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00019606-201006000-00004ArticleDiagnostic Molecular PathologyDiagnostic Molecular Pathology© 2010 Lippincott Williams & Wilkins, Inc.19June 2010 p 83-91Brooke-Spiegler Syndrome: Report of 10 Patients From 8 Families With Novel Germline MutationsEvidence of Diverse Somatic Mutations in the Same Patient Regardless of Tumor TypeOriginal ArticlesSima, Radek MSc*; Vanecek, Tomas PhD*; Kacerovska, Denisa MD, PhD*; Trubac, Pavel MSc†; Cribier, Bernard MD‡; Rutten, Arno MD§; Vazmitel, Marina MD∥; Spagnolo, Dominic V. MMBS¶; Litvik, Radek MD♯; Vantuchova, Yvetta MD♯; Weyers, Wolfgang MD**; Pearce, Robert L. MD††; Pearn, John MD‡‡; Michal, Michal MD* §§; Kazakov, Dmitry V. MD, PhD**Department of Pathology, Charles University Medical Faculty Hospital, Pilsen♯Department of Dermatology, Medical Faculty Hospital, Ostrava†Department of Genetics, Hospital Ceske Budejovice§§Bioptical Laboratory, Pilsen, Czech Republic‡Clinique Dermatologique, Hôpitaux Universitaires, Strasbourg, France§Dermatopathologische Gemeinschaftspraxis, Friedrichshafen**Center for Dermatopathology, Freiburg, Germany∥Department of Pathology, Academy of Medical Postgraduate Education of Belarus, Minsk, Republic of Belarus¶Division of Tissue Pathology, PathWest Laboratory Medicine WA, Nedlands††Hollywood Specialist Centre, Nedlands‡‡Royal Children's Hospital, Herston, Queensland, AustraliaSupported in part by the Internal Grant Agency of the Ministry of Health of the Czech Republic (NS 9734).Reprints: Dmitry V. Kazakov, MD, PhD, Sikl's Department of Pathology, Charles University Medical Faculty Hospital, Alej Svobody 80, Pilsen 304 60, (e-mail: [email protected]).Radek Sima and Tomas Vanecek contributed equally to the study.AbstractBrooke-Spiegler syndrome (BSS) is an inherited autosomal dominant disease characterized by the development of multiple adnexal cutaneous neoplasms including spiradenoma, cylindroma, spiradenocylindroma, and trichoepithelioma (cribriform trichoblastoma). BSS patients have various mutations in the CYLD gene, a tumor suppressor gene located on chromosome 16q. Our search of the literature revealed 51 germline CYLD mutations reported to date. Somatic CYLD mutations have rarely been investigated. We studied 10 patients from 8 families with BSS. Analysis of germline mutations of the CYLD gene was performed using either peripheral blood or nontumorous tissue. In addition, 19 formalin-fixed paraffin-embedded tumor samples were analyzed for somatic mutations, including loss of heterozygosity studies. A total of 38 tumors were available for histopathologic review. We have identified 8 novel germline mutations, all of which consisted of substitutions, deletions, and insertions/duplications and all except one led to premature stop codons. The substitution mutation in a single case was also predicted to disrupt protein function and seems causally implicated in tumor formation. We demonstrate for the first time that somatic events, loss of heterozygosity, or sequence mutations may differ among multiple neoplasms even of the same histologic type, occurring in the same patient.Brooke-Spiegler syndrome (BSS) is an inherited autosomal dominant disease characterized by the development of multiple adnexal cutaneous neoplasms including spiradenoma, cylindroma, spiradenocylindroma, and trichoepithelioma (cribriform trichoblastomas, according to the latest WHO classification of tumors of the skin).1–4 Rarely, malignant tumors arise in association with preexisting benign neoplasms.5,6 Apart from the skin, morphologically similar neoplasms may arise in the salivary glands or other organs, but these are exceedingly rare.7–11BSS patients have various mutations in the CYLD gene, a tumor suppressor gene located on chromosome 16q.2 Our search of the literature revealed 51 germline CYLD gene mutations reported to date (Fig. 1).2,12–28 Somatic CYLD mutations have rarely been investigated.1,2,14,20,29 Our goals in this study were (1) to report novel germline mutations in BSS; (2) to study various neoplasms from the same patients to identify the spectrum of secondary genetic events; (3) and to review all published mutations of the CYLD gene in BSS and related disorders (multiple familial trichoepitheliomas).JOURNAL/dimp/04.03/00019606-201006000-00004/figure1-4/v/2021-02-17T200020Z/r/image-jpeg Germline mutations and their distribution in the CYLD gene reported to date. Novel mutations identified in our study are indicated in red. Exons 1 to 8 are not drawn to scale. Mutations are written according to the authors' original records despite the fact that some of the mutations do not match the currently used nomenclature. In addition, the precise nature of some mutations remains unresolved: (a), Mutation c.1364 to 1365delAA in exon 15 reported originally by Liang et al18 in fact appear to be located in exon 10. (b), Mutation N403X reported originally by Almeida et al23 is here recorded as ?403 X because at position 403 of CYLD protein is predicted to be the amino acid glutamine (Q)*. (c), Mutations c.1862+2T>G and c.2241_2242delAG published by Liang et al16 appear to be incorrectly recorded. Position 1862 is located in exon 13, not at an exon-intron junction*, as reported.16 In our opinion, the correct record should be c.1826+2T>G and this mutation should be placed at exon 12, not exon 13. For the mutation c.2241_2242delAG at position 2241 and 2242 of the coding sequence, there is no dinucleotide AG, but rather GG*. In addition, position 2241 is at the end of exon 16 whereas position 2242 is present at the beginning of exon 17. In our opinion, the correct record should be c.2240_2241delAG and this mutation should be placed within exon 16 (confirmed by Dr Liang, personal email communication, February 2009). (d), Mutation c. 2253delG published by Poblete-Gutierez et al19 also appears incorrectly recorded, in that at position 2253 there is no G, but rather T*. The nearest G is at position 2252*; therefore, we suggest that the correct record might be c.2252delG. *according Gene Bank reference sequence ♯NC_000016.8 and BioEdit v. 7.0.9.0 software (http://www.mbio.ncsu.edu/BioEdit/bioedit.html).MATERIALS AND METHODSTen patients from 8 families with BSS were selected for the study. In 2 families mother and daughter were involved. For all cases either peripheral blood or nontumorous tissue was available for the identification of germline mutations. Analysis of germline mutations of the CYLD gene was performed as described in detail elsewhere.30 In brief, genomic DNA from peripheral blood or nontumorous tissue was extracted by the NucleoSpin Tissue Kit (Macherey Nagel, Duren, Germany) according to the manufacturer's protocol. Exons 1 to 20 of the CYLD gene were amplified by a polymerase chain reaction (PCR) using primers listed in Table 1. The primers were designed by using the Primer 3 software (http://frodo.wi.mit.edu/cgi-bin/primer3/primer3_www.cgi)31 and Gene Bank sequence ♯AC007728. PCR conditions were as follows: 12.5 μL of HotStart Taq PCR Master Mix (Qiagen, Hilden, Germany), 10 pmol of each primer, 100 ng of template DNA, and distilled water up to 25 μL. The amplification program for all fragments consisted of denaturation at 95°C for 15 minutes, then 40 cycles of denaturation at 95°C for 1 minute, annealing at temperature mentioned in Table 1 for 1 minute, and extension at 72°C for 1 minute. The program was finished by incubation at 72°C for 7 minutes. Successfully amplified PCR products of the CYLD gene were purified with a Montage PCR Centrifugal Filter Devices (Millipore, Billerica) and both sides were sequenced using a Big Dye Terminator Sequencing kit (Applied Biosystems, Foster City). Samples were then run on an automated sequencer ABI Prism 3130×l (Applied Biosystems) at a constant voltage of 13.2 kV for 20 minutes and compared with the reference sequence.32JOURNAL/dimp/04.03/00019606-201006000-00004/table1-4/v/2021-02-17T200020Z/r/image-tiff Primers and Annealing Temperatures for Analysis of the CYLD GeneIn addition, 19 formalin-fixed paraffin-embedded tumor samples were analyzed for somatic mutations, including loss of heterozygosity (LOH) studies. Sequence mutations were analyzed as mentioned above. For LOH analysis of tumor tissue DNA, short tandem repeat markers, D16S304, D16S308, D16S419, D16S476, and D16S541 located on chromosome arm 16q and D16S407 located on chromosome arm 16p were chosen from the database (Gene Bank UniSTS) and tested as described in detail elsewhere.28 The primers and annealing temperatures are listed in Table 2. PCR conditions were the same as mentioned above.JOURNAL/dimp/04.03/00019606-201006000-00004/table2-4/v/2021-02-17T200020Z/r/image-tiff STR Markers Primers and Annealing Temperatures for LOH AnalysisSuccessfully amplified PCR products were mixed with Gene Scan-500LIZ Size Standard (Applied Biosystems) and run on an automated genetic analyzer ABI Prism 3130×l (Applied Biosystems) at a constant voltage of 15 kV for 20 minutes.A sample was considered LOH positive if the ratio of nontumor DNA to tumor DNA was >2 or <0.51. All identified mutations (germline and somatic) were confirmed twice by newly performed DNA extraction, PCR, and sequencing/LOH analysis.For the analysis of sequences and LOH, Sequencing Analysis v. 5.2, GeneMapper v. 3.2 (Applied Biosystems) and BioEdit v 7.0.9.0 (http://www.mbio.ncsu.edu/BioEdit/bioedit.html) software were used.Peripheral blood samples from 110 randomly selected healthy unrelated individuals were tested to exclude the possibility that CYLD abnormality might represent a polymorphism (benign mutation) rather than a tumor-associated (malignant) mutation. In addition, in one case (see below) prediction of the functional effect of mutation was performed using PolyPhen software (http://genetics.bwh.harvard.edu/pph/).One case (case 8) previously reported without molecular investigation has now had molecular biologic studies performed.33Using Medline and cross-references in culled articles, we reviewed all papers reporting germline or somatic CYLD mutations in BSS. In cases in which we felt that a particular mutation was recorded incorrectly, the corresponding authors of those articles18,19,23 were contacted for clarification. As we received no reply (except from Dr Liang with regard to their report16), these mutations are still included in Figure 1 but with our comments (Fig. 1).The study was approved by the Institutional Review Board of the Charles University Medical Faculty Hospital in Pilsen, Czech Republic.RESULTSClinicopathologic DataThere were 8 female and 2 male patients ranging in age from 22 to 69 years (Table 3). All individuals presented with multiple variably sized papules and nodules, with a predilection for the scalp (Fig. 2A). A total of 38 tumors were available for histopathologic review, sometimes occurring multiply in a single specimen. These consisted of 16 cylindromas, 11 spiradenomas, 7 spiradenocylindromas, and 4 trichoepitheliomas (cribriform trichoblastoma). In addition, small trichoblastomatous foci were identified in 1 of 11 spiradenomas and in 2 of 16 cylindromas (Figs. 2B–E).JOURNAL/dimp/04.03/00019606-201006000-00004/figure2-4/v/2021-02-17T200020Z/r/image-jpeg A-C Multiple nodules involving the scalp (case 9). D1-G Stereotypical histologic appearances of cylindroma, spiradenoma, spiradenocylindroma, and trichoepithelioma (cribriform trichoblastoma). Cylindromas are composed of epithelial cell islands arranged in a jigsaw puzzle manner surrounded by basement membrane material. The epithelial cells at the periphery of the islands are arranged in palisades and are darker than those situated at the periphery (D1, D2). Spiradenomas also manifest a dual epithelial cell population and always contain lymphocytes. There is no jigsaw puzzle arrangement of the basaloid cells (E1, E2). Spiradenocylindromas manifest areas typical of both cylindroma and spiradenoma (F). Trichoepithelioma appears as a biphasic follicular neoplasm composed of follicular germinative cells associated with typical trichogenic stroma, often resembling follicular papillae. The epithelial aggregates are arranged in cribriform structures and focally in small nodules (G).JOURNAL/dimp/04.03/00019606-201006000-00004/table3-4/v/2021-02-17T200020Z/r/image-tiff Salient Clinical Features, Tumor Types, Germline, and Somatic Mutations of CYLD in Patients With Brooke-Spiegler SyndromeMolecular Biologic StudyEight novel previously unreported germline mutations were found (Table 3; Fig. 1, red font; Fig. 3). DNA sequencing from 110 randomly selected healthy unrelated individuals' peripheral blood showed none of these sequence variations.JOURNAL/dimp/04.03/00019606-201006000-00004/figure3-4/v/2021-02-17T200020Z/r/image-jpeg Sequence of 8 novel germline mutations: A, c.1455T>G. B, c.2104delA. C, c.2108G>C. D, c.2119C>T. E, c.2170_2171insTC. F, c.2299A>T. G, c.2729dupC. H, c.2814_2817delGCTT.Of the 19 formalin-fixed paraffin-embedded tumor tissues from 9 individuals, 9 revealed sequence variations and 10 showed LOH (Table 1). In case 5, DNA extracted from the 3 studied tumors was not amplifiable.The detected sequence mutations (germline or somatic) consisted of substitutions, deletions, and insertions/duplications, all except one leading to premature stop codons (Table 3). A case with amino acid substitution (case 5) was subjected to analysis with PolyPhen software, which predicted a possibly damaging effect of this mutation on protein structure and function. In the cases in which LOH was detected, hemizygous germline sequence mutations were present.In 4 cases (cases 1, 2, 7, 9), there were diverse somatic mutations in the same patient regardless of tumor type (Table 3). In case 1, each of the 3 spiradenocylindromas had a different somatic mutation including LOH, one showed a duplication mutation and the last had a substitution mutation. In case 2, one spiradenocylindroma showed LOH and the other a duplication mutation. In case 7, one cylindroma harbored a substitution mutation whereas a second cylindroma revealed an insertion mutation. Finally, in case 9, 2 of 3 cylindromas showed LOH whereas the third showed a substitution mutation. In all these cases, the sequence somatic mutations resulted in a truncated protein.DISCUSSIONMutations in the CYLD gene have been associated with cylindromatosis, multiple familial trichoepithelioma (MFT), and BSS. The CYLD gene consists of 20 exons, the first 3 of which are untranslated. Exons 3 and 7 show alternative splicing.2 The gene encodes a cytoplasmic deubiquinating protein that regulates several signaling pathways. This protein contains 3 cytoskeletal-associated protein–glycine-conserved domains, NEMO, and TRAF2-binding domains, a phosphorylation domain, and a catalytic domain (for details see review34,35).In this study we report 8 novel germline mutations of the CYLD gene in patients with BSS, thus extending the catalogue of known germline mutations to 59 (Fig. 1). All identified mutations except 1 predicted a truncated protein, a common type of alteration found in the CYLD gene.18,22,23,36 The substitution mutation in case 5 was analyzed by the Polyphen software (http://genetics.bwh.harvard.edu/pph/) to determine whether this alteration truly represented a tumor-associated mutation. This analysis, together with the results of sequencing in 110 healthy unrelated individuals, clearly indicated the causal role of this mutation in this patient. Interestingly, one mutation identified in our series, p.Y485X (cases 1 and 2, Table 1), a known mutation at the protein level, resulted from a nucleotide change (c. 1455T>G) different from that reported by Bignell et al (c. 1455T>A).2 To date, the vast majority of CYLD mutations hit the central and C-terminal regions of the NEMO binding and the catalytic domains (exons 9 to 20).2,12–28 The only CYLD mutation described in the N-terminal region (S265X) has been in the setting of multiple myeloma37 and not in BSS. The mutations found in our series of BSS patients are in line with those previously published and were located beyond the exon 9.In accordance with Knudson's hypothesis,38 a tumor suppressor gene requires two hits for its inactivation and initiation of tumor formation. Although the first hit, a germline mutation, has been widely studied in BSS and related lesions, the second hit, a somatic alteration, has rarely been the subject of analysis, and the spectrum of somatic mutations in different neoplasms in the same individual is virtually unknown. Only few investigators have identified LOH or single-sequence mutations in a single tumor.1,2,14,20 From the data presented by Bignell et al it may be assumed that 1 or 2 BSS patients in their series showed a mixed pattern of LOH and somatic sequence mutation in the neoplasms; however, there was no specification as to whether the tested tumors were of the same histologic type.2 We tested by sequencing and LOH analysis a series of 19 tumors from 9 patients. Our analysis of somatic mutations revealed several features. First, the second hit may be represented by both LOH and mutations leading to a change in nucleotide sequence. Second, multiple tumors of the same histologic type (eg, cylindroma) in the same patient may show different somatic mutations (cases 1, 2, 7, 9; Table 1). This observation suggests that the multiple tumors in individual BSS patients are independent events, each arising from separate, unique second mutations (hits) in CYLD. To the best of our knowledge, this is the first description of this phenomenon affecting the CYLD gene. A similar process has been described in few other tumor suppressor genes including BHD and NF1.39,40From a morphologic viewpoint, our study confirms previously published reports describing the occurrence of a variety of adnexal neoplasms in BSS. Although originally cylindromas and facial trichoepitheliomas were described in BSS, other tumor types including spiradenomas, spiradenocylindromas, and their malignant counterparts have now all been reported in BSS patients.3,28,33 Although we performed no formal statistical analysis, it is evident that there is no phenotype-genotype correlation in that a particular tumor type is not associated with a specific germline or somatic alteration.In conclusion, we have identified 8 novel germline mutations, all of which consisted of substitutions, deletions, and insertions/duplications and all except one led to premature stop codons. The substitution mutation in a single case was also predicted to disrupt protein function and seems causally implicated in tumor formation. Finally, we demonstrate for the first time that somatic events, LOH, or sequence mutations, may differ among multiple neoplasms even of the same histologic type, occurring in the same patient.REFERENCES1. 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Am J Hum Genet. 2000;66:393–401.[Context Link][CrossRef][Medline Link]skin adnexal tumors; Brooke-Spiegler syndrome; cylindroma; spiradenoma; spiradenocylindroma; trichoblastoma; CYLD; germline mutation; somatic mutation; loss of heterozygosity00019606-201006000-0000400042358_2005_19_380_kostler_malignancies_|00019606-201006000-00004#xpointer(id(citation_FROM_JRF_ID_d1379e1081_citationRF_FLOATING))|11065404||ovftdb|SL0004235820051938011065404citation_FROM_JRF_ID_d1379e1081_citationRF_FLOATING[Full 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Novel mutations identified in our study are indicated in red. Exons 1 to 8 are not drawn to scale. Mutations are written according to the authors' original records despite the fact that some of the mutations do not match the currently used nomenclature. In addition, the precise nature of some mutations remains unresolved: (a), Mutation c.1364 to 1365delAA in exon 15 reported originally by Liang et al18 in fact appear to be located in exon 10. (b), Mutation N403X reported originally by Almeida et al23 is here recorded as ?403 X because at position 403 of CYLD protein is predicted to be the amino acid glutamine (Q)*. (c), Mutations c.1862+2T>G and c.2241_2242delAG published by Liang et al16 appear to be incorrectly recorded. Position 1862 is located in exon 13, not at an exon-intron junction*, as reported.16 In our opinion, the correct record should be c.1826+2T>G and this mutation should be placed at exon 12, not exon 13. For the mutation c.2241_2242delAG at position 2241 and 2242 of the coding sequence, there is no dinucleotide AG, but rather GG*. In addition, position 2241 is at the end of exon 16 whereas position 2242 is present at the beginning of exon 17. In our opinion, the correct record should be c.2240_2241delAG and this mutation should be placed within exon 16 (confirmed by Dr Liang, personal email communication, February 2009). (d), Mutation c. 2253delG published by Poblete-Gutierez et al19 also appears incorrectly recorded, in that at position 2253 there is no G, but rather T*. The nearest G is at position 2252*; therefore, we suggest that the correct record might be c.2252delG. *according Gene Bank reference sequence ♯NC_000016.8 and BioEdit v. 7.0.9.0 software (http://www.mbio.ncsu.edu/BioEdit/bioedit.html). Primers and Annealing Temperatures for Analysis of the CYLD Gene STR Markers Primers and Annealing Temperatures for LOH Analysis A-C Multiple nodules involving the scalp (case 9). D1-G Stereotypical histologic appearances of cylindroma, spiradenoma, spiradenocylindroma, and trichoepithelioma (cribriform trichoblastoma). Cylindromas are composed of epithelial cell islands arranged in a jigsaw puzzle manner surrounded by basement membrane material. The epithelial cells at the periphery of the islands are arranged in palisades and are darker than those situated at the periphery (D1, D2). Spiradenomas also manifest a dual epithelial cell population and always contain lymphocytes. There is no jigsaw puzzle arrangement of the basaloid cells (E1, E2). Spiradenocylindromas manifest areas typical of both cylindroma and spiradenoma (F). Trichoepithelioma appears as a biphasic follicular neoplasm composed of follicular germinative cells associated with typical trichogenic stroma, often resembling follicular papillae. The epithelial aggregates are arranged in cribriform structures and focally in small nodules (G). Salient Clinical Features, Tumor Types, Germline, and Somatic Mutations of CYLD in Patients With Brooke-Spiegler Syndrome Sequence of 8 novel germline mutations: A, c.1455T>G. B, c.2104delA. C, c.2108G>C. D, c.2119C>T. E, c.2170_2171insTC. F, c.2299A>T. G, c.2729dupC. H, c.2814_2817delGCTT.Brooke-Spiegler Syndrome: Report of 10 Patients From 8 Families With Novel Germline Mutations: Evidence of Diverse Somatic Mutations in the Same Patient Regardless of Tumor TypeSima Radek MSc; Vanecek, Tomas PhD; Kacerovska, Denisa MD, PhD; Trubac, Pavel MSc; Cribier, Bernard MD; Rutten, Arno MD; Vazmitel, Marina MD; Spagnolo, Dominic V. MMBS; Litvik, Radek MD; Vantuchova, Yvetta MD; Weyers, Wolfgang MD; Pearce, Robert L. MD; Pearn, John MD; Michal, Michal MD; Kazakov, Dmitry V. MD, PhDOriginal ArticlesOriginal Articles219p 83-91