Mutations In PTCH1 Gene Research Articles

Metatypical BCC of The Ear: Partial Amputation of The Auricle as Adequate Dermatosurgical Approach

Non-melanoma skin cancer is the most common cancer in the world (1). Basal cell carcinoma (BCC) is the most common malignant neoplasia of the skin, accounting for approximately 80% of all cutaneous tumors (2). High cumulative ultraviolet (UV) light exposure and the presence of Fitzpatrick skin phototype I or II are pathogenetic risk factors (3). UV radiation induces mutations in the tumor suppressor PTCH1 gene, leading to increased Hedgehog (XX/Hh) signaling pathway activity (4). Dysfunction or abnormal activation of the Hedgehog signaling pathway is associated with disorders of embryonic development and the development of cancers such as Goltz–Gorlin syndrome for example (5). BCC has the characteristics of a locally invasive, slow-growing skin cancer, with a metastatic incidence between 0.0028-0.5%, with areas in the head and neck most commonly affected (6). Metatypical basal cell carcinoma (MTBCC) is a rare variant of BCC that has histopathological characteristics of both basal cell carcinoma (BCC) and squamous cell carcinoma (SCC) (7).

Concurrent medulloblastoma and cardiac fibroma: a rare presentation of Gorlin-Goltz syndrome.

Gorlin-Goltz syndrome is a rare autosomal dominant disorder resulting from PTCH1 gene mutation and presents with variable clinical manifestations. The co-occurrence of medulloblastoma and cardiac fibroma in Gorlin-Goltz syndrome is extremely rare. The present article discusses a patient diagnosed with Gorlin-Goltz syndrome and concurrent medulloblastoma and cardiac fibroma. A 19-month-old boy transferred to our hospital after a radiological finding of posterior fossa lesion and hydrocephalus. A pericardial mass was noted after persistent arrhythmias. Both tumors were excised for definitive management. The histopathological sections were diagnostic of desmoplastic nodular medulloblastoma, WHO grade 4 and cardiac fibroma. Molecular and genetic investigations confirmed a pathogenic variant of PTCH1 gene, suggestive of autosomal dominant Gorlin-Goltz syndrome. Co-occurrence of medulloblastoma and cardiac fibroma is extremely rare and poses a management dilemma. Genetic counseling and antenatal screening are of utmost importance to early detect and manage patients with Gorlin-Goltz syndrome.

Epidermal nevus syndrome with the mutation of PTCH1 gene and cerebral infarction: a case report and review of the literature

BackgroundEpidermal nevus syndrome is a group of congenital neuroectodermal and/or mesodermal disorders characterized by the epidermal nevi in common association with cerebral, eye, skeletal, cardiovascular, and renal abnormalities. Epidermal nevus syndrome is a rare syndrome, and epidermal nevus syndrome with the mutation of PTCH1 gene and cerebral infarction is even rarer and has not been reported to the best of our knowledge.Case presentationWe report the case of a 10-month-old Chinese female patient who presented to our pediatric neurologic department, University of Wenzhou medical teaching Hospital, Hangzhou. She has mobility disorders on the right limbs and recurrent seizures. She had congenital disorder accompanied by brownish-black and verrucose plaques on the right side of the face as well as extensive brownish-black plaques and brown nevi on the right side of the trunk and the right arm. Epidermal nevus syndrome was diagnosed on the basis of her symptoms. Somatic sebaceous nevi and hypoplastic defects of skin, cerebra, eyes, skeleton, and cardiovascular and renal system were observed. However, in addition to the typical clinical characteristics, the patient also has a mutation (c.109G > T) in PTCH1 gene and cerebral infarction. We present a novel case report and literature review.ConclusionTo our knowledge, epidermal nevus syndrome with a mutation of PTCH1 gene and cerebral infarction has not been reported previously. This case report may contribute to characterizing the phenotype of epidermal nevus syndrome, help clinicians be aware of the association of this condition with PTCH1 gene and cerebral infarction, raise clinical suspicion, and improve early therapy.

Detection of SMO gene mutations in odontogenic keratocyst

Objective: To detect the SMO mutations in odontogenic keratocyst (OKC) and to explore the mechanism behind. Methods: Patients with OKC who received treatment in the Department of Oral and Maxillofacial Surgery, School and Hospital of Stomatology,Peking University, from September 2012 to June 2017 were enrolled. OKC samples from 10 patients diagnosed as naevoid basal cell carcinoma syndrome (NBCCS)-related OKC (4 females and 6 males) and 20 patients diagnosed as sporadic OKC (7 females and 13 males) were collected. Genomic DNAs were extracted from fibrous capsules and epithelial lining respectively. SMO mutations were detected and analyzed by Sanger sequencing. Results: Three SMO mutations were found in one NBCCS-associated OKC who carrying c.2081C>G (p.P694R) mutation) and two sporadic OKC who carrying c.907C>T (p.L303F) mutation and c.1247_1248delinsAA (p.G416E), respectively), among which the first two mutations were novel mutations that had not been reported before. Besides, two mutations in sporadic OKC were not paired with PTCH1 mutations. Conclusions: In addition to PTCH1 gene mutations, SMO gene mutations also exist in OKC which might be related to the development of OKC.

Aberrant activation of the Hedgehog signalling pathway in squamous cell carcinoma of the vulva as a potential target for cancer therapy

In a previous study, we showed that the Hedgehog (Hh) signalling pathway is aberrantly activated in vulval squamous cell carcinoma (VSCC). In this study, we further validated our findings on a prospective cohort of primary VSCC cases, where immunohistochemical staining confirmed that key Hh pathway components were overexpressed in VSCC compared to normal vulval epithelium. We also undertook a series of in vitro studies to determine the extent of Hh pathway activation in VSCC-derived cell lines, and examine the consequences of pathway inhibition on the growth of these cells. We found that of six cell lines tested, four displayed elevated baseline Hh pathway activity that was dependent on SHH ligand, or in one case, a PTCH1 gene mutation. Hh signalling appeared necessary to sustain cell growth, as SHH ligand depletion with Robotikinin or SMO inhibition, either with chemical inhibitors (Itraconazole or LDE-225) or SMO-specific siRNA, attenuated GLI1 activity and cell proliferation in both monolayer and organotypic raft culture. Furthermore, treatment of Hh-dependent cell lines with SMO inhibitors sensitised cells to Cisplatin. Findings from our study offer us the opportunity to explore further the development of targeted chemotherapy for women with VSCC driven by aberrant Hh activation.

ODONTOGENIC KERATOCYST - THE ROLE OF PTCH1 AND HEDGEHOG SIGNALING IN ITS PATHOGENESIS

Objectives Mutations in PTCH1gene, a receptor in the Hedgehog (Hh) signaling, are responsible for Gorlin syndrome (GS) and are related in tumors associated with this syndrome. The aims of this series of studies were to determine the role of PTCH1 mutation and misregulation of the Hh signaling in the pathogenesis of GS-related and sporadic odontogenic keratocysts (OKCs). Findings Based on screening of 73 sporadic and 30 GS-related OKCs, we identified PTCH1 mutations in 35.6% (somatic, 26/73) of sporadic cases and 83.3% (germ-line, 25/30) of GS-related OKCs. However, a much higher mutation rate (79%, 30/38) in sporadic OKCs was detected by analyzing epithelial samples separated from the fibrous capsules. The previously underestimated mutation rate in sporadic cases might be due to the masking effect of the attached stromal tissues. Mutations in other genes of the Hh signaling such as PTCH2, SUFU, and SMO were rare and their pathologic roles in OKC were uncertain. Using whole-exome sequencing (WES), we further characterized the mutational landscape of 5 OKC samples lacking PTCH1 mutation and revealed 22 novel mutations, among which two significantly altered genes (CDON and MAPK1) were predicted to affect Hh signaling activity in two cases. However no recurrent mutations were identified in the WES samples and validation cohort of 10 OKCs. Functional analysis revealed that PTCH1 mutations activated Hh signaling and resulted in aberrant cell proliferation via both classical and non-canonical Hh pathways. Conclusions Our data confirmed the high PTCH1mutation rate in both GS-related and sporadic OKCs. In PTCH1-negative cases, other genetic alterations were rare, but could also be related to Hh signaling. These results suggested that an inhibitor of the Hh pathway may be effective for the treatment of OKCs.

681 Development of a topical Hedgehog inhibitor for prevention of new surgically eligible basal cell carcinomas in patients with Gorlin Syndrome: Phase 3 trial

Identification of PTCH1 gene mutations in the Gorlin syndrome two decades ago led to the development of small molecule Hedgehog (HH) inhibitors that replace the function of the mutant gene. These drugs have remarkable oral efficacy against advanced BCCs and off-label vs. the multiple BCCs in patients with Gorlin syndrome. Unfortunately, on target, extra-cutaneous adverse effects cause patients to stop these drugs, after which BCCs in complete clinical and histologic remission generally recur. Therefore, PellePharm is developing a small molecule HH inhibitor for topical use. Our goal is to develop a drug that produces skin concentrations high enough to inhibit HH signaling but not so high that circulating levels produce the unwanted adverse effects. We have incorporated the cyclopamine derivative patidegib into a gel that in two Phase 2 trials has demonstrated efficacy potential vs. BCCs - complete response (12 of 45 tumors in patidegib topical gel arms vs. 0 of 16 in vehicle) and fewer new BCCs (3 out of 12 subjects in patidegib topical gel arms vs. 3 out of 5 in vehicle; ITT one-sided P=0.05); with none of the significant oral HH inhibitor class adverse events observed. Very low to undetectable systemic exposure of the drug has been observed - circulating levels 500-1000x lower than those when patidegib is administered orally. These data suggest that the benefit-risk of patidegib topical gel in patients with Gorlin syndrome is positive. Therefore, we have initiated a Phase 3 Trial in North America and Europe with the aim of enrolling 150 Gorlin subjects randomized 1:1 for application of active vs. placebo gel to the face for a year, testing prevention of the development of new surgically eligible BCCs (ClinicalTrials.gov Identifier: NCT03703310). Patients interested in participating and clinicians interested in more details can contact us at [email protected]

The BRAF p.V600E mutation is a common event in ameloblastomas but is absent in odontogenic keratocysts.

Odontogenic keratocysts (OKCs) are jaw lesions with a tendency to recur. PTCH1 gene mutations are common events in most OKCs; however, other genetic alterations underlying OKC pathogenesis have not yet been elucidated. BRAF p.V600E mutations have recently been detected in some odontogenic tumors, such as ameloblastoma and ameloblastic fibroma, although their involvement in OKC is still unclear. In this study we aimed to clarify the presence and/or frequency of BRAF p.V600E mutations in OKCs. Thirty-five cases of OKCs, 13 of which were associated with Gorlin syndrome, were evaluated for BRAF p.V600E mutations by direct sequencing of the formalin-fixed, paraffin-embedded, and frozen tissue samples. Seventeen cases of ameloblastoma and six cases of dentinogenic ghost cell tumor were also included in this study for comparative purposes. BRAF p.V600E mutations were not detected in any of the OKCs or dentinogenic ghost cell tumors. In contrast, 14 of 17 cases of ameloblastoma (82.35%) were proven to harbor BRAF p.V600E mutations. BRAF p.V600E mutations were common in ameloblastomas, as previously reported, but were absent in OKCs and dentinogenic ghost cell tumors. These results further confirmed the noninvolvement of BRAF in OKCs and suggested different pathogenic mechanisms involved in various odontogenic lesions.

Nevoid Basal Cell Carcinoma Syndrome: PTCH1 Mutation Profile and Expression of Genes Involved in the Hedgehog Pathway in Argentinian Patients.

Nevoid basal cell carcinoma syndrome (NBCCS) is an autosomal dominant disorder characterized by multiple basal cell carcinomas (BCC), mainly caused by PTCH1 gene mutations. Our current study aimed to establish (1) PTCH1 germinal and somatic mutational status, (2) component and Hedgehog (HH) pathway targets gene expression patterns, and (3) profile variations according to the genetic background in BCC and normal surrounding skin (NSS). We collected 23 blood and 20 BCC patient samples and analyzed the PTCH1 gene using bidirectional sequencing and multiplex ligation-dependent probe amplification. Quantitative PCR was used to determine the mRNA expression levels of PTCH1, SMO, GLI3, and CCND1 in paired samples of BCC and NSS from 20 patients and four non-NBCCS skin controls (C). Our analyses identified 12 germline and five somatic sequence variants in PTCH1. mRNA levels of PTCH1, SMO, and GLI3 were higher in NSS compared to C samples, reaching maximum values in BCC samples (p < 0.05). NSS with PTCH1 germline mutations had modified SMO, PTCH1, and GLI3 mRNA levels compared to samples without mutation (p < 0.01). Two PTCH1 mutations in BCC led to an increase in PTCH1, SMO, and GLI3, and a decrease in CCND1 mRNA levels (p < 0.01 vs. BCC with germline mutation only). These results indicate that besides PTCH1, other genes are responsible for NBCCS and BCC development in a population exposed to high UV radiation. Additionally, the mutational events caused increased expression of HH-related genes, even in phenotypically normal skin.

Novel PTCH1 Gene Mutation in Nevoid Basal Cell Carcinoma Syndrome.

The purpose of this study was to report clinical characteristics, surgical results, and new PTCH1 gene mutations in nevoid basal cell carcinoma syndrome (NBCCS). Five patients were referred to the Department of Oral and Maxillofacial Surgery from local dental clinics between 2006 and 2016 to treat multiple keratocystic odontogenic tumors (KOTs). The cystic lesions were enucleated and peripheral ostectomy was performed to obtain safety margin. Recurrence and/or de novo development of KOT were assessed. Gene analysis using peripheral blood was performed in all patients to identify the mutation of PTCH1 gene. Three patients showed familial history of first-degree relatives. Of the major criteria, all patients presented KOT but only 1 patient had basal cell carcinoma. Of the minor criteria, 4 of the 5 patients presented macrocephaly and hypertelorism. During follow-up periods, all patients showed recurrence and/or de novo development of KOT in the jaw bone. Mutation analysis of PTCH1 gene showed 3 frameshifts (c.817_818ins(T), c.1226_1227ins(A), and c.2748del(C)), 1 splicing (c.1504-2A>T), and 1 missense (c.385T>C) mutation. Mutations were found in exon 1, 6, 9, 17, and intron 10. Regular follow-up is necessary because recurrence rate of KOT was very high. To help early diagnosis, it is essential to routinely perform genetic testing to detect PTCH1 gene mutations among patients with NBCCS.

Abstract 4289: Whole-exome sequencing study of nevoid basal cell carcinoma syndrome (NBCCS) families to identify disease-causing exonic mutations

Abstract NBCCS is an autosomal dominant disorder with nearly complete penetrance and variable expression. Clinical findings include multiple basal cell carcinomas, keratocysts of the jaw, pits of the palms and/or soles, and more rarely medulloblastoma. The PTCH1 gene is the major NBCCS susceptibility gene; it regulates the sonic hedgehog (SHH) pathway. Here, we are evaluating mutations in unknown NBCCS families to identify potential disease-causing mutations. Our study included specimens and clinical data from 21 NBCCS families. PTCH1 targeted sequencing and CGH array were previously performed. We subsequently whole-exome sequenced (WES) affected family members with no mutation detected from prior targeted analyses (N=9). We focused our analyses on rare variants of PTCH1, genes that directly interact with PTCH1, SHH pathway genes, and cancer predisposing genes. Variants were considered rare if minor allele frequency (MAF) was less than 1% in publicly available databases (ESP, ExAC, and 1000 genome), 1000 in-house population cancer-free controls, and an in-house database of approximately 2,000 familial samples that underwent WES in parallel with our NBCCS families. We used in-silico prediction models, variant impact on the protein (i.e., nonsynonymous, nonsense, frameshift, splice site), and public mutation databases to assess pathogenicity. Rare variants in PTCH1 were considered pathogenic if they were (a) previously reported as disease-causing in NBCCS, or (b) predicted high impact (ie, frameshift, nonsense mutation), or (c) predicted damaging by at least five of seven in-silico prediction programs (CADD, PolyPhen 2, SIFT, Assessor, Mutation Taster, LRT, FATHMM). Ten families (N= 17 individuals) without a PTCH1 mutation were assessed with WES. WES identified PTCH1 mutations in six families. Overall, only one PTCH1 variant was previously reported (p.S732fs) in HGMD or ClinVar databases. Six novel variants were identified: three frameshifts, p.Y92fs, p.S732fs and p.T212fs; one nonsense, p.W862*; one nonsynonymous variant, p.E835K; and, one splice site variant, c.2716-2A&amp;gt;C. The nonsynonymous variant was a heterozygous C to T transversion (chromosome 9, position 98 229 452) and predicted damaging. In the four families without a PTCH1 mutation, two separate families had a rare nonsynonymous variant in the same gene that directly interacts with PTCH1. Both variants had a MAF of less than 0.1%, but only one was predicted damaging. Another family had a rare nonsynonymous variant in a known cancer predisposing gene that was deleterious in five of seven in-silico prediction tools and found in both the proband and affected mother. Overall, in our 21 NBCCS families, 81% had PTCH1 gene mutations detected with targeted sequencing, aCGH, or WES. Additionally, WES detected two potentially new disease-associated genes that we are currently evaluating further. Citation Format: Matthew Gianferante, Alisa Goldstein, Mingyi Wang, Bin Zhu, Belynda Hicks, NCI DCEG Cancer Genomics Research Laboratory, Lisa Mirabello. Whole-exome sequencing study of nevoid basal cell carcinoma syndrome (NBCCS) families to identify disease-causing exonic mutations [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 4289. doi:10.1158/1538-7445.AM2017-4289

Emergence of Squamous Cell Carcinoma during Treatment of Basal Cell Carcinoma with Vismodegib

Introduction: Basal cell carcinoma accounts for 80% of all non-melanoma skin cancer. Vismodegib is the hedgehog signaling pathway inhibitor, which has shown improved outcome in both locally advanced and metastatic basal cell carcinoma. There are, however, reports of cutaneous squamous cell carcinomas developing while on active treatment with vismodegib. We present a case of transition to squamous cell carcinoma after vismodegib treatment in a patient with a 10-year history of basal cell carcinoma. Case presentation: 44-year-old Caucasian man with 10 year history of basal cell carcinoma on his left chest wall and left shoulder was treated with local resection and actively on vismodegib. He presented with enlarging and infected mass. He underwent left forequarter amputation of his left arm, shoulder and clavicle. Pathology reported basosquamous cell carcinoma with scapula invasion and axillary lymph node metastases. Staging was stage III T4N1M0. He continued on vismodegib post-operation. Three months after his amputation, the patient presented with a recurrent left shoulder mass with nonhealing surgical wound. Imaging revealed vascular invasion. Biopsy of the lesion was consistent with invasive squamous cell carcinoma with genomic profiling of PIK3R1, PTCH1 and STK11 gene mutations. At the patient’s request he was subsequently transferred to another facility for a second surgical opinion. Conclusion: Biopsy and genetic analyses of basal cell carcinoma lesions should be considered in every case that has treatment plan for hedgehog signaling pathway inhibitor to evaluate for potential secondary squamous cell carcinoma growth. Further study is needed to confirm the mechanism of basal cell resistance to anti-smoothened therapy and eventual squamous cell carcinoma growth.

Mutation analysis of the PTCH1 gene in a pedigree with nevoid basal cell carcinoma syndrome

Objective To analyze mutations in the PTCH1 gene in a pedigree with nevoid basal cell carcinoma syndrome (NBCCS).Methods Blood samples were collected from a 58-year-old male proband with NBCCS (Ⅱ 5),his brothers (Ⅱ 1 and Ⅱ 3) and son (Ⅲ4),and 50 unrelated healthy human controls.DNA was extracted from these blood samples.PCR and direct DNA sequencing were performed to determine mutation sites in the PTCH1 gene.According to the mutation sites,allele-specific oligonucleotide primers were designed and used to confirm the pathogenic mutations in this pedigree through PCR.Results A nonsense mutation (c.2137C),which leads to the substitution of CAG by TAG with the generation of a premature termination codon (Q714X),was identified in exon 14 in one allele of the PTCH1 gene in the proband and his son,but in none of the healthy human controls.Conclusion The nonsense mutation (c.2137C ＞ T) in the PTCH1 gene may be a specific mutation causing the clinical symptoms in the patient with NBCCS. Key words: Nevoid basal cell carcinoma syndrome; PTCH1 gene; Codon, nonsense

Abstract 07: Challenges of applying tumor genome analysis to the germline: Examples from GI oncology

Abstract Purpose: To describe the spectrum of potential and confirmed germline genomic events identified incidentally during routine medium throughput somatic tumor DNA sequencing, and to provide a framework for pre- and post-test consent and counseling for these patients and families. Patients and Methods: Targeted next generation sequencing was used to evaluate for possible actionable genomic events in tumor tissue obtained from consecutive new patients seen at the University of Chicago Gastrointestinal Medical Oncology clinic between 9/2012 and 9/2013. Patients had a diagnosis of either metastatic gastroesophageal, hepatobiliary or colorectal cancer. A panel consisting of medical oncologists, an oncology fellow, cancer geneticists and genetic counselors reviewed the results of each case (N=112). Patients were grouped based on their post-test probability of possessing a potentially inherited mutation in a cancer susceptibility gene. The patients within the high-risk group included those with a somatic mutation in one or more of the genes within accepted panels that test for inherited cancer syndromes. Patient age and family history were also taken into account. The high-risk patients were then contacted and formally evaluated and counseled by our cancer risk specialists. When possible and indicated, germline genetic testing was obtained. Results: One hundred and twelve cases were analyzed. Of these, 23 cases (21%) were identified to have somatic, and potentially germline, mutations in BRCA1, BRCA2, PTEN, CDH1, STK11 or MLH1/MSH6 via routine NGS of tumor samples. Seven patients ultimately underwent germline testing of which three (43%) had confirmed germline mutations - interestingly, all were BRCA2. Most identified cases would not meet current criteria to refer for genetic counseling. Variants of unknown significance in germline BRCA2 posed a challenge with respect to counseling and recommendations. There was one positive control patient with a known clinical diagnosis of Gorlin syndrome, in whom routine NGS of his gastric tumor sample identified a PTCH1 gene mutation (previously unknown). Conclusions: Next generation sequencing technology offers much promise, as we enter the age of individualized medicine, but also poses many challenges for both germline and somatic DNA testing. We identified, incidentally, several cases (∼20%) with a potentially inherited cancer susceptibility gene via routine somatic tumor DNA sequencing. Of patients available and willing to undergo further testing, several (43%, 3/7) of these cases were confirmed germline events. Many of these patients would not have been referred for counseling without the somatic sequencing information. This report raises awareness of the challenges facing NGS tumor analyses, and provides a framework for pre- and post-test consent and counseling of patients undergoing routine tumor sequencing. Citation Format: Andrea Amico, Sarah Nielsen, Daniel Geynisman, Brittany Rambo, George Ben Carey, Cassandra Gulden, Jim Fackenthal, Olufunmilayo Olopade, Daniel Catenacci. Challenges of applying tumor genome analysis to the germline: Examples from GI oncology. [abstract]. In: Proceedings of the AACR Special Conference: Cancer Susceptibility and Cancer Susceptibility Syndromes; Jan 29-Feb 1, 2014; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(23 Suppl):Abstract nr 07. doi:10.1158/1538-7445.CANSUSC14-07

Early‐onset acral basal cell carcinomas in Gorlin syndrome

Two patients are reported in whom early-onset, distal papules with a histopathological diagnosis of basal cell carcinoma were the first manifestation of Gorlin syndrome (GS). These lesions showed no progression and remained stable through follow-up. Two different PTCH1 gene mutations were detected in the two patients, and thus a phenotype-genotype correlation of this manifestation of GS was not possible.

Síndrome de Gorlin-Goltz: caso clínico

Introduction: The Gorlin-Goltz syndrome is a rare autosomal dominant inherited condition characterized by: basal cell carcinomas, odontogenic keratocysts, palmar or plantar pits, calcification of the falx cerebri and skeletal malformations. Medulloblastoma and other tumors are also associated with it.Case report: An 11-year-old female, with a history of macrocephaly, was referred to the Stomatology Department for recurrent mandibular cyst. Histopathological exam revealed odontogenic keratocysts, so the patient was referred to the Pediatric Department. Physical examination revealed macrocephaly and coarse face, with frontal bossing and hypertelorism. The genetic study performed detected a mutation in PTCH1 gene, confirming the clinical suspicion.Discussion: Odontogenic keratocysts are the most representative fi nding in Gorlin-Goltz Syndrome in the fi rst two decades of life, therefore a high suspicion level is mandatory among pediatricians concerning detection of minor changes. After the diagnosis, a multidisciplinary team is required for adequate follow-up and timely treatment.

Correction: PTCH1 Gene Mutations in Keratocystic Odontogenic Tumors: A Study of 43 Chinese Patients and a Systematic Review

Correction: PTCH1 Gene Mutations in Keratocystic Odontogenic Tumors: A Study of 43 Chinese Patients and a Systematic Review

Axillary basal cell carcinoma in patients with Goltz-Gorlin syndrome: report of basal cell carcinoma in both axilla of a woman with basal cell nevus syndrome and literature review

Basal cell carcinoma of the axilla, an area that is not usually exposed to the sun, is rare. Individuals with basal cell nevus syndrome, a disorder associated with a mutation in the patch 1 (PTCH1) gene, develop numerous basal cell carcinomas. To describe a woman with basal cell nevus syndrome who developed a pigmented basal cell carcinoma in each of her axilla and to review the features of axillary basal cell carcinoma patients with Goltz-Gorlin syndrome. Pubmed was used to search the following terms: axillary basal cell carcinoma and basal cell nevus syndrome. The papers and their citations were evaluated. Basal cell nevus syndrome patients with basal cell carcinoma of the axilla were observed in two women; this represents 2.5% (2 of 79) of the patients with axillary basal cell carcinoma. Both women had pigmented tumors that were histologically nonaggressive. The cancers did not recur after curettage or excision. Basal cell carcinoma of the axilla has only been described in 79 individuals; two of the patients were women with pigmented tumors who had basal cell nevus syndrome. Similar to other patients with axillary basal cell carcinoma, the tumors were histologically nonaggressive and did not recur following treatment. Whether PTCH1 gene mutation predisposes basal cell nevus patients to develop axillary basal cell carcinomas remains to be determined.

PTCH1 Gene Mutations in Keratocystic Odontogenic Tumors: A Study of 43 Chinese Patients and a Systematic Review

BackgroundThe keratocystic odontogenic tumor (KCOT) is a locally aggressive cystic jaw lesion that occurs sporadically or in association with nevoid basal cell carcinoma syndrome (NBCCS). PTCH1, the gene responsible for NBCCS, may play an important role in sporadic KCOTs. In this study, we analyzed and compared the distribution pattern of PTCH1 mutations in patients with sporadic and NBCCS-associated KCOTs.MethodsWe detected PTCH1 mutations in 14 patients with NBCCS-associated KCOTs and 29 patients with sporadic KCOTs by direct sequencing. In addition, five electronic databases were searched for studies detecting PTCH1 mutations in individuals with NBCCS-associated or sporadic KCOTs, published between January 1996 and June 2013 in English language.ResultsWe identified 15 mutations in 11 cases with NBCCS-associated KCOTs and 19 mutations in 13 cases with sporadic KCOTs. In addition, a total of 204 PTCH1 mutations (187 mutations from 210 cases with NBCCS-associated and 17 mutations from 57 cases with sporadic KCOTs) were compiled from 78 published papers.ConclusionsOur study indicates that mutations in transmembrane 2 (TM2) are closely related to the development of sporadic KCOTs. Moreover, for the early diagnosis of NBCCS, a genetic analysis of the PTCH1 gene should be included in the new diagnostic criteria.

Perigestational Dietary Folic Acid Deficiency Protects Against Medulloblastoma Formation in a Mouse Model of Nevoid Basal Cell Carcinoma Syndrome

Hereditary nevoid basal cell carcinoma syndrome (NBCCS) is caused by PTCH1 gene mutations that result in diverse neoplasms including medulloblastoma (MB). Epidemiological studies report reduced pediatric brain tumor risks associated with maternal intake of prenatal vitamins containing folic acid (FA) and FA supplements specifically. We hypothesized that low maternal FA intake during the perigestational period would increase MB incidence in a transgenic NBCCS mouse model, which carries an autosomal dominant mutation in the Ptch1 gene. Female wild-type C57BL/6 mice (n = 126) were randomized to 1 of 3 diets with differing FA amounts: 0.3 mg/kg (low), 2.0 mg/kg (control), and 8.0 mg/kg (high) 1 mo prior to mating with Ptch1 +/− C57BL/6 males. Females were maintained on the diet until pup weaning; the pups were then aged for tumor development. Compared to the control group, offspring MB incidence was significantly lower in the low FA group (Hazard Ratio = 0.47; 95% confidence interval 0.27–0.80) at 1 yr. No significant difference in incidence was observed between the control and high FA groups. Low maternal perigestational FA levels may decrease MB incidence in mice genetically predisposed to tumor development. Our results could have implications for prenatal FA intake recommendations in the presence of cancer syndromes.