Laryngeal Cancer - Molecular Biology


Literature Analysis

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Tag cloud generated 10 March, 2017 using data from PubMed, MeSH and CancerIndex

Mutated Genes and Abnormal Protein Expression (10)

How to use this data tableClicking on the Gene or Topic will take you to a separate more detailed page. Sort this list by clicking on a column heading e.g. 'Gene' or 'Topic'.

TP53 17p13.1 P53, BCC7, LFS1, TRP53 -TP53 and Laryngeal Cancer
GSTM3 1p13.3 GST5, GSTB, GTM3, GSTM3-3 -GSTM3 and Laryngeal Cancer
NAT2 8p22 AAC2, PNAT, NAT-2 -NAT2 and Laryngeal Cancer
CDKN1A 6p21.2 P21, CIP1, SDI1, WAF1, CAP20, CDKN1, MDA-6, p21CIP1 -CDKN1A Expression in Laryngeal Cancer
RECQL4 8q24.3 RECQ4 -RECQL4 and Laryngeal Cancer
ADH1C 4q23 ADH3 -ADH1C and Laryngeal Cancer
PARK7 1p36.23 DJ1, DJ-1, HEL-S-67p -PARK7 and Laryngeal Cancer
TFG 3q12.2 TF6, HMSNP, SPG57, TRKT3 -TFG and Laryngeal Cancer
MIR1297 13 MIRN1297, mir-1297, hsa-mir-1297 -MicroRNA miR-1297 and Laryngeal Cancer

Note: list is not exhaustive. Number of papers are based on searches of PubMed (click on topic title for arbitrary criteria used).

Latest Publications

Wang B, Lv K, Chen W, et al.
miR-375 and miR-205 Regulate the Invasion and Migration of Laryngeal Squamous Cell Carcinoma Synergistically via AKT-Mediated EMT.
Biomed Res Int. 2016; 2016:9652789 [PubMed] Free Access to Full Article Related Publications
Previous studies have found that miR-375 and miR-205 were significantly dysregulated in laryngeal squamous cell carcinoma, which contributed to the invasion and migration of LSCC. However, the mechanisms of miR-375 and miR-205 regulating the invasion and migration of LSCC remain unknown. qRT-PCR was performed in 40 pairs of tissue samples to investigate the expression of miR-375 and miR-205 in LSCC and paracarcinoma tissues. To investigate whether or not miR-375 and miR-205 regulated the invasion and migration of LSCC synergistically via AKT-mediated epithelial-mesenchymal transition, miR-375 mimic and miR-205 inhibitor were transfected into SNU899 cells and miR-375 inhibitor and miR-205 mimic were transfected into SNU899 cells, respectively, with or without AKT inhibitor. Then the expressions of miR-375 and miR-205 were validated by qRT-PCR, cell migration and invasion were determined by wound healing assay and transwell invasive assay, and western blot analysis was performed to detect the expression of related proteins. Our results showed that miR-375 and miR-205 regulated the invasion and migration of LSCC via AKT-mediated EMT synergistically. In conclusion, our findings provided not only new information about the molecular mechanism of miRNAs regulating invasion and migration of LSCC, but also a theoretical principle for potential targeting therapy of laryngeal squamous carcinoma.

Jili S, Eryong L, Lijuan L, Chao Z
RUNX3 inhibits laryngeal squamous cell carcinoma malignancy under the regulation of miR-148a-3p/DNMT1 axis.
Cell Biochem Funct. 2016; 34(8):597-605 [PubMed] Related Publications
Laryngeal squamous cell carcinoma (LSCC) is a highly aggressive malignant cancer and accounts for 1% to 2% of all malignancies diagnosed worldwide. Runt-related transcription factor 3 (RUNX3), an important tumor suppressor, is known to related to lymph node metastasis and the development of LSCC. However, the biological roles and potential mechanisms RUNX3 expression was not well understood. In this study, we reported that the RUNX3 was significantly downregulated and highly methylated in LSCC compared with their matched normal. The enforced expression of RUNX3 inhibited LSCC cell migration, invasion, and proliferation, whereas the inhibition of RUNX3 did the opposite. We identified that RUNX3 was regulated by miR-148a-3p and found that the expression level of miR-148-3p was significantly decreased and positively related with the expression of RUNX3 in LSCC. We also identified that DNA methyltransferase enzyme DNA (cytosine-5-)-methyltransferase 1 (DNMT1) was targeted by miR-148a-3p in LSCC. The knockdown of DNMT1 promoted the expression of RUNX3 and inhibited migration, invasion, and proliferation in LSCC cells. In summary, our study demonstrated that miR-148a-3p may regulate RUNX3 expression through the modulation of DNMT1-dependent DNA methylation in LSCC, providing a novel target and a potential therapeutic pathway against LSCC. LSCC is a highly aggressive malignant cancer and accounts for 1% to 2% of all malignancies diagnosed worldwide. In this study, we reported that RUNX3, an important tumor suppressor, was significantly downregulated and highly methylated in LSCC compared with their matched normal. The overexpression of RUNX3 inhibited LSCC cell migration, invasion, and proliferation, whereas the inhibition of RUNX3 did the opposite. Moreover, RUNX3 was regulated by miR-148a-3p, which targeted DNA methyltransferase enzyme DNMT1 in LSCC cells. Therefore, miR-148a-3p may regulate RUNX3 expression through the modulation of DNMT1-dependent DNA methylation in LSCC, providing a novel target and a potential therapeutic pathway against LSCC.

Wu WQ, Zhang LS, Liao SP, et al.
Association between XRCC1 polymorphisms and laryngeal cancer susceptibility in a Chinese sample population.
Genet Mol Res. 2016; 15(4) [PubMed] Related Publications
Laryngeal cancer is the major malignant tumor affecting the upper respiratory tract. Previous studies have reported on the association between XRCC1 genetic polymorphisms and risk of laryngeal cancer, but with conflicting results. In this study, we attempted to assess the association between XRCC1 Arg194Trp, Arg280His and Arg399Gln polymorphisms and risk of laryngeal cancer in a Chinese population. A total of 126 laryngeal cancer patients and 254 control subjects were recruited to this study from the Second Medical College of Jinan University between December 2013 and May 2015. The XRCC1 Arg194Trp, Arg280His, and Arg399Gln polymorphic sites were genotyped by polymerase chain reaction-restriction fragment length polymorphism. Our results revealed a significant association between the AA genotype of XRCC1 Arg280His [odds ratio (OR) = 2.51, 95% confidence interval (CI) = 1.29-4.87, P = 0.01] and an increased risk of laryngeal cancer susceptibility compared to the GG genotype. Moreover, the A allele showed a higher risk of laryngeal cancer susceptibility compared to the G allele (OR = 1.63, 95%CI = 1.19-2.50, P = 0.002). In conclusion, the results of our study suggest that the AA genotype and A allele of the XRCC1 Arg280His polymorphism are associated with an increased laryngeal cancer risk in a Chinese population.

Shen Z, Chen X, Li Q, et al.
Elevated methylation of CMTM3 promoter in the male laryngeal squamous cell carcinoma patients.
Clin Biochem. 2016; 49(16-17):1278-1282 [PubMed] Related Publications
OBJECTIVE: CKLF-like MARVEL transmembrane domain containing 3 (CMTM3), as a tumor suppressor gene, plays an important role in the suppression of cell growth and apoptosis. The goal of our study is to investigate the association between CMTM3 promoter methylation and laryngeal squamous cell carcinoma (LSCC).
DESIGN AND METHODS: Using the bisulfite pyrosequencing technology, DNA methylation levels of seven CpG sites in CMTM3 promoter are measured in tumor tissues and their adjacent tissues of 76 male LSCC patients.
RESULTS: Our results reveal a significantly elevated promoter methylation of CMTM3 in tumor tissues compared with their adjacent tissues (P<0.001). A breakdown analysis by age shows that significant association of CMTM3 promoter methylation with cancer risk is specific to the LSCC patients older than 55years (P<0.001) but not in the younger patients (P=0.305). Moreover, the association is only observed in the LSCC patients with smoking behavior (P=0.001). Breakdown analysis also shows that CMTM3 promoter methylation is associated with cancer risk among patients with stage I LSCC (P<0.001).
CONCLUSION: In conclusion, our study indicates that elevated CMTM3 methylation is a risk factor in male LSCC patients, especially in the patients with age over 55years and with smoking behavior.

Chen F, Chen C, Qu Y, et al.
Selenium-binding protein 1 in head and neck cancer is low-expression and associates with the prognosis of nasopharyngeal carcinoma.
Medicine (Baltimore). 2016; 95(35):e4592 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Selenium-binding protein 1 (SELENBP1) expression is reduced markedly in many types of cancers and low SELENBP1 expression levels are associated with poor patient prognosis.
METHODS: SELENBP1 gene expression in head and neck squamous cell carcinoma (HNSCC) was analyzed with GEO dataset and characteristics of SELENBP1 expression in paraffin embedded tissue were summarized. Expression of SELENBP1 in nasopharyngeal carcinoma (NPC), laryngeal cancer, oral cancer, tonsil cancer, hypopharyngeal cancer and normal tissues were detected using immunohistochemistry, at last, 99 NPC patients were followed up more than 5 years and were analyzed the prognostic significance of SELENBP1.
RESULTS: Analysis of GEO dataset concluded that SELENBP1 gene expression in HNSCC was lower than that in normal tissue (P < 0.01), but there was no significant difference of SELENBP1 gene expression in different T-stage and N-stage (P > 0.05). Analysis of pathological section concluded that SELENBP1 in the majority of HNSCC is low expression and in cancer nests is lower expression than surrounding normal tissue, even associated with the malignant degree of tumor. Further study indicated the low SELENBP1 expression group of patients with NPC accompanied by poor overall survival and has significantly different comparing with the high expression group.
CONCLUSION: SELENBP1 expression was down-regulated in HNSCC, but has no associated with T-stage and N-stage of tumor. Low expression of SELENBP1 in patients with NPC has poor over survival, so SELENBP1 could be a novel biomarker for predicting prognosis.

Shi Q, Lian M, Fang JG, et al.
[A preliminary analysis on potentially targeted genes of induced chemotherapy in supraglottic laryngeal squamous cell carcinoma].
Zhonghua Er Bi Yan Hou Tou Jing Wai Ke Za Zhi. 2016; 51(7):504-10 [PubMed] Related Publications
OBJECTIVE: To analyze the differentially expressed genes produced by paclitaxel, cisplatin and 5-fluorouracil(TPF) regimen induction chemotherapy and the potentially functionally targeted genes of the induced chemotherapy in supraglottic laryngeal squamous cell carcinoma.
METHODS: A total of 11 tissue samples from patients diagnosed as supraglottic carcinoma who didn't receive any treatment before were analyzed with microarray. The patients were divided into two groups based on their responses to the induction chemotherapy: 7 were sensitive to chemotherapy and 4 were non-sensitive. Gene expressions were detected by Illumina Human HT-12 BeadChip. The bioinformatics analysis online was used to analyze the differentially expressed genes.
RESULTS: A total of 1 554 differentially expressed genes related to chemosensitivity were found. Analyzed with GO database, the up-regulated genes included the functional sets of biological adhesion, immune system development and stem cell proliferation, and the down-regulated genes included the functional sets of cell junction organization, phosphorus metabolic process and cell morphogenesis involved in differentiation. Analyzed with KEGG database, the up-regulated pathways included p53, cell adhesion and Ras signaling pathways, and the down-regulated pathways included focal adhesion, endocytosis and ErbB signaling pathways. There were statistically significant differences in the expressions of MAPK10, PIK3R5 and JUN genes, which had biological significance, between sensitive patients and non-sensitive patients.
CONCLUSION: MAPK10, PIK3R5 and JUN may be considered as potentially functional genes of the induced chemotherapy in supraglottic carcinoma.

Zatonski T, Ciesielska U, Nowinska K, et al.
Expression of Cell Cycle-Related Proteins p16, p27, p53 and Ki-67 in HPV-positive and -negative Samples of Papillomas of the Upper Respiratory Tract.
Anticancer Res. 2016; 36(8):3917-24 [PubMed] Related Publications
BACKGROUND: The role of human papillomavirus (HPV) infection as an etiological factor of respiratory tract papillomas has been described in numerous studies, however its role in malignant transformation has not been clearly defined. Depending on their oncogenic potential they have been classified as low- and high-risk HPVs. We analyzed the expression of four cell cycle-related proteins in order to understand the processes leading to malignant transformation.
MATERIALS AND METHODS: Fifty-six cases of pharyngeal and laryngeal papillomas were analyzed. Nested multiplex polymerase chain reactions to detect the presence of the HPV types, as well as immunohistochemical reactions were performed for the detection of cell cycle-related proteins p16, p27, p53 and Ki-67.
RESULTS: The presence of HPVs 6/11 and 16 was confirmed in 10/56 cases. The expression of all analyzed cell cycle-related proteins was increased in HPV-infected papillomas.
CONCLUSION: HPV infection of the upper respiratory tract may influence the expression of cell cycle-related proteins, that could indicate its possible role in the process of malignant transformation.

Starska K, Forma E, Jóźwiak P, et al.
Gene/protein expression of CAPN1/2-CAST system members is associated with ERK1/2 kinases activity as well as progression and clinical outcome in human laryngeal cancer.
Tumour Biol. 2016; 37(10):13185-13203 [PubMed] Related Publications
Recent evidence indicates the involvement of calpains (CAPNs), a family of cysteine proteases, in cancer development and progression, as well as the insufficient response to cancer therapies. The contribution of CAPNs and regulatory calpastatin (CAST) and ERK1/2 kinases to aggressiveness, disease course, and outcome in laryngeal cancer remains elusive. This study was aimed to evaluate the CAPN1/2-CAST-ERK1/2 enzyme system mRNA/protein level and to investigate whether they can promote the dynamic of tumor growth and prognosis. The mRNA expression of marker genes was determined in 106 laryngeal cancer (SCLC) cases and 73 non-cancerous adjacent mucosa (NCLM) controls using quantitative real-time PCR. The level of corresponding proteins was analyzed by Western Blot. SLUG expression, as indicator of pathological advancement was determined using IHC staining. Significant increases of CAPN1/2-CAST-ERK1/2 levels of mRNA/protein were noted in SCLC compared to NCLM (p < 0.05). As a result, a higher level of CAPN1 and ERK1 genes was related to larger tumor size, more aggressive and deeper growth according to TFG scale and SLUG level (p < 0.05). There were also relationships of CAPN1/2 and ERK1 with incidences of local/nodal recurrences (p < 0.05). An inverse association for CAPN1/2, CAST, and ERK1/2 transcripts was determined with regard to overall survival (p < 0.05). In addition, a higher CAPN1 and phospho-ERK1 protein level was related to higher grade and stage (p < 0.05) and was found to promote worse prognosis. This is the first study to show that activity of CAPN1/2- CAST-ERK1/2 axis may be an indicator of tumor phenotype and unfavorable outcome in SCLC.

Shen Z, Zhou C, Li J, et al.
Promoter hypermethylation of miR-34a contributes to the risk, progression, metastasis and poor survival of laryngeal squamous cell carcinoma.
Gene. 2016; 593(2):272-6 [PubMed] Related Publications
MiR-34a is a direct transcriptional target of p53, which induces cell cycle arrest, senescence, and apoptosis. Recently, we and others identified abnormal expression of miR-34a in laryngeal squamous cell carcinoma (LSCC). The aim of our present study was to investigate the contribution of miR-34a promoter methylation to LSCC. Bisulfite pyrosequencing technology was applied to measure DNA methylation levels of six CpG sites in the miR-34a promoter from 104 LSCC tumor tissues and their corresponding adjacent tissues. Our results showed that the methylation levels of the miR-34a promoter were significantly higher in cancer tissues compared with the adjacent tissues (adjusted P=5.05E-10). A breakdown analysis for cigarette smoking behavior indicated a significantly elevated tendency of miR-34a methylation level in LSCC patients with smoking behavior but not in LSCC patients without smoking behavior (Smoking: Tumor vs Normal, adjusted P=3.12E-9; Non-smoking: Tumor vs Normal, adjusted P=0.073). In addition, miR-34a promoter methylation frequency remarkably increased in the advanced stage patients (adjusted P=0.003) and advanced T classified tumors (adjusted P=0.015). Moreover, significant association of miR-34a promoter hypermethylation with LSCC lymph metastasis was observed (adjusted P=0.002). Meanwhile, Kaplan-Meier survival curves results showed that high methylation of miR-34a promoter were associated with poor overall survival (log-rank test, P=0.023). Our study revealed that miR-34a promoter hypermethylation was a risk factor for LSCC, played a critical role in the disease progression and metastasis, and could serve as a poor prognostic factor for LSCC.

Xu Y, Lin YP, Yang D, et al.
Clinical Significance of miR-149 in the Survival of Patients with Laryngeal Squamous Cell Carcinoma.
Biomed Res Int. 2016; 2016:8561251 [PubMed] Free Access to Full Article Related Publications
MicroRNAs (miRNAs) play critical roles in the progression of laryngeal cancer (LC). In this study, we aimed to investigate whether miR-149 is associated with the prognosis of patients with LC. A total of 97 laryngeal squamous cell carcinoma patients who underwent tumor resection were included in our follow-up study. In vitro studies was performed in cancer cell line Hep-2 to explore the antitumor role of miR-149 in LC. We found that the expression of miR-149 was significantly lower in tumor tissues, compared with vocal cord polyp tissues (P < 0.05). Kaplan-Meier analysis revealed that miR-149 expression status is significantly associated with survival duration (log rank test, P < 0.05), and multivariate Cox regression analysis revealed that patients with low miR-149 expression had shorter survival times compared with patients with high miR-149 expression. In vitro studies revealed that the exogenous expression of miRNA-149 inhibits the proliferation of human Hep-2 cells and induces cell apoptosis. Our study suggests that miR-149 expression in laryngeal squamous cell carcinoma tissues is critically associated with the prognosis of patients, and the ectopic expression of miR-149 in Hep-2 cells inhibits proliferation and cell cycle progression.

Tang D, Tang WJ, Shi XL, et al.
Association of the microsatellite (GT)n repeat polymorphisms of the HO-1 gene promoter and corresponding serum levels with the risk of laryngeal squamous cell carcinoma.
Acta Otolaryngol. 2016; 136(8):806-11 [PubMed] Related Publications
CONCLUSION: Long (GT)n repeat polymorphisms in the heme oxygenase-1 (HO-1) gene promoter and decreased serum HO-1 levels are associated with a higher susceptibility to laryngeal squamous cell carcinoma (LSCC).
OBJECTIVE: In this case-control study, the association of HO-1 microsatellite (GT)n repeat polymorphisms and serum levels with the risk of LSCC was investigated.
METHODS: A total of 142 LSCC patients, 54 vocal leukoplakia patients and 98 healthy controls, were examined for (GT)n polymorphisms by sequencing, and the serum HO-1 levels were detected in a sub-set from participants above by ELISA.
RESULTS: Compared with the controls, the LSCC group had significantly higher frequencies of L-allele (> 29 repeats) and L-allele carriers (p < 0.001, OR = 2.037 and p = 0.005, OR = 2.152, respectively). The frequencies of lymph node metastasis and of moderate or poor differentiation were significantly higher in L-allele carriers compared to non-L-allele carriers (p < 0.05). Significantly lower serum HO-1 levels were detected in LSCC patients (p < 0.001), and patients with lower serum HO-1 levels had more advanced cancer stage and a higher lymph node metastasis rate (p < 0.05). Furthermore, the L-allele carriers had lower serum HO-1 concentrations compared with the non-L-allele carriers (p = 0.019).

Yang L, Zhou Q, Chen X, et al.
Activation of the FAK/PI3K pathway is crucial for AURKA-induced epithelial-mesenchymal transition in laryngeal cancer.
Oncol Rep. 2016; 36(2):819-26 [PubMed] Related Publications
Laryngeal squamous cell carcinoma (LSCC) is one of the most common malignant tumors, and the main cause of death is metastasis. Overexpression of aurora kinase A (AURKA) plays an important role in the metastasis of LSCC. However, the mechanism by which AURKA promotes the metastasis of LSCC is poorly understood. Recent accumulating evidence indicates that epithelial-mesenchymal transition (EMT) may be one of the mechanisms of tumor metastasis. In the present study, we studied whether AURKA may induce EMT to promote the metastasis of LSCC. CCK-8 and plate colony-formation assays were carried out to show that AURKA significantly promoted the proliferation of Hep2 cells. Immunofluorescence staining and western blotting showed that EMT-related proteins changed in a time-dependent manner along with the alteration of AURKA, with decreased expression of N-cadherin, vimentin and slug and increased expression of E-cadherin. Additionally, downregulation of the expression of AURKA inhibited FAK/PI3K pathway activity. Inhibition of the FAK/PI3K pathway caused less mesenchymal-like characteristics and reduced the mobility, migration and invasion of Hep2 cells. In conclusion, AURKA may induce EMT to promote metastasis via activation of the FAK/PI3K pathway in LSCC. Those regulatory factors may present new diagnostic biomarkers and potential therapeutic targets for LSCC.

Guo Y, An R, Zhao R, et al.
miR-375 exhibits a more effective tumor-suppressor function in laryngeal squamous carcinoma cells by regulating KLF4 expression compared with simple co-transfection of miR-375 and miR-206.
Oncol Rep. 2016; 36(2):952-60 [PubMed] Related Publications
MicroRNAs (miRNAs) are reported to be important regulators of cancer-related processes, and function either as oncogenes or as tumor-suppressor genes. It was found that miR-375 was downregulated in samples of laryngeal squamous cell carcinomas (LSCCs) as compared to the level noted in adjacent non-tumor tissues, and it was inversely correlated with T grade, lymph node metastases and clinical tumor stage. Overexpression of miR-375 led to a decreased protein level of Krüppel-like factor 4 (KLF4) and marked suppression of the proliferation and invasion, and induced apoptosis of LSCC cell line Hep-2 using Cell Counting Kit-8, Transwell chamber and cell cycle assays. In addition, we examined the influence of the upregulation of miR-206 alone and upregulation of both miR-375 and miR-206 on the expression of KLF4 and Hep-2 cell behavior. The results showed that compared with the function of miR-375 in tumor suppression by regulating KLF4, co-transfection of miR-375 and miR-206 exhibited a less effective inhibitory effect not only on tumor cell proliferation and invasion, but also on tumor cell apoptosis. Taken together, miR-375 is possibly a tumor suppressor in LSCC by regulating KLF4. In addition, simple overexpression of several miRNAs did not entail higher efficacy than a single miRNA, similar to co-transfecions of miR-375 and miR-206.

Ye J, Li L, Feng P, et al.
Downregulation of miR-34a contributes to the proliferation and migration of laryngeal carcinoma cells by targeting cyclin D1.
Oncol Rep. 2016; 36(1):390-8 [PubMed] Related Publications
Laryngeal carcinoma is one of the most common head and neck cancers. MicroRNAs are a class of small non-coding RNAs 18-25 nucleotides in length that post-transcriptionally regulate gene expression and have a pivotal role in many biological processes including cancer development. In this study, we investigated the role of miR-34a in laryngeal carcinoma and confirmed the regulation of cyclin D1 (CCND1) by miR-34a. We examined miR-34a expression levels in 71 laryngeal carcinoma patient specimens by quantitative reverse transcription-PCR, and analyzed the clinicopathological significance of the obtained data. Then, functional assays were performed to investigate the potential effects of miR-34a on cancer cell proliferation and migration. In addition, western blotting, luciferase reporter assay and several algorithms were conducted to confirm that CCND1 is directly regulated by miR-34a. We demonstrated that the miR-34a expression level was significantly downregulated in laryngeal carcinoma clinical specimens compared with that observed in their paired adjacent normal tissues. Additionally, miR-34a expression was also inversely correlated with lymph node metastasis and clinical stage. Functional assays showed that ectopic expression of miR-34a inhibited cell proliferation and migration in laryngeal carcinoma cells. Bioinformatic analysis identified CCND1 as a potential target of miR-34a. Moreover, we confirmed that miR-34a inhibited the expression of CCND1 by directly binding to its 3'-untranslated region. Silencing of CCND1 induced effects similar to those of miR-34a ectopic expression, and in laryngeal carcinoma tissues, miR-34a and CCND1 were inversely correlated. Our data suggest that tumor suppressor miR-34a could serve as a new potential diagnostic marker and that ectopic expression of miR-34a may be used as a therapeutic target for laryngeal carcinoma.

Coskun C, Verim A, Farooqi AA, et al.
Are there possible associations between MnSOD and GPx1 gene variants for laryngeal cancer risk or disease progression?
Cell Mol Biol (Noisy-le-grand). 2016; 62(5):25-30 [PubMed] Related Publications
Laryngeal squamous cell carcinoma (LSCC) is a multifaceted and genomically complex disease and cellular and preclinical studies have demystified wide ranging molecular mechanisms which underpin its development and progression and resistance against wide ranging molecular therapeutics. Oxidative stress is a widely studied molecular mechanism and reportedly involved in carcinogenesis. Increasingly it is being realized that accumulation of Reactive Oxygen Species (ROS) activates defensive mechanism to counteract oxidative stress induced damage. Manganese superoxide dismutase (MnSOD) and glutathione peroxidase (GPx) are important members of defensive machinery. We investigated whether the polymorphisms of MnSOD (Ala-9Val, rs4880) and GPx1 (Pro198Leu, rs1050450) are associated with LSCC and also evaluated possible interactions between these polymorphisms and various lifestyle factors or pathological features of patients. For this purpose, 67 LSCC patients and 73 healty controls were enrolled. Molecular assessment of MnSOD and GPx1 variants were determined with polymerase chain reaction-restriction fragment length polymorphism techniques. We found that the frequency of both heterozygous PL genotype and P allele was considerably higher in patients with advanced tumor stage (T3/T4) than in those with early tumor stage (T1/T2) (OR= 5.106; 95% CI=1.372-19.004; p<0.001, OR=5.787; 95% CI =1.564-21.414; p<0.001 respectively). Although the frequency of ValVal/LL combine genotype was significantly decreased (OR=0.204, 95% CI=0.055-0.760; p=0.021), the frequency of ValAla/PL combine genotypes was higher in patients with stage T3/T4 than in those patients with stage T1/T2 (p=0.027). Consequently, we have concluded that variants of GPx1 and MnSOD should not be considered as a risk factor of LSCC, only may be accepted as a prognostic markers. Use of new technologies such as metabolomics and deep DNA sequencing will prove to be helpful in developing a deeper knowledge related to how cancer cell metabolism adapts and provides a buffer against increased oxidative stress.

Wang Y, Zhang ZX, Chen S, et al.
Methylation Status of SP1 Sites within miR-23a-27a-24-2 Promoter Region Influences Laryngeal Cancer Cell Proliferation and Apoptosis.
Biomed Res Int. 2016; 2016:2061248 [PubMed] Free Access to Full Article Related Publications
DNA methylation plays critical roles in regulation of microRNA expression and function. miR-23a-27a-24-2 cluster has various functions and aberrant expression of the cluster is a common event in many cancers. However, whether DNA methylation influences the cluster expression and function is not reported. Here we found a CG-rich region spanning two SP1 sites in the cluster promoter region. The SP1 sites in the cluster were demethylated and methylated in Hep2 cells and HEK293 cells, respectively. Meanwhile, the cluster was significantly upregulated and downregulated in Hep2 cells and HEK293 cells, respectively. The SP1 sites were remethylated and the cluster was significantly downregulated in Hep2 cells into which methyl donor, S-adenosyl-L-methionine, was introduced. Moreover, S-adenosyl-L-methionine significantly increased Hep2 cell viability and repressed Hep2 cell early apoptosis. We also found that construct with two SP1 sites had highest luciferase activity and SP1 specifically bound the gene cluster promoter in vitro. We conclude that demethylated SP1 sites in miR-23a-27a-24-2 cluster upregulate the cluster expression, leading to proliferation promotion and early apoptosis inhibition in laryngeal cancer cells.

Antonsson A, Law MH, Neale RE, et al.
Variants of EVER1 and EVER2 (TMC6 and TMC8) and human papillomavirus status in patients with mucosal squamous cell carcinoma of the head and neck.
Cancer Causes Control. 2016; 27(6):809-15 [PubMed] Related Publications
PURPOSE: There is a growing association of human papillomavirus (HPV) with some cases of mucosal squamous cell carcinoma of the head and neck (HNSCC), particularly of the oropharynx. Persistent oral HPV infection is believed to increase the likelihood of malignancy, and it is possible that host genetic factors can determine susceptibility to persistent HPV infection. Polymorphisms in the two EV genes (EVER1 and EVER2, also known as transmembrane channel protein (TMC) 6 and 8) have been identified as strong candidate genes, since a small number of critical mutations in these genes have been shown to cause profound and florid skin HPV infections, and some of them have been linked to susceptibility to cervical cancer.
METHODS: We sought to determine whether there was a difference in the frequency of single nucleotide polymorphisms (SNPs) in EVER1 (rs2613516, rs12449858) and EVER2 (rs7205422, rs12452890) between HNSCC patients with HPV-positive and HPV-negative tumors, and healthy controls. We used logistic regression to analyze SNPs in 219 patients with histologically confirmed primary SCC of the oropharynx, oral cavity, hypopharynx, or larynx, and 321 healthy controls.
RESULTS: We did not find any associations with the EVER1/EVER2 SNPs and HPV status or being a HNSCC case or a control.
CONCLUSIONS: The present data do not provide evidence for a role of genetic variations in EVER1 or EVER2 for HPV status of mucosal HNSCC or between HNSCC patients and controls.

Yang L, Wen S, Lin J, Zhang X
[Effect of CD14 promoter variants on the susceptibility to laryngeal cancer].
Zhonghua Er Bi Yan Hou Tou Jing Wai Ke Za Zhi. 2016; 51(3):197-202 [PubMed] Related Publications
OBJECTIVE: To investigate the effects of -260C>T and -651C>T genetic variants in the promoter region of CD14 on the susceptibility to laryngeal cancer.
METHODS: A total of 163 patients with laryngeal cancer and 326 healthy subjects as controls were included. Genotypes of CD14 -260C>T (rs2569190) and -651C>T (rs5744455) variants were determined by polymerase chain reaction-based restriction fragment length polymorphism (PCR-RFLP). Odd ratios (OR) and 95% confidence intervals (95%CI) were calculated with logistic regression analysis.
RESULTS: Compared with CD14 -651CC genotype carriers, -651TT genotype carriers had the increased risk of laryngeal cancer with the OR (95%CI) of 5.79 (2.38-14.11). When the -651TT genotype carriers were stratified by smoking status, the OR (95%CI) for laryngeal cancer was 8.64 (1.88-39.77) in nonsmokers and 4.74 (1.69-13.25) in smokers; the OR (95%CI) was 5.40 (1.10-26.45) in the light smokers and 4.30 (1.10-16.75) in the hevey smokers. When the -651TT genotype carriers were stratified by drinking status, the OR (95%CI) for laryngeal cancer was 6.48 (2.81-14.95) in nondrinkers and 2.01 (0.65-6.26) in drinkers. There was no significant difference in CD14 -260C>T genotype distribution between patients and controls.
CONCLUSION: Polymorphisms of -651C>T in CD14 promoter contribute to the susceptibility to laryngeal cancer in Chinese population.

Cybula M, Wieteska Ƚ, Józefowicz-Korczyńska M, et al.
New miRNA expression abnormalities in laryngeal squamous cell carcinoma.
Cancer Biomark. 2016; 16(4):559-68 [PubMed] Related Publications
BACKGROUND: Although the development of novel diagnostic and treatment strategies concerning laryngeal cancer is highly intensive, the survival rate remains virtually unchanged. Small non-coding RNAs appear to be very promising biomarkers - and so remain the focus of extensive investigation in laryngeal cancer.
OBJECTIVE: We examined the expression of five miRNA and five genes related to cancer whether they could be potential laryngeal cancer biomarkers.
METHODS: We performed an analysis in 47 patients diagnosed with laryngeal cancer. The qPCR technique was used to investigate the expression profile.
RESULTS: While miR-21-3p and miR-525-5p were found to be significantly up-regulated, miR-139-3p and miR-885-5p expression is lower in laryngeal cancer. Moreover, PIK3R1 and HACE1 were found to be also down-regulated.
CONCLUSIONS: The change in miRNA expression is frequent than the expression of other tested genes. The expression of passenger strands such as miR-21-3p and miR-139-3p, which are rarely investigated, is also significantly affected in laryngeal cancer. While PIK3R1, HACE1, miR-139-3p, and miR-885-5p may act as tumor suppressor genes in the studied tumour type, miR-21-3p and miR-525-5p seem to have oncogenic properties. Our findings suggest that miR-885-5p and PIK3R1 are the best indicators for the classification of laryngeal cancer tissue and normal mucosa.

Trivedi S, Rosen CA, Ferris RL
Current understanding of the tumor microenvironment of laryngeal dysplasia and progression to invasive cancer.
Curr Opin Otolaryngol Head Neck Surg. 2016; 24(2):121-7 [PubMed] Article available free on PMC after 01/04/2017 Related Publications
PURPOSE OF REVIEW: This review examines the historical tumor progression genetic model of laryngeal carcinomas, from dysplasia to invasive carcinoma and the role of infiltrating immune and inflammatory cells as contributors to this process.
RECENT FINDINGS: Classically, the genetic model of carcinogenesis describes overexpression of oncogenes and/or silencing of tumor suppressor genes which, when combined with exposure to environmental carcinogens over the course of time, results in damage to cellular DNA. Increasing evidence indicates that innate and adaptive immune mediators also play an important role in tumor progression of laryngeal carcinomas. Cellular mediators of immune suppression are often over represented in the tumor microenvironment and these cells release cytokines, which perpetuate immune suppression allowing for tumor immune evasion.
SUMMARY: Future therapies targeting laryngeal malignancies should focus on a combined approach which targets both genetic variations and immune mediators.

Bednarek K, Kiwerska K, Szaumkessel M, et al.
Recurrent CDK1 overexpression in laryngeal squamous cell carcinoma.
Tumour Biol. 2016; 37(8):11115-26 [PubMed] Article available free on PMC after 01/04/2017 Related Publications
In this study, we analyzed the expression profile of four genes (CCNA2, CCNB1, CCNB2, and CDK1) in laryngeal squamous cell carcinoma (LSCC) cell lines and tumor samples. With the application of microarray platform, we have shown the overexpression of these genes in all analyzed LSCC samples in comparison to non-cancer controls from head and neck region. We have selected CDK1 for further analysis, due to its leading role in cell cycle regulation. It is a member of the Ser/Thr protein kinase family of proven oncogenic properties. The results obtained for CDK1 were further confirmed with the application of reverse transcription quantitative polymerase chain reaction (RT-qPCR) technique, Western blot, and immunohistochemistry (IHC). The observed upregulation of CDK1 in laryngeal squamous cell carcinoma has encouraged us to analyze for genetic mechanisms that can be responsible this phenomenon. Therefore, with the application of array-CGH, sequencing analysis and two methods for epigenetic regulation analysis (DNA methylation and miRNA expression), we tried to identify such potential mechanisms. Our attempts to identify the molecular mechanisms responsible for observed changes failed as we did not observe significant alterations neither in the DNA sequence nor in the gene copy number that could underline CDK1 upregulation. Similarly, the pyrosequencing and miRNA expression analyses did not reveal any differences in methylation level and miRNA expression, respectively; thus, these mechanisms probably do not contribute to elevation of CDK1 expression in LSCC. However, our results suggest that alteration of CDK1 expression on both mRNA and protein level probably appears on the very early step of carcinogenesis.

Li F, Wang J, Chen M
Single nucleotide polymorphisms in DNA repair genes and the risk of laryngeal cancer: A meta-analysis.
Biomed Pharmacother. 2016; 78:92-100 [PubMed] Related Publications
Laryngeal cancer is the most common type of head and neck cancer with poor prognosis and high relapse rate. Several genes involved in DNA repair pathways have been identified for their potential role in laryngeal cancer risk. However, the results remain inconclusive. The aim of this study was to investigate the association between polymorphisms of XRCC1 Arg399Gln, XRCC3 Thr241Met, and XPD Lys751Gln and laryngeal cancer risk. Relevant case-control studies published between 2000 and 2015 were retrieved. The odds ratio (OR) with its 95% confidence interval (CI) were employed to calculate the strength of correction. Finally, total 16 articles (8 for XRCC1 Arg399Gln variant, 8 for XRCC3 Thr241Met variant and 7 for XPD Lys751Gln variant) were screened out, including 2242 laryngeal cancer cases and 3811 matched controls. Overall, our results found that only AA genotype of the XRCC1 gene Arg399Gln polymorphism under the homozygous model was associated with increased the risk of patients with laryngeal cancer (AA vs. GG: OR=1.29, 95% CI=1.00-1.65, P=0.05). This significant relationship was not detected between XRCC3 Thr241Met, XPD Lys751Gln polymorphisms and laryngeal cancer risk (P>0.05). In conclusions, our results suggested that XRCC1 gene Arg399Gln polymorphism might be a risk factor for laryngeal cancer. Future studies with large-scales, more ethnicities are still needed to further evaluate the role of these three genes mutations in laryngeal cancer susceptibility.

Liu ZH, Liu JJ, Li SS, Yang XM
Association of RUNX3 Methylation with Clinical Outcome and Cell Migration/Invasion in Laryngeal Squamous Cell Carcinoma.
Cancer Invest. 2016; 34(2):105-13 [PubMed] Related Publications
This study identifies promoter methylation status of RUNX3 in 77 LSCC patient tissues and their paired adjacent healthy tissues. Hypermethylation percentage RUNX3 occurred in LSCC samples was significantly higher than that in normal tissues, as well as associated with suppression of RUNX3 expression, TNM classification of malignant tumors stage, lymph node metastasis and poor overall survival rate. Reduced methylation and increased expression of RUNX3 genes in vitro was observed and decreased cell migration was further confirmed following 5-azacytidine treatment. RUNX 3 promoter hypermethylation can lead to down-regulation of RUNX3 in LSCC cancerous tissue.

Wang JL, Wang X, Yang D, Shi WJ
The Expression of MicroRNA-155 in Plasma and Tissue Is Matched in Human Laryngeal Squamous Cell Carcinoma.
Yonsei Med J. 2016; 57(2):298-305 [PubMed] Article available free on PMC after 01/04/2017 Related Publications
PURPOSE: Tumor-associated microRNAs have been detected in cancer, though whether plasma microRNA-155 (miR-155) could be a potential biomarker for laryngeal squamous cell carcinoma (LSCC) prognosis is unclear. We aimed to determine how miR-155 can be used to predict the clinical characteristics of patients with LSCC and correctly diagnose them.
MATERIALS AND METHODS: We collected tissue samples and peripheral blood samples before and after treatment from 280 LSCC cases and 560 controls. Real-time quantitative reverse transcription PCR was employed in this study to compare the relative expression of miR-155.
RESULTS: A total of 280 LSCC patients and 560 age- and sex-matched controls were included in the study. The miR-155 level was more up-regulated in LSCC tissue than in the non-tumor tissues (13.6 ± 2.4 vs. 3.1 ± 0.80, p<0.001). Additionally, a significantly higher miR-155 level in plasma samples from LSCC patients than in those of the controls (8.9 ± 1.25 vs. 1.8 ± 0.8, p<0.001) was reported. Tissue miR-155 showed an area under the curve (AUC) of 0.933, with a sensitivity of 82.6% and a specificity of 89.2%. The AUC for plasma miR-155 was 0.757, with a sensitivity of 58.4% and a specificity of 69.5%. When early LSCC in TNM I stage was considered, tissue miR-155 showed an area under the curve of 0.804, with a sensitivity of 85.2% and a specificity of 87.3%.
CONCLUSION: The expression of tissue and plasma miR-155 were significantly up-regulated in patients with LSCC. Our work will serve as a basis for further investigation, preferably large-scale validation in clinical trials.

Chen D, Gong L, Jiang Q, et al.
Interaction between MLL3 genetic polymorphisms, smoking, and alcohol drinking in laryngeal cancer: a case-control study.
Cancer Med. 2016; 5(3):527-33 [PubMed] Article available free on PMC after 01/04/2017 Related Publications
A previous study indicated that MLL3 genetic polymorphisms were associated with human cancer. However, whether MLL3 genetic variants are associated with the risk of laryngeal cancer is not clear. This study investigated the association between MLL3 gene polymorphisms and laryngeal cancer in a Chinese population. Four polymorphisms of the MLL3 gene (rs6943984, rs4725443, rs3800836, rs6464211) were genotyped using the TaqMan method in 592 patients with larynx cancer and 602 age- and sex-matched noncancer controls. We found that rs6943984 and rs4725443 of the MLL3 gene were significantly associated with the risk of larynx cancer after Bonferroni correction. The minor allele A for rs6943984 was associated with increased larynx cancer risk (P < 0.001, OR = 1.960, 95% CI = 1.587-2.420). C allele frequency (0.151) for rs4725443 was significantly higher in the case group than the control group (0.072, P < 0.001). Haplotype analyses showed that haplotypes A-T-A-C and G-T-G-C increased the risk of laryngeal cancer (OR = 2.406, 95% CI: 1.820-3.180, P < 0.001; OR = 1.399, 95% CI: 1.180-1.659, respectively), and haplotypes G-T-A-C and G-T-G-T significantly reduced the risk of laryngeal cancer (OR = 0.332, 95% CI: 0.271-0.408, P < 0.001; OR = 0.742, 95% CI: 0.607-0.908, respectively). We also found that MLL3 rs6943984 and rs4725443 polymorphisms had synergistic effects with smoking or alcohol drinking for the risk of laryngeal cancer. This study indicated that MLL3 genetic polymorphisms and haplotypes were associated with larynx cancer in a Chinese population. There was a mutually synergistic effect between smoking, alcohol drinking, and MLL3 gene polymorphisms for laryngeal cancer.

Shen Z, Chen X, Li Q, et al.
SSTR2 promoter hypermethylation is associated with the risk and progression of laryngeal squamous cell carcinoma in males.
Diagn Pathol. 2016; 11:10 [PubMed] Article available free on PMC after 01/04/2017 Related Publications
BACKGROUND: Somatostatin receptor 2 (SSTR2) encodes somatostatin receptor that can inhibit the cell proliferation of solid tumors. Promoter hypermethylation is likely to silence the expression of SSTR2. The goal of our study was to investigate the association between SSTR2 promoter methylation and the risk and progression of laryngeal carcinoma.
METHODS: In the current study, tumor tissues and their adjacent non-tumor tissues were collected from a total of 87 laryngeal squamous cell carcinoma (LSCC) male patients. DNA methylation levels of nine SSTR2 promoter CpGs were measured using the bisulphite pyrosequencing technology.
RESULTS: Our results revealed that there was a significantly increased SSTR2 promoter methylation in LSCC tissues than in their adjacent non-cancerous tissues (adjusted P = 0.003). Breakdown analysis by age indicated that the significant association was mainly contributed by patients younger than 60 (adjusted P = 0.039) but not in patients older than 60. Meanwhile, the significant association was observed in the patients with moderately (adjusted P = 0.037) and well differentiated tissues (adjusted P = 0.028), as well as the patients with histological stage IV (adjusted P = 0.031). Multivariate Cox analysis suggested that SSTR2 promoter methylation was an independent prognostic factor of LSCC (HR = 1.127, 95 % CI = 1.034-1.228).
CONCLUSIONS: In conclusion, SSTR2 promoter hypermethylation might be associated with the risk and progression of LSCC in males.

Huangfu H, Pan H, Wang B, et al.
Association between UGT1A1 Polymorphism and Risk of Laryngeal Squamous Cell Carcinoma.
Int J Environ Res Public Health. 2016; 13(1) [PubMed] Article available free on PMC after 01/04/2017 Related Publications
Laryngeal cancer is one of the largest subgroups of head and neck cancers. In addition to smoking and alcohol consumption, genetic polymorphisms are also risk factors for the development of laryngeal cancer. However, the exact relation between genetic variants and pathogenesis of laryngeal cancer has remained elusive. The aim of this study was to examine UGT1A1*6 (rs4148323 A/G) polymorphisms in 103 patients with laryngeal cancer and 220 controls using the high resolution melting curve (HRM) technique and to explore the association between UGT1A1*6 (rs4148323 A/G) polymorphisms and laryngeal cancer. The results showed an association between the rs4148323 G allele and increased risk of laryngeal cancer. While there was no statistically significant difference between rs4148323 genotype frequencies and different histological grades or different clinical stages of laryngeal cancer, stratification analysis indicated smoking or alcohol consumption and rs4148323 G allele combined to increase the risk of laryngeal cancer. In conclusion, the rs4148323 G allele is associated with the high UGT1A1 enzyme activity, and might increase the risk of laryngeal cancer. Furthermore, smoking or alcohol consumption and the rs4148323 G allele act synergistically to increase the risk of laryngeal cancer.

Ramakodi MP, Kulathinal RJ, Chung Y, et al.
Ancestral-derived effects on the mutational landscape of laryngeal cancer.
Genomics. 2016; 107(2-3):76-82 [PubMed] Free Access to Full Article Related Publications
Laryngeal cancer disproportionately affects more African-Americans than European-Americans. Here, we analyze the genome-wide somatic point mutations from the tumors of 13 African-Americans and 57 European-Americans from TCGA to differentiate between environmental and ancestrally-inherited factors. The mean number of mutations was different between African-Americans (151.31) and European-Americans (277.63). Other differences in the overall mutational landscape between African-American and European-American were also found. The frequency of C>A, and C>G were significantly different between the two populations (p-value<0.05). Context nucleotide signatures for some mutation types significantly differ between these two populations. Thus, the context nucleotide signatures along with other factors could be related to the observed mutational landscape differences between two races. Finally, we show that mutated genes associated with these mutational differences differ between the two populations. Thus, at the molecular level, race appears to be a factor in the progression of laryngeal cancer with ancestral genomic signatures best explaining these differences.

Li M, E Q, Liu J, et al.
[Establishment of a comprehensive database for laryngeal cancer related genes and the miRNAs].
Zhonghua Er Bi Yan Hou Tou Jing Wai Ke Za Zhi. 2015; 50(9):765-8 [PubMed] Related Publications
OBJECTIVE: By collecting and analyzing the laryngeal cancer related genes and the miRNAs, to build a comprehensive laryngeal cancer-related gene database, which differs from the current biological information database with complex and clumsy structure and focuses on the theme of gene and miRNA, and it could make the research and teaching more convenient and efficient.
METHODS: Based on the B/S architecture, using Apache as a Web server, MySQL as coding language of database design and PHP as coding language of web design, a comprehensive database for laryngeal cancer-related genes was established, providing with the gene tables, protein tables, miRNA tables and clinical information tables of the patients with laryngeal cancer.
RESULTS: The established database containsed 207 laryngeal cancer related genes, 243 proteins, 26 miRNAs, and their particular information such as mutations, methylations, diversified expressions, and the empirical references of laryngeal cancer relevant molecules. The database could be accessed and operated via the Internet, by which browsing and retrieval of the information were performed. The database were maintained and updated regularly.
CONCLUSION: The database for laryngeal cancer related genes is resource-integrated and user-friendly, providing a genetic information query tool for the study of laryngeal cancer.

Janiszewska J, Szaumkessel M, Kostrzewska-Poczekaj M, et al.
Global miRNA Expression Profiling Identifies miR-1290 as Novel Potential oncomiR in Laryngeal Carcinoma.
PLoS One. 2015; 10(12):e0144924 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Laryngeal squamous cell carcinoma (LSCC) is the most common group among head and neck cancers. LSCC is characterized by a high incidence in Europe. With the aim of better understanding its genetic background we performed global miRNA expression profiling of LSCC cell lines and primary specimens. By this approach we identified a cohort of 33 upregulated and 9 downregulated miRNA genes in LSCC as compared to epithelial no tumor controls.
RESULTS: Within this group we identified overexpression of the novel miR-1290 gene not reported in the context of LSCC before. Using a combined bioinformatical approach in connection with functional analysis we delineated two putative target genes of miR-1290 namely ITPR2 and MAF which are significantly downregulated in LSCC. They are interesting candidates for tumor suppressor genes as they are implicated in apoptosis and other processes deregulated in cancer.
CONCLUSION: Taken together, we propose miR-1290 as the new oncomiR involved in LSCC pathogenesis. Additionally, we suggest that the oncogenic potential of miR-1290 might be expressed by the involvement in downregulation of its target genes MAF and ITPR2.

Recurring Structural Abnormalities

Selected list of common recurrent structural abnormalities

Abnormality Type Gene(s)
8p23 Loss in Laryngeal Cancer

This is a highly selective list aiming to capture structural abnormalies which are frequesnt and/or significant in relation to diagnosis, prognosis, and/or characterising specific cancers. For a much more extensive list see the Mitelman Database of Chromosome Aberrations and Gene Fusions in Cancer.

8p23 Loss in Laryngeal Cancer

Jin C, Jin Y, Wennerberg J, et al.
Nonrandom pattern of cytogenetic abnormalities in squamous cell carcinoma of the larynx.
Genes Chromosomes Cancer. 2000; 28(1):66-76 [PubMed] Related Publications
Cytogenetic analysis of short-term cultures from 105 squamous cell carcinomas of the larynx (LSCC) revealed clonal chromosome aberrations in 56 tumors. Simple karyotypic changes (less than four aberrations per clone) were found in 24 cases, and the remaining 32 tumors had complex karyotypes with multiple numerical as well as unbalanced structural rearrangements. Extensive intratumor heterogeneity, in the form of multiple related subclones or unrelated clones, was observed in a large fraction of the tumors. The structural changes most often affected chromosomes 3, 1, 11, 7, 2, 15, 5, 4, 8, and 12, with rearrangements in the centromeric regions, i.e., the centromeric bands p10 and q10 and the juxtacentromeric bands p11 and q11, accounting for 43% of the total breakpoints. The most common imbalances brought about by numerical and unbalanced structural rearrangements were loss of chromosomal region 3p21-pter, chromosome arms 4p, 6q, 8p, 10p, 13p, 14p, 15p, and 17p, and gain of chromosomal regions 3q21-qter, 7q31-pter, and 8q. Among 17 recurrent aberrations identified, the most common were i(8q), hsr(11)(q13), i(3q), i(5p), and del(3)(p11). No statistically significant association was found between major karyotypic features and histological differentiation or TNM stage. The karyotypic features of the LSCC were also compared with previously published oral SCC, a subgroup of SCC that has been more extensively characterized cytogenetically. No clear-cut karyotypic differences were found between LSCC and oral SCC, with the exception that i(8q) was significantly more frequent among the latter.

Scholnick SB, Haughey BH, Sunwoo JB, et al.
Chromosome 8 allelic loss and the outcome of patients with squamous cell carcinoma of the supraglottic larynx.
J Natl Cancer Inst. 1996; 88(22):1676-82 [PubMed] Related Publications
BACKGROUND: Loss of genetic heterogeneity (allelic loss or loss of heterozygosity) on chromosome arm 8p is frequent in squamous cell carcinomas of the head and neck and has been associated with poor prognosis. We have previously demonstrated that there are three minimal regions of allelic loss on this chromosome arm. The location of each region is marked by a microsatellite locus: D8S264 (8p23), D8S552 (8p23-p22), and D8S133 (8p21). These findings imply the existence of at least three putative tumor suppressor genes on this chromosome arm that may become inactivated during the progression of squamous cell carcinoma.
PURPOSE: We used allelic loss data from these three loci to determine if inactivation of these putative suppressors is associated with poor prognosis for patients with squamous cell carcinoma of the supraglottic larynx. We also used multivariate statistics to compare the prognostic power of allelic loss at these genetic markers with that of demographic, clinical, and histopathologic parameters.
METHODS: We examined the D8S264, D8S552, and D8S133 microsatellites in tumors from a retrospective population of 59 patients. All patients had histologically confirmed squamous cell carcinoma of the supraglottic larynx and had been treated surgically. DNA was extracted from matched sets of normal and microdissected tumor tissue and used for polymerase chain reaction amplification of the microsatellite markers. Reaction products were separated by denaturing gel electrophoresis and visualized by autoradiography. Patient data were obtained from the original pathology report and from the tumor registry of the Department of Otolaryngology-Head and Neck Surgery, Washington University School of Medicine, St. Louis, MO. Histopathologic data were obtained by reviewing the portion of the resection specimen used for DNA extraction. Parameters whose association with reduced disease-free interval and reduced disease-specific survival was statistically significant were identified by use of the Kaplan-Meier method and the logrank statistic. Multivariate Cox proportional hazards models were used to identify independent predictors of poor prognosis. All statistical tests were two-sided.
RESULTS: In this patient population, allelic loss at the D8S264 locus was associated with both shorter disease-free interval (logrank P = .028) and reduced disease-specific survival (logrank P = .004). Allelic loss at the next most centromeric locus, D8S552, had a statistically significant association with only reduced disease-specific survival (logrank P = .034), whereas allelic loss at the most centromeric region, D8S133, showed no statistically significant association with reductions in either interval. Multivariate Cox models suggested that D8S264 was the only 8p marker of the three microsatellites with a statistically significant and independent association with shortened disease-free interval (relative risk [RR] = 3.38; P = .0107) and reduced disease-specific survival (RR = 3.41; P = .0105).
CONCLUSIONS: Allelic loss in the p23 region of chromosome 8 appears to be a statistically significant, independent predictor of poor prognosis in patients with supraglottic squamous cell carcinoma.

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