and neck squamous cell carcinoma tumorigenesis (original) (raw)
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Genetic alterations in head and neck squamous cell carcinomas
Brazilian Journal of Medical and Biological Research, 1999
The genetic alterations observed in head and neck cancer are mainly due to oncogene activation (gain of function mutations) and tumor suppressor gene inactivation (loss of function mutations), leading to deregulation of cell proliferation and death. These genetic alterations include gene amplification and overexpression of oncogenes such as myc, erbB-2, EGFR and cyclinD1 and mutations, deletions and hypermethylation leading to p16 and TP53 tumor suppressor gene inactivation. In addition, loss of heterozygosity in several chromosomal regions is frequently observed, suggesting that other tumor suppressor genes not yet identified could be involved in the tumorigenic process of head and neck cancers. The exact temporal sequence of the genetic alterations during head and neck squamous cell carcinoma (HNSCC) development and progression has not yet been defined and their diagnostic or prognostic significance is controversial. Advances in the understanding of the molecular basis of head and neck cancer should help in the identification of new markers that could be used for the diagnosis, prognosis and treatment of the disease.
PLOS ONE, 2016
Genomic alteration in head and neck squamous cell carcinoma (HNSCC) was studied in two cell line pairs (HN30-HN31 and HN4-HN12) using conventional C-banding, multiplex fluorescence in situ hybridization (M-FISH), and array comparative genomic hybridization (array CGH). HN30 and HN4 were derived from primary lesions in the pharynx and base of tongue, respectively, and HN31 and HN12 were derived from lymph-node metastatic lesions belonging to the same patients. Gain of chromosome 1, 7, and 11 were shared in almost all cell lines. Hierarchical clustering revealed that HN31 was closely related to HN4, which shared eight chromosome alteration cases. Large C-positive heterochromatins were found in the centromeric region of chromosome 9 in HN31 and HN4, which suggests complex structural amplification of the repetitive sequence. Array CGH revealed amplification of 7p22.3p11.2, 8q11.23q12.1, and 14q32.33 in all cell lines involved with tumorigenesis and inflammation genes. The amplification of 2p21 (SIX3), 11p15.5 (H19), and 11q21q22.3 (MAML2, PGR, TRPC6, and MMP family) regions, and deletion of 9p23 (PTPRD) and 16q23.1 (WWOX) regions were identified in HN31 and HN12. Interestingly, partial loss of PTPRD (9p23) and WWOX (16q23.1) genes was identified in HN31 and HN12, and the level of gene expression tended to be the down-regulation of PTPRD, with no detectable expression of the WWOX gene. This suggests that the scarcity of PTPRD and WWOX genes might have played an important role in progression of HNSCC, and could be considered as a target for cancer therapy or a biomarker in molecular pathology.
Genome-Wide Analyses on Loss of Heterozygosity in Head and Neck Squamous Cell Carcinomas
Laboratory Investigation, 2003
Head and neck squamous cell carcinoma (HNSCC) is a frequent malignancy with a poor survival rate. Identifying the tumor suppressor gene (TSG) loci by genomic studies is an important step to uncover the molecular mechanisms involved in HNSCC pathogenesis. We therefore performed comprehensive analyses on loss of heterozygosity (LOH) using a genome-wide panel of 191 microsatellite markers in 22 HNSCC samples. We found 53 markers with significantly high LOH (Ͼ30%) on 21 chromosomal arms; the highest values of those were observed on 3p, 9p, 13q, 15q, and 17p, corresponding to D3S2432 (67%), D9S921-D9S925 (67%) and GATA62F03 (86%), D13S1493 (60%), D15S211 (62%), and D17S1353 (88%), respectively. Fifteen hot spots of LOH were defined in 13 chromosomal arms: 2q22-23, 4p15.2, 4q24-25, 5q31, 8p23, 9p23-24, 9q31.3, 9q34.2, 10q21, 11q21-22.3, 14q11-13, 14q22.3, 17p13, 18q11, and 19q12 as loci reported previously in HNSCCs. Furthermore, we identified five novel hot spots of LOH on three chromosomal arms in HNSCC at 2q33 (D2S1384), 2q37 (D2S125), 8q12-13 (D8S1136), 8q24 (D8S1128), and 15q21 (D15S211). In conclusion, our comprehensive allelotype analyses have unveiled and confirmed a total of 20 possible TSG loci that could be involved in the development of HNSCC. These results provide useful clues for identification of putative TSGs involved in HNSCC by fine mapping of the suspected regions and subsequent analysis for functional genes.
Cancer Genetics and Cytogenetics, 2007
Most human cancers are characterized by genetic instabilities. Chromosomal aberrations include segments of allelic imbalance identifiable by loss of heterozygosity (LOH) at polymorphic loci, which may be used to implicate regions harboring tumor suppressor genes. Here we performed whole genome LOH profiling on over 40 human head and neck squamous cell carcinoma (HNSCC) cell lines. Several frequent LOH regions have been identified on chromosomal arms 3p, 4p, 4q, 5q, 8p, 9p, 10p, 11q, and 17p. A genomic region of ∼7 Mb located at 8p22-p21.3 exhibits the most frequent LOH (87.9%), which suggested that this region harbors important tumor suppressor gene(s). Mitochondrial tumor suppressor gene 1 (MTUS1) is a recently identified candidate tumor suppressor gene that resides in this region. Consistent down-regulation in expression was observed in HNSCC for MTUS1 as measured by real-time quantitative RT-PCR. Sequence analysis of MTUS1 gene in HNSCC revealed several important sequence variants in the exon regions of this gene. Thus, our results suggested that MTUS1 is one of the candidate tumor suppressor gene(s) reside in 8p22-p21.3 for HNSCC. The identification of these candidate genes will facilitate the understanding of tumorigenesis of HNSCC. Further studies are needed to functionally evaluate those candidate genes.
The role of genetic susceptibility in head and neck squamous cell carcinoma
2008
Our research is an additional genetic study to uncover the molecular mechanisms involved in head and neck squamous cell carcinoma (HNSCC) pathogenesis by studying loss of heterozygosity (LOH) and microsatellite instability (MSI) in both premalignant and malignant patients and to highlight the genotype of HNSCC in Upper Egypt. Patients with HNSCC from various parts of the world may have unique genotypes and this is the first genetic study of HNSCC in Sohag 500 KM to the south of Cairo. We performed a prospective study of 41 patients with precancerous and 79 patients with cancerous laryngeal, esophageal, nasopharyngeal, nasal and oral lesions, and 50 controls (The control patients were cases admitted for ear surgery or simple nasal surgery, from whom we took biopsy from mucosal lining of nasopharynx). The present study included 170 individuals who were admitted to the Ear, Nose and Throat department, Sohag University Hospital, Sohag, in Egypt in the period between April 2001 and March 2003. Samples which were taken by punch biopsy were frozen and stored at −80°C and were subjected to histopathological examination. We investigated LOH and MSI by using six microsatellite markers located at chromosomes 3, 5, 9, and 17. The markers used were D3S1286, D9S171, D9S753, D17S654, D17S695, and CFS1-R. LOH was in all premalignant and malignant lesions at 5q33.3-q34 and 13% of Controls. LOH at 17p21 was absent in all premalignant lesions and was found in 53% of malignant lesions and 12.4% of Controls. In premalignant lesions, LOH was at 3pter-3p24.2 (73% of cases), at 9p21 (46%), at 9q21.1-22.3 (37%), and at 17p13 (37%). These percents increased in malignant lesions to 87, 80, 67, and 63%, respectively. They were 14, 19.4, 17, and 19% in controls. Examination of LOH could improve diagnosis, adds additional confidence, in HNSCC by DNA extraction from suspicious lesions in high-risk groups (smokers and alcoholics) and LOH at 3p/9p seems to be of particular value for early detection and definition of progression risk. If there are high percent of LOH at these chromosomes, active intervention should be done (chemoprevention and regular follow up head and neck examination for very early detection and management).
Oral Oncology, 2002
The candidate tumor suppressor genes' (TSG) loci on human chromosome 3 (chr.3) were mapped in six dysplastic lesions and 51 primary squamous cell carcinoma from head and neck region of an Indian patient population by using 20 highly polymorphic microsatellite markers. The two chromosomal regions 3p12-13 and 3p21.2-22 have shown the highest losses of heterozygosity (LOHs) of 34.6-38% and 37-46%, respectively with statistically significant clinical correlation's with tobacco habit, positive lymph node and tumor stages. In addition, high frequencies of microsatellite size alterations (MAs) of 16.2-28.5% and 23.8-28.2% were observed in the chromosomal 3p11-13 and 3p21.2-22 regions, respectively, with significant above-mentioned clinical correlation only in the 3p11-13 region. In the dysplastic lesions, the prevalence of LOHs compared to the MAs had indicated that LOHs might be the early events. Five tumors at stage-III/IV seemed to have lost an entire normal copy of chr.3. It was of particular note that 17% (10/57) of the samples showed rare bi-allelic alterations mainly in and around the high LOHs regions. Thus, (1) the gradual increase of LOHs/MAs during progression of the tumor, (2) high frequencies of MAs, (3) rare bi-allelic alterations in and around high LOHs regions and (4) loss of wild type chr.3 in the later stages of tumor development have suggested that such alterations might provide selective growth advantage to the tumors. Also, we propose from our data that the high LOHs regions (3p12-13 and 3p21.2-22) could harbour putative TSG(s), responsible for the development of head and neck squamous cell carcinoma.
Genome-wide Loss of Heterozygosity Analysis in Head and Neck Squamous Cell Carcinomas
Journal of Hard Tissue Biology, 2005
Identifying the tumor suppressor gene (TSG) loci by genomic studies is an important step to uncover the molecular mechanisms involved in HNSCC pathogenesis. We therefore performed comprehensive analyses on loss of heterozygosity (LOH) using a genome-wide panel of 191 microsatellite markers in 22 HNSCC samples. We found 53 markers with significantly high LOH (>30%) on 21 chromosomal arms, the highest values of those were observed on 3p, 9p, 13q, 15q, and 17p, corresponding to D3S2432 (67%), D9S921-D9S925 (67%) and GATA62F03 (86%), D13S1493 (60%), D15S211 (62%) and D17S1353 (88%), respectively. Fifteen hot spots of LOH were defined in 13 chromosomal arms reported previously in HNSCCs. Furthermore, we identified 5 novel hot spots of LOH on 3 chromosomal arms in HNSCC at 2q33 (D2S1384), 2q37 (D2S125), 8q12-13 (D8S1136), 8q24 (D8S1128) and 15q21 (D15S211). In conclusion, our comprehensive allelotype analyses have unveiled and confirmed a total of 20 possible TSG loci that could be involved in the development of HNSCC. These results provide useful clues for identification of putative TSGs involved in HNSCC by fine mapping of the suspected regions.
Head and neck squamous cell carcinoma (HNSCC) is a frequent malignancy with a poor survival rate. Identifying the tumor suppressor gene (TSG) loci by genomic studies is an important step to uncover the molecular mechanisms involved in HNSCC pathogenesis. Therefore, comprehensive analyses were performed to 170 subjects. They were 41 premalignat patients, 79 malignant patients, and 50 control subjects. The chromosomal aberrations included Translocation which ranged from 4.8% and 19% in premalignant and malignant HNSCCs, respectively. Gain ranged from 19.5% to 52%. While loss was found to be higher 29.3 and 87 in both. Duplication and breakpoint ranged 19.5% to 59.5% and 24.3% to 35.4% for premalignant and HNSCC, respectively. Loss of heterozygosity (LOH) and microsatellite instability (MSI) were detected and showed an allelic imbalance mainly in six regions (3pter-3p24.2, 5q33.3-q34, 9p21, 9q21.1-22.3, 17p, and 17p12) of chromosomes 3, 5, 9 and 17 in premalignant, and HNSCC patients c...