yoon JM and Crawford JR (2016) Novel PTCH1 mutation in a young child with Gorlin syndrome and medulloblastoma. Pediatric Blood & Cancer 63 (6): 1128–1129.

Gorlin RJ and Goltz RW (1960) Multiple nevoid basal‐cell epithelioma, jaw cysts and bifid rib: a syndrome. New England Journal of Medicine 262: 908–912.

Guo YY, Zhang JY, Li XF, et al. (2013) PTCH1 gene mutations in keratocystic odontogenic tumors: a study of 43 Chinese patients and a systematic review. PLoS One 8 (10): e77305.

Haliasos EC, Kerner M, Jaimes N, et al. (2013) Dermoscopy for the pediatric dermatologist, part II: dermoscopy of genetic syndromes with cutaneous manifestations and pediatric vascular lesions. Pediatric Dermatology 30 (2): 172–181.

Jain S, Song R and Xie J (2017) Sonidegib: mechanism of action, pharmacology, and clinical utility for advanced basal cell carcinomas. OncoTargets and Therapy 10: 1645–1653.

Johansson G, Andersson U and Melin B (2016) Recent developments in brain tumor predisposing syndromes. Acta Oncologica 55 (4): 401–411.

John AM and Schwartz RA (2016) Basal cell naevus syndrome: an update on genetics and treatment. British Journal of Dermatology 174 (1): 68–76.

Khamaysi Z, Bochner R, Indelman M, et al. (2016) Segmental basal cell naevus syndrome caused by an activating mutation in smoothened. British Journal of Dermatology 175 (1): 178–181.

Kijima C, Miyashita T, Suzuki M, Oka H and Fujii K (2012) Two cases of nevoid basal cell carcinoma syndrome associated with meningioma caused by a PTCH1 or SUFU germline mutation. Familial Cancer 11 (4): 565–570.

Kim DJ, Kim J, Spaunhurst K, et al. (2014) Open‐label, exploratory phase II trial of oral itraconazole for the treatment of basal cell carcinoma. Journal of Clinical Oncology 32 (8): 745–751.

Lam C, Ou JC and Billingsley EM (2013) “PTCH”‐ing it together: a basal cell nevus syndrome review. Dermatologic Surgery 39 (11): 1557–1572.

Lindstrom E, Shimokawa T, Toftgard R and Zaphiropoulos PG (2006) PTCH mutations: distribution and analyses. Human Mutation 27 (3): 215–219.

Lo Muzio L, Pastorino L, Levanat S, et al. (2013) Clinical utility gene card for: Gorlin syndrome – update 2013. European Journal of Human Genetics 21 (10): 299.

Metcalfe C and de Sauvage FJ (2011) Hedgehog fights back: mechanisms of acquired resistance against smoothened antagonists. Cancer Research 71 (15): 5057–5061.

Meyers‐Needham M, Lewis JA, Gencer S, et al. (2012) Off‐target function of the sonic hedgehog inhibitor cyclopamine in mediating apoptosis via nitric oxide‐dependent neutral sphingomyelinase 2/ceramide induction. Molecular Cancer Therapeutics 11 (5): 1092–1102.

Migden MR, Guminski A, Gutzmer R, et al. (2015) Treatment with two different doses of sonidegib in patients with locally advanced or metastatic basal cell carcinoma (BOLT): a multicentre, randomised, double‐blind phase 2 trial. Lancet Oncology 16 (6): 716–728.

North JP, McCalmont TH and LeBoit P (2012) Palmar pits associated with the nevoid basal cell carcinoma syndrome. Journal of Cutaneous Pathology 39 (8): 735–738.

Nusslein‐Volhard C and Wieschaus E (1980) Mutations affecting segment number and polarity in Drosophila. Nature 287 (5785): 795–801.

Ozcan G, Balta B, Sekerci AE, et al. (2016) A novel PTCH1 gene mutation in a pediatric patient associated multiple keratocystic odontogenic tumors of the jaws and Gorlin‐Goltz syndrome. Indian Journal of Pathology & Microbiology 59 (3): 335–338.

Pastorino L, Ghiorzo P, Nasti S, et al. (2009) Identification of a SUFU germline mutation in a family with Gorlin syndrome. American Journal of Medical Genetics 149A (7): 1539–1543.

Pierard‐Franchimont C, Hermanns‐Le T, Paquet P, et al. (2015) Hedgehog‐ and mTOR‐targeted therapies for advanced basal cell carcinomas. Future Oncology 11 (22): 2997–3002.

Reinders MG, Boersma HJ, Leter EM, et al. (2017) Postzygotic mosaicism in basal cell naevus syndrome. British Journal of Dermatology 177 (1): 249–252.

Schulman JM, Oh DH, Sanborn JZ, et al. (2016) Multiple hereditary infundibulocystic basal cell carcinoma syndrome associated with a germline SUFU mutation. JAMA Dermatology 152 (3): 323–327.

Sekulic A, Migden MR, Oro AE, et al. (2012) Efficacy and safety of vismodegib in advanced basal‐cell carcinoma. New England Journal of Medicine 366 (23): 2171–2179.

Sekulic A, Mangold AR, Northfelt DW and LoRusso PM (2013) Advanced basal cell carcinoma of the skin: targeting the hedgehog pathway. Current Opinion in Oncology 25 (3): 218–223.

Sekulic A, Migden MR, Lewis K, et al. (2015) Pivotal ERIVANCE basal cell carcinoma (BCC) study: 12‐month update of efficacy and safety of vismodegib in advanced BCC. Journal of the American Academy of Dermatology 72 (6): 1021–1026.

Smith MJ, Beetz C, Williams SG, et al. (2014) Germline mutations in SUFU cause Gorlin syndrome‐associated childhood medulloblastoma and redefine the risk associated with PTCH1 mutations. Journal of Clinical Oncology 32 (36): 4155–4161.

Veenstra‐Knol HE, Scheewe JH, van der Vlist GJ, van Doorn ME and Ausems MG (2005) Early recognition of basal cell naevus syndrome. European Journal of Pediatrics 164 (3): 126–130.

Von Hoff DD, LoRusso PM, Rudin CM, et al. (2009) Inhibition of the hedgehog pathway in advanced basal‐cell carcinoma. New England Journal of Medicine 361 (12): 1164–1172.

Wahid M, Jawed A, Mandal RK, et al. (2016) Vismodegib, itraconazole and sonidegib as hedgehog pathway inhibitors and their relative competencies in the treatment of basal cell carcinomas. Critical Reviews in Oncology/Hematology 98: 235–241.

Wang C, Wu H, Katritch V, et al. (2013) Structure of the human smoothened receptor bound to an antitumour agent. Nature 497 (7449): 338–343.

Yin VT, Merritt H and Esmaeli B (2014) Targeting EGFR and sonic hedgehog pathways for locally advanced eyelid and periocular carcinomas. World Journal of Clinical Cases 2 (9): 432–438.

Further Reading

Ally MS, Ransohoff K, Sarin K, et al. (2016) Effects of combined treatment with arsenic trioxide and itraconazole in patients with refractory metastatic basal cell carcinoma. JAMA Dermatology 152 (4): 452–456.

Athar M, Li C, Kim AL, Spiegelman VS and Bickers DR (2014) Sonic hedgehog signaling in basal cell nevus syndrome. Cancer Research 74 (18): 4967–4975.

Basset‐Seguin N, Hauschild A, Grob JJ, et al. (2015) Vismodegib in patients with advanced basal cell carcinoma (STEVIE): a pre‐planned interim analysis of an international, open‐label trial. Lancet Oncology 16 (6): 729–736.

Dreno B, Kunstfeld R, Hauschild A, et al. (2017) Two intermittent vismodegib dosing regimens in patients with multiple basal‐cell carcinomas (MIKIE): a randomised, regimen‐controlled, double‐blind, phase 2 trial. Lancet Oncology 18 (3): 404–412.

Dummer R, Guminski A, Gutzmer R, et al. (2016) The 12‐month analysis from basal cell carcinoma outcomes with LDE225 treatment (BOLT): a phase II, randomized, double‐blind study of sonidegib in patients with advanced basal cell carcinoma. Journal of the American Academy of Dermatology 75 (1): 113–125.

John AM and Schwartz RA (2016) Basal cell naevus syndrome: an update on genetics and treatment. British Journal of Dermatology 174 (1): 68–76.

Migden MR, Guminski A, Gutzmer R, et al. (2015) Treatment with two different doses of sonidegib in patients with locally advanced or metastatic basal cell carcinoma (BOLT): a multicentre, randomised, double‐blind phase 2 trial. Lancet Oncology 16 (6): 716–728.

Sekulic A, Migden MR, Oro AE, et al. (2012) Efficacy and safety of vismodegib in advanced basal‐cell carcinoma. New England Journal of Medicine 366 (23): 2171–2179.

Sekulic A, Migden MR, Lewis K, et al. (2015) Pivotal ERIVANCE basal cell carcinoma (BCC) study: 12‐month update of efficacy and safety of vismodegib in advanced BCC. Journal of the American Academy of Dermatology 72 (6): 1021–1026.

Contact Editor close
Submit a note to the editor about this article by filling in the form below.

* Required Field

How to Cite close
John, Ann M, and Schwartz, Robert A(Mar 2018) Molecular Genetics of Basal Cell Naevus Syndrome. In: eLS. John Wiley & Sons Ltd, Chichester. http://www.els.net [doi: 10.1002/9780470015902.a0027325]