Gorlin Syndrome Research

Efficacy of Sunscreen for Prevention of BCCs in Gorlin Syndrome Patients

By Reid Waldman, MD – University of Connecticut Health Center Department of Dermatology
Submitted to the BCCNS Alliance: December 2018

Dr. Jane Grant-Kels and I wanted to thank the BCCNS Alliance with a special acknowledgment to all of you who participated in our recent study titled “Survey Assessing the Efficacy of Sunscreen for Prevention of Basal Cell Carcinoma in Individuals with Basal Cell Carcinoma Nevus Syndrome.”  For this study, we administered a survey to individuals with BCCNS that asked about sunscreen use patterns and frequency of basal cell carcinoma development.  The study was designed to build on recent research published by Dr. Jean Tang and colleagues in JAMA Dermatology titled “Risk factors for basal cell carcinoma among patients with basal cell nevus syndrome: development of a basal cell nevus syndrome patient registry” which suggested that BCC development in individuals with BCCNS is triggered by sun exposure.  Based on their finding that individuals with BCCNS develop BCCs from sun exposure, we set out to determine whether blocking sun exposure by applying sunscreen decreases the rate of BCC development in individuals with BCCNS.  Importantly, the efficacy of sunscreen for preventing BCCs in individuals with BCCNS has never previously been demonstrated despite the fact that sunscreen use is frequently recommended for the prevention of BCC development.

At the onset of this study, we had three main goals that motivated studying whether sunscreen is effective at preventing BCCs in individuals with BCCNS:

  1. this would support that individuals with BCCNS should in fact be using sunscreen;
  2. this would demonstrate that BCC prevention strategies that are employed in individuals without BCCNS may be effective for individuals with BCCNS; and
  3. this would help encourage additional funding of research into BCCNS as it would demonstrate that findings from studies that focused on preventing BCC development in individuals with BCCNS would also be applicable to individuals without BCCNS.

With all of this in mind, we are pleased to announce that the study has had several findings that we hope will be used for guiding future research and for directing care of individuals with BCCNS:

  • Sunscreen use does in fact appear to be associated with decreased rates of BCC development in individuals with BCCNS. Importantly, our statistical analysis did not reach statistical significance; however, we attribute this to having a small sample size as clear trends in the data supporting this finding were seen.
  • Childhood sunscreen use is important for preventing BCCs too! This is especially important as our study showed that many children with BCCNS are not beginning to use sunscreen until after they develop their first BCC.
  • The majority of individuals we surveyed are doing an excellent job applying sunscreen frequently.

In conclusion, Dr. Grant-Kels and I are hopeful that our study spurs additional research into BCCNS as it highlights that researching BCCNS helps all individuals at risk of developing BCCs. Furthermore, we are hopeful that our research encourages individuals with BCCNS, including children who have not yet developed a BCC, to develop excellent sun protection habits as it is likely that doing so will help decrease their rate of BCC development.

Again, thank you all for your assistance! We are very grateful to have had this opportunity.

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

Abstract

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.

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Cancer Surveillance in Gorlin Syndrome and Rhabdoid Tumor Predisposition Syndrome

Published:  June 2017
William D. Foulkes, Junne Kamihara, D. Gareth R. Evans, Laurence Brugières, Franck Bourdeaut, Jan J. Molenaar, Michael F. Walsh, Garrett M. Brodeur and Lisa Diller
DOI: 10.1158/1078-0432.CCR-17-0595Abstract
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.

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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.

Introduction

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.

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Multi-layered mutation in hedgehog-related genes in Gorlin syndrome may affect the phenotype

Published: September 15, 2017
Shoko Onodera, Conceptualization, Data curation,1,2 Akiko Saito, Data curation,1 Daigo Hasegawa, Resources,3 Nana Morita, Resources,4 Katsuhito Watanabe, Resources,3 Takeshi Nomura, Resources,4 Takahiko Shibahara, Resources,3 Shinsuke Ohba, Writing – review & editing,2 Akira Yamaguchi, Writing – review & editing,5 and Toshifumi Azuma, Conceptualization, Supervision1,5,*Alvaro Galli, EditorAbstract

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.

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Keratocystic Odontogenic Tumor: A Retrospective analysis of genetic, immunohistochemical and therapeutic features. Proposal of a multicenter tool

Published: 2013

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

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Features of Basal Cell Carcinoma in Basal Cell Nevus Syndrome

Published: 2011

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)

Published: 2011

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.

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