Advances in genetic understand of gorlin syndrome
Published: May 2019
Shawn Shih, Christina Dai, Ahmed Ansari, Brittany A Urso, Amy I Laughlin & James A Solomon
Introduction: Basal cell carcinoma nevus syndrome (BCCNS) is a rare syndrome characterized by multiple basal cell carcinomas (BCC), odontogenic keratocysts, and other abnormalities. The most common etiology, the loss-of-function PTCH1 mutations and consequent constitutive hedgehog signaling, can be blocked by smoothened inhibitors (SIs). However, other causes and alternative pathways have been identified.
Areas covered: Vismodegib and sonidegib are SIs approved for treating advanced BCCs and BCCNS-BCCs, but not without adverse effects. Other SIs include itraconazole, SUBA-itraconazole, and paridegib. Their roles in treating resistance to vismodegib and sonedegib warrant further investigation. Inhibition of downstream hedgehog signaling or PI3K by arsenic trioxide, imiquimod, and busparlisib may control SI resistance. Other potential therapeutic targets to control resistance include TP53, BRCA1, wnt, and SUFU.
Expert opinion: BCCNS is more complex than a genetic disease whose consequences result from the predominant PTCH mutation. Other gene mutations, genetic modulation, stromal and surrounding tissue interactions, as well as molecular and electrical chemical constituents contribute to BCCNS being a complex adaptive system with individual and varying presentations in affected patients. Current technology needs to be applied to elucidate the dynamics of disease activity for individual patients.
Cancer Surveillance in Gorlin Syndrome and Rhabdoid Tumor Predisposition Syndrome
Gorlin syndrome and rhabdoid tumor predisposition syndrome (RTPS) are autosomal dominant syndromes associated with an increased risk of childhood-onset brain tumors. Individuals with Gorlin syndrome can manifest a wide range of phenotypic abnormalities, with about 5% of family members developing medulloblastoma, usually occurring in the first 3 years of life. Gorlin syndrome is associated with germline mutations in components of the Sonic Hedgehog pathway, including Patched1 (PTCH1) and Suppressor of fused (SUFU)SUFU mutation carriers appear to have an especially high risk of early-onset medulloblastoma. Surveillance MRI in the first years of life in SUFU mutation carriers is, therefore, recommended. Given the risk of basal cell carcinomas, regular dermatologic examinations and sun protection are also recommended. Rhabdoid tumors (RT) are tumors initially defined by the descriptive “rhabdoid” term, implying a phenotypic similarity with rhabdomyoblasts at the microscopic level. RTs usually present before the age of 3 and can arise within the cranium as atypical teratoid/rhabdoid tumors or extracranially, especially in the kidney, as malignant rhabdoid tumors. However, RTs of both types share germline and somatic mutations in SMARCB1 or, more rarely, SMARCA4, each of which encodes a chromatin remodeling family member. SMARCA4 mutations are particularly associated with small cell carcinoma of the ovary, hypercalcemic type (SCCOHT). The outcome following a diagnosis of any of these tumors is often poor, and the value of surveillance is unknown. International efforts to determine surveillance protocols are underway, and preliminary recommendations are made for carriers of SMARCB1 and SMARCA4 mutations.
Clin Cancer Res; 23(12); e62-e67. ©2017 AACRSee all articles in the online-only CCR Pediatric Oncology Series.
Gorlin Syndrome (Basal Cell Nevus)
Published: February 8, 2017
Alison M. Spiker; Michael L. Ramsey1.
Gorlin syndrome, also called Gorlin-Goltz syndrome, basal cell nevus syndrome (BCNS), or nevoid basal cell carcinoma syndrome, is an autosomal dominant familial cancer syndrome. It is characterized by numerous basal cell carcinomas (BCCs), along with skeletal, ophthalmologic, and neurologic abnormalities. Multiple neoplasms arise starting in childhood.
Multi-layered mutation in hedgehog-related genes in Gorlin syndrome may affect the phenotype
Gorlin syndrome is a genetic disorder of autosomal dominant inheritance that predisposes the affected individual to a variety of disorders that are attributed largely to heterozygous germline patched1 (PTCH1) mutations. PTCH1 is a hedgehog (Hh) receptor as well as a repressor, mutation of which leads to constitutive activation of Hh pathway. Hh pathway encompasses a wide variety of cellular signaling cascades, which involve several molecules; however, no associated genotype-phenotype correlations have been reported. Recently, mutations in Suppressor of fused homolog (SUFU) or PTCH2 were reported in patients with Gorlin syndrome. These facts suggest that multi-layered mutations in Hh pathway may contribute to the development of Gorlin syndrome. We demonstrated multiple mutations of Hh-related genes in addition to PTCH1, which possibly act in an additive or multiplicative manner and lead to Gorlin syndrome. High-throughput sequencing was performed to analyze exome sequences in four unrelated Gorlin syndrome patient genomes. Mutations in PTCH1 gene were detected in all four patients. Specific nucleotide variations or frameshift variations of PTCH1 were identified along with the inferred amino acid changes in all patients. We further filtered 84 different genes which are closely related to Hh signaling. Fifty three of these had enough coverage of over ×30. The sequencing results were filtered and compared to reduce the number of sequence variants identified in each of the affected individuals. We discovered three genes, PTCH2, BOC, and WNT9b, with mutations with a predicted functional impact assessed by MutationTaster2 or PolyPhen-2 (Polymorphism Phenotyping v2) analysis. It is noticeable that PTCH2 and BOC are Hh receptor molecules. No significant mutations were observed in SUFU. Multi-layered mutations in Hh pathway may change the activation level of the Hh signals, which may explain the wide phenotypic variability of Gorlin syndrome.
Keratocystic Odontogenic Tumor: A Retrospective analysis of genetic, immunohistochemical and therapeutic features. Proposal of a multicenter tool
Michael W. Finkelstein, DDS, MS, John W. Hellstein, DDS, MS, Kimberly S. Lake, BA, and Steven D. Vincent, DDS, MS. 2013. University of Iowa, College of Dentistry, Iowa City, IA. Vol 116, No. 1 July 2013
Features of Basal Cell Carcinoma in Basal Cell Nevus Syndrome
Tom WL, Hurley MY, Oliver DS, Shah MR, Bree AF. 2011. Features of basal cell carcinomas in basal cell nevus syndrome. Am J Med Genet Part A 155:2098–2104.
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Consensus Statement From the First International Colloquium on Basal Cell Nevus Syndrome (BCNS)
Bree AF, Shah MR fore the BCNS Colloquium Group. 2011. Consensus statement from the first international colloquium on basal cell nevus syndrome (BCNS). Am J Med Genet Part A 155-2091-2097.