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• W2139615283 abstract "Malignant sinonasal tumours of epithelial origin are uncommon. The incidence is estimated to be less than 1:100,000/year (Robin et al., 1979); however, they generally tend to be aggressive, delicate to treat, and are frequently diagnosed only at an advanced stage. The histological typing of tumours of the upper respiratory tract and the ear by the World Health Organization specifies 19 different histological types of malignant epithelial tumours arising in the nasal cavity and paranasal sinuses (Shanmugaratnam, 1991). Sinonasal carcinomas, the most frequent subtype, can be differentiated histologically into the more frequent keratinizing squamous cell carcinomas and the very rare non-keratinizing, cylindrical cell, or transitional-type carcinomas. Non-keratinizing or transitional-type carcinomas accounted for only 8% of all sinonasal carcinomas in the study of Robin et al. (1979). A small percentage of transitional-type carcinomas may arise in preexisting transitional cell papilloma, as reported by Robin et al. (1979) and Svane-Knudsen et al. (1998). Knowledge on the underlying genetic changes in sinonasal malignant tumours of epidermal origin is in general very limited and there are no reports on molecular genetic changes in transitional-type carcinomas of the nasal cavity and the paranasal sinuses so far. We have analysed fresh frozen tumour specimens from 7 such patients, with their written and informed consent. In 3 tumour specimens (tumour 1: pT3N0M0 tumour from the right lateral nasal wall; tumour 2: pT2N0M0 tumour originating from the nasal septum; tumour 3: pTxN3M0 lymph node metastasis at the left mandibular angle) the histologic diagnosis was non-keratinizing, transitional-type carcinoma, or cylindrical cell carcinoma (ICD-O 8121/3). In tumour 3, the diagnosis was also based on immunohistochemical results with negative intra- and extracellular staining with periodic acid-Schiff (PAS), strong expression of cytokeratin 5, 10, and 11 and weak expression of cytokeratins 8 and 18. Tumour 4 was a pT3N0M0 keratinizing squamous cell carcinoma of the left maxillary sinus (ICD-O 8070/3); tumour 5 was a pT4N2aM0 adenocarcinoma of the left choana with deep infiltration of the skull base and the nasopharynx (ICD-O 8140/3); and tumour 6 was a pT4N0M0 adenoid cystic carcinoma of the left ethmoid sinus with infiltration of the orbit and the skull base (ICD-O 8200/3). Additionally, one transitional cell papilloma arising at the left lateral nasal wall (tumour 7, ICD-O 8121/0) was analysed. DNA from the tumour and from leukocytes was extracted using standard procedures. Loss of heterozygosity (LOH) was investigated at 15 genomic locations with high frequencies of LOH in many histological types of human cancer using polymorph microsatellite markers (Table I). Sequences of the primers were used as described by the Genome Data Base (www.gdb.org/). After amplification by polymerase chain reaction (PCR), the PCR products were analysed on 6% denaturating acrylamide gels, transferred to a nylon membrane and hybridised with 32P-labeled primer for 6 hr. Following LOH results, exons 1–3 of the von Hippel-Lindau disease gene (vHL), exon 3–10 of fragile histidine triad (FHIT), and exon 5–9 of p53 were investigated by single-strand conformational polymorphism (SSCP) analysis. The SSCP was performed at least twice with the addition of 5% and 10% glycerin to 6% non-denaturating polyacrylamide gels. The gels were run at 250 V, 50 mA, and 15 W for 4–5 hr and were constantly water cooled. The bands were visualised by routine silver staining. For double-strand sequencing analysis following SSCP analysis, an ABI Prism BigDye Terminator Cycle Sequencing Ready Reaction Kit was used (Applied Biosystems, Weiterstadt, Germany). Subsequent electrophoresis was performed using an ABI Prism 377 DNA Sequencer. Sequencing data were screened with the Analysis 1.1.1 software (Applied Biosystems) and analysed with the Sequencer 3.0 software (Gene Codes, Ann Arbor, MI). Immunochemical analyses were performed on frozen tissue to assess the expression of the putative tumour suppressors FHIT, vHL and p53. Monoclonal antibodies were G59–12 and DO-7 against p53, Ig32 against vHL (PharMingen, Hamburg, Germany) and ZR44 against FHIT (Zymed, San Francisco, CA). Biotinylated anti-mouse and anti-rabbit IgG as a secondary antibody and the avidin-streptavidin peroxidase protocol were used for staining. The expression was tested from at least 3 different tumour sites in 3 staining procedures for each protein and each tumour. A variety of frozen neoplastic and non-neoplastic tissues and cell lines were used as positive and negative controls. Tumour 1 exhibited LOH at 3p25.1 and 3p14.2 by using microsatellites D3S656 and D3S1234. Microsatellite D3S656 is close to the tumour-suppressor gene vHL and D3S1234 is located between exon 8 and 9 of the tumour-suppressor gene FHIT. This tumour also showed LOH at 8p23.22 (D8S552), whereas TP53 at 17p13.1, the location of the tumour-suppressor gene p53, retained heterozygosity. Tumour 2 also showed LOH at 3p25.1 with a homozygous constitution at 3p14.2. This tumour showed a heterozygous constitution at 17p13.1. Tumour 3 exhibited LOH solely at 17p13.1 using TP53 and exhibited a homozygous constitution at 3p25.1 and a heterozygous constitution at 3p14.2. Examplary results of the LOH analysis from tumours 1–3 are shown in Figure 1. Tumour 4 (a keratinizing squamous cell carcinoma arising in the maxillary sinus) also showed, like cases 1 and 2, LOH at 3p25.1 and additionally showed LOH for D5S82, which is located at 5q14–21. This region contains the tumour-suppressor gene APC. Tumour 5 (an adenocarcinoma) also showed LOH with marker D5S82 and additionally LOH at 4q25 (D4S407), 10q25–26 (D10S587) and 11p14–13 (D11S904). Tumour 6 (an adenoid cystic carcinoma) showed no LOH at any of the investigated locations, and, interestingly, neither did case 7, a sinonasal papilloma (Table I). Following the results of LOH analysis, with detected genomic alterations at 3p14.2, 8p23–22, and 17p13.1 in 1 and 3p25.1 in 2 cylindrical cell carcinomas, we analysed the coding regions of the tumour-suppressor genes vHL, FHIT and p53 for intragenic mutations by SSCP analysis and double-strand sequencing in case of suspect SSCP findings. None of the tumours 1–7 carried a mutation leading to a change in the amino acid sequence. In tumour 3, we detected a polymorphism in exon 8 of the FHIT gene, codon 98 [CAT(His)-CAC (His)]. In tumour 6 (an adenoid cystic carcinoma) we detected a silent mutation in exon 6, codon 213 [CGA(Arg)-CGC(Arg)] of p53. We also investigated the expression of the tumour-suppressor genes vHL, FHIT and p53 by immunohistochemistry. Every tumour specimen (1–7) showed strong expression of vHL. Particularly tumours 1, 2 and 4, with detectable LOH at the site of the tumour-suppressor gene vHL, showed no reduction of expression compared with all other tumour specimens and non-neoplastic nasal mucosa. However, there was only minimal intensity of FHIT staining in tumours 1 and 2, both showing LOH at chromosomal arm 3p. All other tumour specimens as well as non-neoplastic nasal mucosa expressed FHIT. Interestingly, none of the tumours (1–7) showed nuclear accumulation of p53, which is known to be an indicator for p53 alteration. Autoradiographs of microsatellites D3S656, D3S1234 and D8S552 (case 1), D3S656 (case 2) and TP53 (case 3) showing loss of one allele in the tumour. Left lane: nonneoplastic DNA from lymphocytes; right lane: DNA extracted from tumour tissue. Because of the presence of nonneoplastic tissue in the specimens, a faint band remains visible instead of complete loss. It would be of particular interest for the understanding of multistep transformation into malignancy to establish a genetic model of tumourigenesis in transitional type carcinoma, particularly when arising in its putative precursor, transitional type papilloma. However, the factors contributing to the genesis of sinonasal carcinomas as well as sinonasal papillomas are poorly understood. Viral cofactors in the etiology of sinonasal papilloma have been suggested (Macdonald et al., 1995; Mirza et al., 1998). The understanding of the role of the tumour-suppressor gene p53 in sinonasal papilloma is limited to 2 immunohistochemical studies of p53 expression in sinonasal papillomas (Mirza et al., 1998) and sinonasal papillomas compared with associated squamous cell carcinomas (Fang et al., 1998). In both studies, nuclear accumulation of p53 was detected in part of the papillomas as well as in squamous cell carcinomas: Mirza et al. (1998) detected p53-positive cells in 30% of sinonasal papillomas whereas the only cylindrical cell papilloma of their study showed weak p53 staining. Our understanding of genomic changes in sinonasal papillomas is restricted to the cytogenetic analysis of Jin et al. (1997) on 3 inverted nasal papillomas, in which all 3 short-term cultures exhibited cytogenetic abnormalities, and a detailed cytogenetic analysis of 6 short-term cultures derived from malignant tumours of the nasal cavity and the paranasal sinuses, including 3 squamous cell carcinomas (Jin et al., 1995). All investigated tumours showed complex chromosomal rearrangements. So far, our findings on LOH in malignant epithelial nasal tumours cannot be compared with LOH findings in large series of sinonasal papillomas; however, in our study, the transitional cell papilloma (case 7) showed no allelic loss or allelic imbalance at all, as compared with allelic imbalance at multiple loci demonstrated in cases 1 and 2, suggesting that a possible passage from transitional cell papilloma to malignant cylindrical cell, transitional-type carcinoma corresponds to a considerable gain in genomic instability. The inactivation of p53 appears to play no etiologic role in the 3 cylindrical cell carcinomas of our study and in neither of the additionally analysed malignancies, as only one tumour (case 3) showed LOH at 17p13.1 and none of the tumours carried a mutant p53 allele leading to a change in the amino acid sequence. Furthermore, none of the analysed specimens showed overexpression or nuclear accumulation of p53 protein, which would be indicative of p53 alteration, due to the short half-time of the wild-type protein. In our opinion, this is an important hint for a specific genetic pathway of epithelial neoplasms of the nasal cavity and the paranasal sinuses, because p53 alterations are among the most frequent and the earliest genetic changes in many histologic types of human cancer, including head and neck squamous cell carcinoma. Although 17p alterations were not frequent, and p53 alterations could not be detected at all, 3p alterations were present in case 1, as demonstrated by LOH at 3p14.2 and 3p25.1, and in case 2 with LOH at 3p25.1 and a homozygous constitution at 3p14.2. Furthermore, the keratinizing squamous cell carcinoma in our study also showed LOH at 3p25.1, making this chromosomal arm the most frequently altered region that we could identify. This chromosomal arm is affected by allelic imbalance in many types of human cancer, including oral cancer and nasopharyngeal cancer (Deng et al., 1998; Ishwad et al., 1996). Chromosomal arm 3p harbours the tumour-suppressor genes vHL at 3p25 and FHIT encompassing the FRA3B fragile region at 3p14.2. While vHL was not mutated in any of our specimens and the expression was uniformly strong in all specimens, FHIT expression was markedly decreased in cases 1 and 2, as assessed by immunohistochemistry. We did not detect any intragenic mutations within exon 3–10 of FHIT; however, this gene is more frequently altered by homozygous intragenic deletions rather than mutations (Druck et al., 1997). Even if we did not demonstrate homozygous deletions of FHIT, the reduced expression of this gene compared with non-neoplastic mucosa emerges as an indicator for the inactivation of FHIT in some cylindrical cell carcinomas. Yours sincerely, Karl Götte karl.goette@hno.ma.uni-heidelberg.de, Frank Riedel, Carsten Schäfer, Johannes Coy, Karl Hörmann" @default.
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• W2139615283 title "Cylindrical cell carcinomas of the paranasal sinuses do not show p53 alterations but loss of heterozygosity at 3p and 17p" @default.
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