Multiple Familial Trichoepithelioma Caused by Mutations in the Cylindromatosis Tumor Suppressor Gene

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[CANCER RESEARCH 64, 5113–5117, August 1, 2004] Multiple Familial Trichoepithelioma Caused by Mutations in the Cylindromatosis Tumor Suppressor Gene

Aicha Salhi,1 Dorothea Bornholdt,2 Frank Oeffner,2 Sajid Malik,2 Ernest Heid,4 Rudolf Happle,3 and Karl-Heinz Grzeschik2 1Department of Dermatology, University of Algiers, Algiers, Algeria; Departments of 2Human Genetics and 3Dermatology, Philipp University, Marburg, Germany; and 4Department of Dermatology, Universite´Louis Pasteur, Strasbourg, France

ABSTRACT In some MFT tumors, structures reminiscent of basal cell carcinoma (BCC) may be found (14), although MFT clearly differs from The recessive oncogene cylindromatosis (CYLD) mapping on 16q12-q13 Gorlin syndrome (multiple nevoid BCC syndrome) that is caused by is generally implicated in familial cylindromatosis, whereas a gene region mutations in the patched gene (PTCH1) on 9q22.3. In half of a series for multiple familial trichoepithelioma has been assigned to 9p21. Mark- ers from both chromosome intervals were subjected to linkage analysis in of sporadic TEs loss of heterozygosity (LOH) at 9q22.3, the region a large family with multiple hereditary trichoepithelioma (TE) from where PTCH1 maps was detected by Matt et al. (15) who postulated Algeria. Linkage to 9p21 was excluded, whereas CYLD remained as a a common gatekeeper mechanism for both TE and BCC. Their ob- candidate. Mutation analysis identified a single bp germ-line deletion servations corroborate a previous report that sporadic TE contain expected to result in truncation or absence of the encoded protein, which somatic mutations in the overexpressed PTCH gene, suggesting that a segregated with the multiple TE phenotype. In individual tumors, loss of failure in the negative feedback mechanism in the sonic hedgehog- heterozygosity at 16q or a somatic point mutation in the CYLD gene was patched (SHH-PTC) signaling pathway may be an early and necessary detected. Hence, mutations of the tumor suppressor gene CYLD at 16q12- event in TE development (16). q13 may give rise to familial TE indistinguishable from the phenotype We describe a large family of Algerian origin with 21 individuals assigned to 9p21. affected with multiple TE in four consecutive generations. All of these patients showed the typical clinical and histopathological features of INTRODUCTION multiple TE preponderantly involving the face and in some patients Multiple familial trichoepithelioma (MFT; MIM 601606) is char- also the scalp. Tumors suggesting a diagnosis of cylindroma, spira- acterized by numerous, firm skin-colored papules that originate from denoma, or BCC were absent. We exclude involvement of a locus on hair follicles. Histopathologically, trichoepitheliomas (TE) contain chromosome 9p as well as LOH in tumors on 9q and identify a branching nests of basaloid cells, horn cysts, and abortive hair papil- germ-line mutation in the tumor suppressor gene CYLD on chromo- lae. The tumors represent benign hamartomas of the pilosebaceous some 16q12-q13 segregating with MFT in affected members of this apparatus. Guggenheim (1) reported that TE, which is also called family. We demonstrate LOH or a point mutation eliminating the epithelioma adenoides cysticum (2), may occur in a family or even in function of the second copy of this gene. In view of the previ- one patient together with cylindroma as described by Spiegler (3), ous assignment to 9p21, these results suggest genetic heterogeneity which is why they postulated their genetic identity. This has been of MFT. corroborated by multiple reports on the coexistence of cylindromas and TEs and, occasionally, spiradenomas (4). Therefore, an entity MATERIALS AND METHODS called Spiegler-Brooke syndrome (MIM 605041) has been created, which is thought to be associated with defects in the regulation of the Subjects and Analyzed Samples. A 25-year-old woman and her 24-year- proliferation and differentiation of putative stem cells of the follicu- old sister presented for advice because of multiple facial tumors. Physical losebaceous-apocrine unit giving rise to different adnexal skin tumors examination showed numerous, firm skin-colored papules and nodules involv- as well as to other neoplasms (5). ing the nasal root, the medial part of the eyebrows, and the nasolabial folds. The family history revealed that 21 individuals belonging to four consecutive In 1996, Harada et al. (6) reported linkage of autosomal dominant generations were similarly affected, and this was confirmed in part by physical multiple TE to chromosome 9p21. However, in contrast to the notion examination (Fig. 1A). In some of them, a few papules or nodules were of genetic identity of cylindroma and TE, defects of a tumor repressor likewise found on the scalp and in the periauricular areas. The tumors tended gene on chromosome 16, CYLD, were documented to cause familial to become obvious after puberty but in several family members, some small cylindromatosis (7, 8). CYLD mutations were recently detected in papules had already appeared during childhood. Chinese families with MFT (9, 10). Because some families with This large Algerian kindred in which MFT segregated was analyzed for the CYLD mutations were affected with both cylindromas and TEs (11, underlying genetic defect. Blood samples were obtained from 13 family 12), CYLD deficiency appears to be associated with Spiegler-Brooke members (Fig. 2) and from 100 unrelated, unaffected Caucasian-control indi- syndrome (MIM 605041). In fact, familial cylindromatosis may rep- viduals after informed consent for inclusion in the study. Tumors excised for resent one end of a clinical spectrum of a group of adnexal neoplasms therapeutic reasons were fixed in 70% ethanol or formaldehyde for DNA extraction and histopathological examination, respectively. Information on of the skin (13). clinical status was obtained by clinical examination for all of the individuals However, there still remains the question whether MFT without from which biological samples were obtained. The disease status of deceased associated cylindroma represents a separate genetic entity linked to individuals or of cases that were for other reasons not available for direct 9p21 (MIM 601606), or whether it may likewise originate from clinical evaluation was based on photographic documentation or family mutations at the locus of Spiegler-Brooke syndrome (MIM 605041). history. Histopathological Examination. For histopathological examination, sec- Received 1/30/04; revised 3/29/04; accepted 5/25/04. tions obtained from facial lesions of 3 family members (III, 4; IV, 3; and IV, The costs of publication of this article were defrayed in part by the payment of page 6) and from a scalp lesion of an individual (IV, 6) were stained with H&E charges. This article must therefore be hereby marked advertisement in accordance with following manufacturer’s procedures. 18 U.S.C. Section 1734 solely to indicate this fact. Mutation Analyses. DNA from individual tumor specimens that were Requests for reprints: Karl-Heinz Grzeschik, Department of Human Genetics, Phil- ipp University, Bahnhofstrasse 7, D35037 Marburg, Germany. Phone: 49-6421-286-6233; separated macroscopically from surrounding tissue was extracted by use of a Fax: 49-6421-286-8920; E-mail: [email protected]. “QIAamp DNA Mini Kit” (Qiagen) following the “tissue protocol” of the 5113

Fig. 1. A, multiple trichoepithelioma (TE); characteristic facial involvement in a 28-year-old man (IV, 6). B, TE; the dermis is filled with basaloid proliferations surrounding horn cysts with a fully keratinized center (H&E; bar, 0.1 mm). C, germ- line mutation c.2104_2105 ins A in exon 15 segregating with the phenotype multiple familial trichoepithelioma. This mutation results in a premature chain termination I702fsX723. D, somatic mutation (c.2541GϾA) detected in one TE in addition to the germ-line mutation c.2104_2105 ins A. This second hit generates a stop codon (W847X).

supplier. DNA from blood lymphocytes was extracted by standard procedures. conditions described in the Genome Database5 and analyzed with the Geno- Patient and control DNA was taken at a concentration of 50 ng/␮l as template typer program (Applied Biosystems). Microsatellite markers CDRP28 and for PCR. Exons 4–19 of CYLD including intron-exon boundaries were ampli- CDRP23 were amplified as described by Bignell et al. (8). fied by PCR. We applied the primer combinations and, with minor modifica- Linkage and LOH Analysis. Two-point limit of detection-score analyses tions, the procedures described by Bignell et al. (8). were performed for linkage between disease status and every marker using the The coding exons 4 to 19 of CYLD were sequenced in lymphocyte DNA MLINK program of Linkage software package version 5.1 (17) assuming a from individual III, 1 and in DNA from tumors (III, 1 tum1; IV, 6 tum3; and monogenic effect in a dominant mode of inheritance, a disease allele frequency IV, 7 tum1) on an automated DNA sequencer model 377 (Applied Biosystems) of 1:10,000, and a penetrance of 98%. Locus order was derived from the by the dye terminator procedure. The sequences were compared with the human genome working draft database6 for markers on chromosomes 9 and normal control sequences and the published cDNAs (GenBank accession no. from Bignell et al. (8) for markers on chromosome 16. Allele frequencies were AJ250014) by use of the ABI Prism Sequencing Analysis Version 2.1.1 and adopted from the Genome Database,5 where possible, or set to be equally Sequence Navigator software programs (Applied Biosystems). In all of the distributed (CDRP23, 28, and D16S416). Genotypic and phenotypic informa- individuals tested from this family as well as from 100 unrelated controls, the tion given in the pedigree displayed in Fig. 2 and in Table 1 was used for the PCR products of exons 15 and 19, in which genomic mutations have been analyses. Multipoint analysis was performed using GeneHunter software, found by sequencing, were subjected to single-strand conformation analysis by version 2.1 (18). Several untyped individuals were removed from analysis electrophoresis in 12% polyacrylamide gels in 0.5 ϫ Tris-borate EDTA buffer because of time and memory constraints of the software. The disease model at 20°Cor10°C, respectively, for 10 h at 200 V or 90 min at 600 V, followed was assumed same as in pair-wise analysis, and the order of the markers was by silver staining. Bands deviating in mobility from the ones detected in essentially as shown in Table 1. The constitutional genotype of each individual unaffected individuals were eluted from the gel, reamplified by PCR, purified was determined from lymphocyte DNA. To establish the presence of LOH, an by a QIAquick PCR purification kit (Qiagen), and resequenced. allelic imbalance was assessed by comparing signal intensity recorded by the Typing of Microsatellite Markers. Microsatellite markers D9S925, Genotyper program (Applied Biosystems) of normal and tumor alleles from 6 D9S171, and D9S169 covering the region 9p2 in which, previously, linkage patients. with the MFT phenotype had been detected (6), microsatellite markers D9S15, D9S252, D9S303, and D9S287 encompassing the PTCH1 locus on chromosome 9q22.3 and microsatellites encompassing the CYLD locus on chromosome 16 (Table 1) were genotyped on an automated DNA sequencer model 5 Internet address: http://www.gdb.org. 377 (Applied Biosystems) after PCR amplification by use of primers and 6 Internet address: http://genome.ucsc.edu. 5114

Fig. 2. Partial pedigree of an Algerian family with multiple hereditary trichoepithelioma. Genotypes observed in DNA from blood lymphocytes and individual tumors are indicated for microsatellite markers on chromosomes 9 and 16; T, tumors excised from the respective patients. In tumors showing loss of heterozygosity (III1, Tum1; III5, Tum1; 2, IV6, Tum1; and 2, IV8, Tum1), the missing alleles are indicated by a dash. The haplotype segregating with the phenotype multiple familial trichoepithelioma is marked with a vertical line. The individuals marked with a horizontal line above the symbol have been examined physically.

Table 1 Two-point limit of detection scores for the phenotype familial multiple phenotype in this family. In the region that had shown previously linkage trichoepithelioma and microsatellite markers on chromosomes 16 and 9 with MFT on chromosome 9p (6), linkage was excluded for the micro- Recombination fraction satellite markers D9S925, D9S171, and D9S169 (Table 1; Fig. 2). In Marker .00 .10 .20 .30 .40 contrast, analysis with markers encompassing the CYLD locus on chro- Chromosome 16 mosome 16 revealed a two-point limit of detection score above 2, D16S 769 Ϫ2.91 ϩ0.14 ϩ0.16 ϩ0.05 Ϫ0.04 suggesting linkage (Table 1). This analysis was corroborated by a mul- D16S 753 ϩ2.44 ϩ1.98 ϩ1.48 ϩ0.93 ϩ0.37 tipoint linkage analysis for the phenotype MFT and the same microsat- CDRP 28 ϩ2.40 ϩ1.98 ϩ1.53 ϩ1.02 ϩ0.49 CDRP 23 ϩ1.48 ϩ1.27 ϩ1.01 ϩ0.71 ϩ0.37 ellite markers on chromosomes 16. Markers D16S753 to D16S673 en- D16S 416 ϩ0.14 ϩ0.10 ϩ0.07 ϩ0.04 ϩ0.02 compassing the CYLD gene show limit of detection scores above 3.0 (Fig. ϩ ϩ ϩ ϩ ϩ D16S 771 2.61 2.16 1.65 1.09 0.49 3). Hence, the CYLD gene was considered a strong candidate and sub- D16S 673 ϩ2.70 ϩ2.24 ϩ1.73 ϩ1.17 ϩ0.57 Chromosome 9 jected to mutation analysis. D9S 925 Ϫ3.65 Ϫ0.52 Ϫ0.21 Ϫ0.07 Ϫ0.01 Identification of a Disease-Associated Germ-Line Mutation. D9S 171 Ϫ8.96 Ϫ1.66 Ϫ0.84 Ϫ0.41 Ϫ0.15 D9S 169 Ϫ9.32 Ϫ1.69 Ϫ0.86 Ϫ0.42 Ϫ0.16 Three hundred-400 bp fragments encompassing exons and flanking intron sequences of the CYLD gene were amplified by PCR by use of

RESULTS

Histopathological Features. Histopathological examination of lesions from both face and scalp consistently showed islands of small basophilic cells of basaloid appearance. Peripheral palisading and central formation of keratin cysts was noted. In the surrounding dermis, reticular proliferations of small basaloid cells were present, and occasionally abortive hair differentiation was found (Fig. 1B). In no part of the specimens, including those obtained from scalp lesions, was any structure reminiscent of cylindroma seen. In particular, there were no hyaline sheaths surrounding the islands of basaloid cells. In all of the specimens, the dermis was filled with circumscribed proliferative formations of basophilic basaloid cells surrounding numerous cysts with a fully keratinized center. The walls of these horn cysts contained some layers of cells with eosinophilic cytoplasm and large vesicular nuclei. Some of the basophilic cells were arranged in an adenoid network. All of these histopathological features were characteristic of TE. The Multiple TE Phenotype Segregates with Markers on Fig. 3. Diagram showing the results of multipoint linkage analysis (18) for the phenotype familial multiple trichoepithelioma and microsatellite markers on chromo- 16q12-q13 But Not on 9p. Both previously identified candidate loci for somes 16 listed in Table 1. Markers D16S753 to D16S673 encompassing the CYLD gene MFT and familial cylindromatosis were screened for linkage with the show limit of detection scores above 3.0. 5115

genomic DNA from lymphocytes of one affected individual and screened cylindromatosis as well as in Spiegler-Brooke syndrome (8, 11). We for mutations by sequence analysis. The sequence of the exon 15 PCR conclude that there may be two forms of MFT, one that is a linked to product revealed an insertion c.2104_2105 ins A, resulting in a premature 9p, and another one that is linked to 16q12-q13 (MIM 601606), chain termination I702fsX723 (Fig. 1C). An abnormally migrating band corroborating recent observations from Chinese families (9, 10). Re- was observed in single-strand conformational analysis with the product of markably, Matt et al. (15) who analyzed sporadic TE with polymor- exon 15 in all of the affected individuals but not in unaffected family phic markers from 9p21 were unable to document LOH at this locus. members (data not shown). Cloning of the deviating band of exon 15 The clinical and molecular findings present in this family show that followed by sequence analysis of several clones confirmed the presence mutations in the CYLD gene may cause the classical phenotype of of the insertion mutation. Control single-strand conformational analysis multiple TE without any clinical or histopathological overlapping of this CYLD exon in 100 chromosomes 16 from healthy, unrelated blood with cylindroma. This finding may be explained either by allelic donors excluded that the observed electrophoretic pattern was because of heterogeneity at the CYLD locus or by the action of a modifying gene. a DNA polymorphism. A modifier gene restricting the phenotype to TE would have to be LOH or a Somatic Point Mutation Affecting CYLD Cause a closely linked to CYLD, because otherwise segregation with occur- Second Hit in Individual Tumors. To search for an inactivating rence of cylindroma in this family would be expected. Alternatively, mutation in the second allele in individual tumors, 9 TEs excised from specific alleles of a modifier might determine the phenotype of 6 affected family members were screened for LOH of polymorphic cylindroma or even spiradenoma associated with TE. These alleles markers CDRP28, CDRP23, and D16S416 from the chromosome might not occur in the Algerian population sample from which this interval encompassing CYLD (8) by comparing the amounts of allelic family originates. products amplified from blood or tumor tissue. LOH in the haplotype that did not contain the disease-associated germ-line mutation was A failure in the negative feedback mechanism in the SHH-PTCH observed in 6 tumors. The alleles missing in these tumors (III1, Tum1; signaling pathway may be an early and necessary event in skin III5, Tum1 and Tum2; IV6, Tum1 and Tum2; IV8, Tum1) are indi- tumorigenesis (31), possibly involving up-regulation of GLI1 gene cated in Fig. 2 by dashes. The entire coding sequence of CYLD from expression (32–35). For adnexal skin tumors such as TE, a gate- the three remaining tumors was subjected to sequence analysis. In one keeper function may be associated with the functioning of PTCH1, of the samples that had not shown LOH, an intragenic somatic a receptor for hedgehog proteins, which is mutated in BCCs (16). mutation (c.2541GϾA) was detected, resulting in a stop codon Malignant changes (BCC) have been noted occasionally in cylin- (W847X; Fig. 1D). dromas (36) and TEs (14, 37). Experimentally induced BCC in The PTCH1 Locus on Chromosome 9q22.3 Is Not Affected by mice tend to be associated with other hair follicle neoplasias such LOH. Microsatellite markers flanking the PTCH1 locus on chromo- as trichoblastoma, TE, and cylindroma (32). Conversely, patients some 9q22.3 were analyzed for LOH in tumor samples and in the with Gorlin syndrome (MIM 109400) caused by mutations in the blood of the individuals from which the tumors had been excised. No PTCH1 gene may have, in addition to BCCs, some skin lesions indication for LOH at this location was detected (data not shown). showing more benign structures in the form of TE (38, 39). Sporadic TEs are associated with deletions at 9q22.3, the site DISCUSSION where PTCH1 maps (15), or they contain somatic mutations in the overexpressed PTCH1 gene (16). On the basis of ample evidence from clinical reports and his- We could not detect LOH at the PTCH1 locus in TEs from this topathological studies, Chalstrey (19) postulated that the inherited, Algerian family. Analogously, no PTCH mutations were detected by multiple, and benign tumors of the epithelial appendages, cylindro- Vorechovsky et al. (16) in two patients with the familial form of mas, and TEs might be manifestations of mutations in the same gene. multiple TE. It would be worthwhile to extend the LOH analysis at the Cylindromas (3, 20, 21) are tumors with cords of basophilic cells PTCH1 locus to test whether a reduction in the amount of this receptor surrounded by a hyaline membrane formed by polysaccharide secre- protein on top of a deficiency of CYLD might result in cylindromas tory cells (22). They show differentiation toward sweat glands, or spiradenomas. whereas TEs (2, 23, 24) originate from the basal cell layer of the CYLD has been identified recently as a negative regulator of the epidermis and from hair follicles and contain structures reminiscent of transcription factor nuclear factor ␬B involved, among other tasks, hair formation (25, 26). Numerous reports of coexistence of both in protection against apoptosis (40– 43). Skin appendages require types of tumors in the same family and even in the same individual nuclear factor ␬B activity for their development (44, 45). Impair- were published (27). There are too many well-documented kindreds in ment of apoptosis resulting from mutations in CYLD might dereg- which subjects were affected with both types of tumors to suggest the ulate proliferation in the developing skin appendages in familial possibility of a chance association of two separate autosomal muta- cylindromatosis as well as trichoepitheliomatosis (40). Other, tions in each case (1, 13, 28, 29). Moreover, syringomas that show differentiation toward sweat ducts may coexist with TEs (30). There- functionally related proteins with ubiquinating activity might in- ␬ fore, multiple familial cylindroma as described by Spiegler (3) and TE hibit nuclear factor B signaling in a similar manner (43, 46). A as described (under the name “epithelioma adenoides cysticum”)by genetic defect in one of them functioning in hair follicles in Brooke (2) have been lumped into one single entity, Spiegler-Brooke parallel with CYLD might similarly shift the balance between syndrome (MIM 605041). proliferation and apoptosis toward proliferation, resulting in tumor On the other hand, a definite clinical and histopathological dichot- growth. This would explain the genetic heterogeneity of the mul- omy between families with cylindromatosis (MIM 132700) and those tiple TE phenotype. with trichoepitheliomatosis (MIM 601606) has been well established Brummelkamp et al. (40) found recently that enhanced protection and is supported at the genetic level because the two phenotypes have from apoptosis resulting from defective CYLD can be reversed by been assigned to two different loci on 9p21 (trichoepitheliomatosis) simple pharmacological agents such as sodium salicylate and pros- and 16q12-q13 (cylindromatosis; Ref. 6). However, in the present taglandin A1. This observation raises hope for a therapy restoring family with a classical TE phenotype, we have excluded linkage to 9p normal growth control in patients with familial TE as well as other and demonstrated mutations in CYLD, the gene affected in familial adnexal tumors. 5116

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Aicha Salhi, Dorothea Bornholdt, Frank Oeffner, et al.

Cancer Res 2004;64:5113-5117.

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