Laryngeal Cancer - Molecular Biology


Literature Analysis

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Tag cloud generated 29 August, 2019 using data from PubMed, MeSH and CancerIndex

Mutated Genes and Abnormal Protein Expression (12)

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
PARK7 1p36.23 DJ1, DJ-1, GATD2, HEL-S-67p -PARK7 and Laryngeal Cancer
TFG 3q12.2 TF6, HMSNP, SPG57, TRKT3 -TFG and Laryngeal Cancer
RECQL4 8q24.3 RECQ4 -RECQL4 and Laryngeal Cancer
ADH1C 4q23 ADH3 -ADH1C and Laryngeal Cancer
TMC8 17q25.3 EV2, EVER2, EVIN2 -TMC8 and Laryngeal Cancer
MIR1297 13q14.3 MIRN1297, mir-1297, hsa-mir-1297 -MicroRNA miR-1297 and Laryngeal Cancer
TMC6 17q25.3 EV1, EVER1, EVIN1, LAK-4P -TMC6 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

Chen S, Li Z, Zhou L, Zhang Y
Nan Fang Yi Ke Da Xue Xue Bao. 2019; 39(5):554-560 [PubMed] Related Publications
OBJECTIVE: To investigate the effect of sputum ubiquitin ligase (Cbl-b) gene known-down on the cytotoxicity of H9 T lymphocytes against human laryngeal squamous cancer Hep-2 cells and explore the underlying mechanism.
CONCLUSIONS: Cbl-b gene silencing effectively enhances the killing effect of H9 T lymphocytes against Hep-2 cells

Nowinska K, Ciesielska U, Piotrowska A, et al.
MCM5 Expression Is Associated With the Grade of Malignancy and Ki-67 Antigen in LSCC.
Anticancer Res. 2019; 39(5):2325-2335 [PubMed] Related Publications
BACKGROUND/AIM: The minichromosome maintenance proteins (MCMs) may be potential biomarkers of cancer cell proliferation. They are essential to initiate DNA replication. The aim of the study was to investigate the level of MCM5 expression in benign lesions (BLs) and laryngeal squamous cell cancer (LSCC).
MATERIALS AND METHODS: Immunohistochemical (IHC) analysis was carried out on 83 LSCCs and 10 BLs. Western-blot, immunofluorescence analysis (IF) and real-time PCR (RT-PCR) were performed using HEp-2 cancer cells and HaCaT keratinocytes.
RESULTS: The expression of MCM5 was higher in LSCC than in the BLs (p<0.0001) and was higher in subsequent malignancies of LSCC. Positive correlations were demonstrated between the expression levels of MCM5 and the Ki-67 antigen. In vitro studies have confirmed that the expression of MCM5 is elevated in cancer cells.
CONCLUSION: MCM5 protein may be used as a potential marker of cancer cell proliferation in LSCC.

Li Q, Ma L, Wu Z, et al.
Zinc finger E‑box binding homeobox 2 functions as an oncogene in human laryngeal squamous cell carcinoma.
Mol Med Rep. 2019; 19(6):4545-4552 [PubMed] Free Access to Full Article Related Publications
Zinc finger E‑box binding homeobox 2 (ZEB2) is a member of the Zfh1 family of two‑handed zinc finger/homeodomain proteins. To date, the role of ZEB2 in human laryngeal carcinoma has not been clearly defined. In the present study, the level of ZEB2 expression in laryngeal squamous cell carcinoma (LSCC) tissues and adjacent normal tissues was evaluated using reverse transcription‑quantitative polymerase chain reaction. The effects of ZEB2 on the growth, migration, invasion, cell cycle distribution and apoptosis of laryngeal cancer cells were also explored using MTT, Transwell and flow cytometry assays. It was identified that ZEB2 was upregulated in LSCC tissues compared with normal tissues. Silencing of ZEB2 inhibited the viability, migration and invasion of LSCC cells. It was also observed that ZEB2 silencing induced cell cycle arrest and apoptosis in LSCC cells. Furthermore, ZEB2 silencing inhibited the process of epithelial‑mesenchymal transition. Overall, the results indicated that ZEB2 promotes the progression of LSCC and that it may be a potential target for the treatment of this type of cancer.

Wang Q, Wang F, Zhong W, et al.
RNA-binding protein RBM6 as a tumor suppressor gene represses the growth and progression in laryngocarcinoma.
Gene. 2019; 697:26-34 [PubMed] Related Publications
Aberrant expression of RBM6 has been implicated in the development of human malignancies. However, the bio-function of RBM6 in laryngocarcinoma is still almost blank. Here we identified that RBM6 was downregulated in laryngocarcinoma tissues, as well as laryngocarcinoma cell lines. Notably, the expression level of RBM6 was lower in laryngocarcinoma patients at stage3/4 than that in laryngocarcinoma patients at stage1/2. Upregulation of RBM6 suppressed the proliferation of TU212 and Hep-2 cells, as shown by decreased cell viability and Ki67 level. In parallel, overexpression of RBM6 inhibited invasion and promoted apoptosis of TU212 and Hep-2 cells, as evidenced by downregulation of MMP-2 and MMP-9 protein expression and upregulation of cleaved caspase-3 protein expression. In vivo, RBM6 overexpression repressed the laryngocarcinoma tumor growth. EGFR mRNA level was higher in the laryngocarcinoma tissues than that in the adjacent normal tissues. Moreover, upregulation of RBM6 reduced the expression of EGFR, ERK and p-ERK in vitro and in vivo. Our data suggest that RBM6 as a tumor suppressor represses the growth and progression in laryngocarcinoma.

Maknı L, Ben Hamda C, Al-ansarı A, et al.
Association of common IL-10 promoter gene variants with the susceptibility to head and neck cancer in Tunisia
Turk J Med Sci. 2019; 49(1):123-128 [PubMed] Related Publications
Background/aim: We investigated the association of three IL-10 promoter single-nucleotide polymorphisms and altered IL-10 plasma levels with the risk of head and neck cancer (HNC).
Materials and methods: Study subjects comprised 194 HNC patients [137 nasopharyngeal cancer (NPC) and 57 laryngeal cancer (LC)], and 263 healthy controls. Genotyping of rs1800896 (-1082A>G), rs1800871 (-819C>T), and rs1800872 (-592A>C) IL-10 variants was performed by real-time PCR; IL-10 levels were measured by enzyme amplified immuno sensitivity assay (EAISA).
Results: Study subjects comprised 194 HNC patients [137 nasopharyngeal cancer (NPC) and 57 laryngeal cancer (LC)], and 263 healthy controls. Genotyping of rs1800896 (-1082A>G), rs1800871 (-819C>T), and rs1800872 (-592A>C) IL-10 variants was performed by real-time PCR; IL-10 levels were measured by enzyme amplified immuno sensitivity assay (EAISA).
Conclusion: Our results demonstrate that IL-10-1082, IL-10-819, and IL-10-592 variants, and haplotypes GC and GT constitute biomarkers for early detection of HNC, especially NPC subtype. IL-10 -819T/C and TA haplotype may be used as biomarkers for early detection of LC.

Yang J, Zhou L, Zhang Y, et al.
DIAPH1 Is Upregulated and Inhibits Cell Apoptosis through ATR/p53/Caspase-3 Signaling Pathway in Laryngeal Squamous Cell Carcinoma.
Dis Markers. 2019; 2019:6716472 [PubMed] Free Access to Full Article Related Publications
Cancer bioinformatics has been used to screen possible key cancer genes and pathways. Here, through bioinformatics analysis, we found that high expression of diaphanous related formin 1 (DIAPH1) was associated with poor overall survival in head and neck squamous cell carcinoma and laryngeal squamous cell carcinoma (LSCC). The effect of DIAPH1 in LSCC has not been previously investigated. Therefore, we evaluated the expression, function, and molecular mechanisms of DIAPH1 in LSCC. Immunohistochemistry and western blot analysis confirmed the significant upregulation of DIAPH1 in LSCC. We used DIAPH1 RNA interference to construct two DIAPH1-knockdown LSCC cell lines, AMC-HN-8 and FD-LSC-1, and validated the knockdown efficiency. Flow cytometry data showed that DIAPH1 inhibited apoptosis. Further, western blot analysis revealed that DIAPH1 knockdown increased the protein levels of ATR, p-p53, Bax, and cleaved caspase-3, -8, and -9. Thus, DIAPH1 is upregulated in LSCC and may act as an oncogene by inhibiting apoptosis through the ATR/p53/caspase-3 pathway in LSCC cells.

Chen L, Liu S, Li K, et al.
Evaluation of microRNA expression profiling in highly metastatic laryngocarcinoma cells.
Acta Otolaryngol. 2018; 138(12):1105-1111 [PubMed] Related Publications
BACKGROUND: Until now, little is known about the role of miRNAs in the invasion and metastasis of Laryngeal squamous cell carcinoma (LSCC).
OBJECTIVES: This study aimed to explore the relationship between microRNA and the invasion and metastasis of LSCC.
MATERIAL AND METHODS: The highly metastatic laryngocarcinoma cells were obtained from the established animal model with spontaneous lymph node metastasis of LSCC in our previous study. MicroRNA expression profiling and bioinformatic analysis were performed to analyze the microRNA expression changes in the highly metastatic laryngocarcinoma cells and the parental tumor cells (HEP-2). RT-PCR was performed for further validation of the result of microarray.
RESULTS: A total of 40 microRNAs were found to be significantly altered in the highly metastatic laryngocarcinoma cells compared to controls. Bioinformatic analysis identified that 19 key microRNAs might involve in LSCC development. Moreover, RT-PCR confirmed that miR-25, miR-100, miR-125b-5p and let-7g were differentially expressed in different laryngocarcinoma cells and human tumor specimens.
CONCLUSIONS AND SIGNIFICANCE: Our findings suggest that microRNA play an important role in the invasion and metastasis of LSCC, and provide the clues for studying the function of microRNA as well as opportunities to analyze the complex molecular abnormalities driving LSCC progression.

Meng W, Cui W, Zhao L, et al.
Aberrant methylation and downregulation of ZNF667-AS1 and ZNF667 promote the malignant progression of laryngeal squamous cell carcinoma.
J Biomed Sci. 2019; 26(1):13 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Dysregulated long noncoding RNAs (lncRNAs) are involved in the development of tumor. Aberrant methylation is one of the most frequent epigenetic alterations that regulate the expression of genes. The aim of this study was to determine the expression and methylation status of ZNF667-AS1 and ZNF667, elucidate their biological function in the development of LSCC, and identify a cis-regulation of ZNF667-AS1 to ZNF667.
METHODS: The expression and methylation status of ZNF667-AS1 and ZNF667 in laryngeal cancer cell lines and LSCC samples were tested respectively. The function of two laryngeal cancer cell lines with overexpression of ZNF667-AS1 or ZNF667 was detected. The regulation between ZNF667-AS1 and ZNF667 was determined.
RESULTS: Significant downregulation of ZNF667-AS1 was detected in laryngeal cancer cell lines and LSCC tumor tissues. The reduced expression of ZNF667-AS1 was associated with moderate/poor pathological differentiation of LSCC tumor tissues. Aberrant hypermethylation of the CpG sites of ZNF667-AS1, closing to the transcriptional start site (TSS), was more critical for gene silencing, and associated with moderate/poor pathological differentiation. In vitro hypermethylation of promoter region closing to TSS of ZNF667-AS1 decreased the luciferase reporter activity. Overexpression of ZNF667-AS1 reduced the proliferation, migration, and invasion ability of AMC-HN-8 and TU177 cells. The sense strand, ZNF667, was positively correlated with ZNF667-AS1 in expression and function. Overexpression of ZNF667-AS1 led to increased expression of ZNF667 in mRNA and protein level. ZNF667-AS1 and ZNF667 may be associated with epithelial-mesenchymal transition (EMT) process.
CONCLUSIONS: ZNF667-AS1 and ZNF667 are both down-regulated by hypermethylation, and they serve as tumor suppressor genes in LSCC. ZNF667-AS1 regulates the expression of ZNF667 in cis.

Marioni G, Ottaviano G, de Filippis C, et al.
Nuclear expression of onco-suppressors nm23-H1 and maspin are associated with lower recurrence rate in laryngeal carcinoma.
Am J Otolaryngol. 2019 Mar - Apr; 40(2):224-229 [PubMed] Related Publications
PURPOSE: The main aim of the study was to preliminarily investigate the possibly related role of nuclear onco-suppressors maspin and nm23-H1, a metastasis suppressor, in laryngeal squamous cell carcinoma (LSCC).
MATERIALS AND METHODS: Maspin expression pattern and nuclear nm23-H1 expression were ascertained in 62 consecutive LSCCs.
RESULTS: Recurrence rate was significantly lower in patients with a nuclear maspin pattern of expression; nuclear nm23-H1 expression was significantly lower in patients who experienced disease recurrence. Disease free survival (DFS) was significantly longer in patients with maspin nuclear pattern or with nuclear nm23-H1 expression ≥10%. A significant association was found between nuclear nm23-H1 expression and maspin pattern of expression in LSCC. KNN discriminant analysis considered N status, maspin sub-cellular localization and nuclear nm23-H1 expression. The selected variables' accuracy in terms of relapse was 82%. Positive predictive accuracy was 100%, and negative predictive accuracy 79%.
CONCLUSIONS: Nuclear nm23-H1 expression and maspin pattern, also in association, show promise as recurrence indicators in LSCC. Further studies are needed to shed more light on the nm23-H1 mechanism of action in LSCC and thus find ways to restore nm23-H1 loss. These preliminary findings suggest that re-activating maspin functions might represent an important goal in the treatment of advanced LSCC.

Malm IJ, Rooper LM, Bishop JA, et al.
Molecular and immunologic analysis of laryngeal squamous cell carcinoma in smokers and non-smokers.
Am J Otolaryngol. 2019 Mar - Apr; 40(2):213-217 [PubMed] Article available free on PMC after 01/03/2020 Related Publications
BACKGROUND: Laryngeal squamous cell carcinoma (LSCC) is strongly associated with tobacco use, but recent reports suggest an increasing incidence of LSCC in patients without traditional risk factors, suggesting an alternative etiology of tumorigenesis. The purpose of this study is to characterize this non-smoking population and to compare immunohistochemical markers in tumor specimens from non-smokers and smokers with LSCC.
METHODS: A retrospective chart review of patients with LSCC at Johns Hopkins Hospital (JHH) was performed. A tissue microarray (TMA) was constructed with tumor specimen from non-smokers with stage and age-matched smokers and stained for a variety of immunologic and molecular targets.
RESULTS: In the JHH cohort of 521 patients, 12% (n = 63) were non-smokers. Non-smokers were more likely to be <45 years old at time of diagnosis (OR 4.13, p = 0.001) and to have glottic tumors (OR 2.46, p = 0.003). The TMA was comprised of tumors from 34 patients (14 non-smokers, 20 smokers). Only 2 patients (6%) were human-papillomavirus (HPV) positive by high-risk RNA in situ hybridization (ISH). There was no correlation between smoking status and p16 (p = 0.36), HPV-ISH positivity (p = 0.79), phosphatase and tensin homolog (PTEN, p = 0.91), p53 (p = 0.14), or programmed death-ligand 1 (PD-L1, p = 0.27) expression.
CONCLUSIONS: Non-smokers with LSCC are more likely to be younger at the time of diagnosis and have glottic tumors than smokers with LSCC. In TMA analysis of stage and age-matched specimens from smoker and non-smokers with LSCC, the pattern of expression for common molecular and immunologic markers is similar. Further, HPV does not appear to be a major causative etiology of LSCC in either smokers or non-smokers in our cohort of patients.

Zhang F, Cao H
MicroRNA‑143‑3p suppresses cell growth and invasion in laryngeal squamous cell carcinoma via targeting the k‑Ras/Raf/MEK/ERK signaling pathway.
Int J Oncol. 2019; 54(2):689-701 [PubMed] Related Publications
MicroRNAs (miRNAs or miRs) have been identified as an important regulator in carcinogenesis and other pathological processes. However, the molecular mechanism underlying the function of miRNAs in the progression and development of laryngeal squamous cell carcinoma (LSCC) remains to be fully elucidated. In the present study, the miRNA expression pattern in LSCC tissues was profiled using miRNA microarray analysis. It was found that a large set of miRNAs are aberrantly expressed in LSCC tissues and that miR‑143‑3p was the most markedly downregulated compared with normal tissues. The low expression of miR‑143‑3p was associated with poor prognosis in LSCC. The overexpression of miR‑143‑3p repressed cellular proliferation and induced apoptosis in vitro, and inhibited tumor growth in vivo. The upregulation of miR‑143‑3p suppressed cell migration and invasion through inhibiting the epithelial‑mesenchymal transition cascade. In addition, it was verified that the oncogene k‑Ras is a target of miR‑143‑3p in LSCC cells, and the suppressive effects of miR‑143‑3p on LSCC cells were abrogated by the overexpression of k‑Ras. It was also revealed that miR‑143‑3p may inhibit cell growth and metastasis through targeting the k‑Ras/Raf/mitogen‑activated protein kinase kinase (MEK)/extracellular signal‑regulated kinase (ERK) signaling pathway. Taken together, the data indicated that the miR‑143‑3p/k‑Ras/Raf/MEK/ERK axis serves a key regulator in the development and progression of LSCC, suggesting that miR‑143‑3p may be a potential prognostic biomarker and therapeutic target in the treatment of LSCC.

Huang C, Li Y, Zhao W, et al.
α2δ1 may be a potential marker for cancer stem cell in laryngeal squamous cell carcinoma.
Cancer Biomark. 2019; 24(1):97-107 [PubMed] Article available free on PMC after 01/03/2020 Related Publications
Cancer stem cells (CSCs) have the ability to dictate tumor initiation, recurrence, and metastasis. Here, we examined the expression of aα2δ1+ in laryngeal cancer tissues and further determined the effect of α2δ1 on the migratory ability and tumorigenicity of laryngeal cancer cells. Immunofluorescence staining revealed that α2δ1 was positive in 13 (13/16, 81.25%) cases in laryngeal squamous cell carcinoma (LSCC) tissues, 7 (7/16, 43.75%) cases in paracancerous tissues and only 2 (2/16, 12.5%) cases in normal tumor tissues. Our quantitative RT-PCR assays further showed that α2δ1+ LSCC cells expressed significantly higher levels of stem cell-associated genes and drug efflux and resistance genes versusα2δ1- cells. Sphere-forming assays demonstrated higher sphere-forming efficiency in the α2δ1+versusα2δ1- subpopulation. Our Matrigel assays showed that α2δ1+ cells exhibited significantly greater invasive and migratory ability than α2δ1- cells. Furthermore, the percentage of purified α2δ1+ in TU686 and TU212 cells treated cisplatin or paclitaxel was significantly higher than that of the control group. Tumor xenograft assays revealed that the tumorigenicity of α2δ1+ cells was much higher than α2δ1- cells. In conclusion, a α2δ1+ subpopulation with CSC-like property was present in laryngeal cancer and possessed high self-renewal activity and was sufficient for tumor growth, differentiation, migration, invasion, and chemotherapeutic resistance. They could represent a promising therapeutic target for LSCC.

Li L, Wang R, He S, et al.
The identification of induction chemo-sensitivity genes of laryngeal squamous cell carcinoma and their clinical utilization.
Eur Arch Otorhinolaryngol. 2018; 275(11):2773-2781 [PubMed] Related Publications
PURPOSE: To identify potential molecular markers for induction chemotherapy of Laryngeal squamous cell carcinoma (LSCC).
METHODS: Differently expressed genes between chemo-sensitive group (seven cases) and chemo-insensitive (five cases) group after induction chemotherapy by TPF were identified by microarrays. Bayes network and Random forest analyses were employed to identify core genes for induction chemotherapy. The diagnostic value of these core genes was also evaluated by ROC analysis.
RESULTS: Six genes (SPP1, FOLR3, KYNU, LOC653219, ADH7 and XAGE1A) are highly expressed, while seven gene (CADM1, NDUFA4L2, CCND2, RARRES3, ERAP2, LYD6 and CNTNAP2) present significantly low expression. Among these genes, genes CADM1, FOLR3, KYNU, and CNTNAP2 are core candidates for LSCC chemo-sensitivity. And that the low expression of CADM1 may result in chemo-sensitivity, which leads to high expression of gene FOLR3 and KYNU, and low expression of gene CNTNAP2. Besides, ROC analysis shows that these four genes exhibit effective diagnostic value for induction chemo-sensitivity.
CONCLUSIONS: CADM1 may be a potential molecular marker for LSCC induction chemotherapy, while CADM1, FOLR3, KYNU, and CNTNAP2 may provide essential guidance for LSCC diagnosis and follow-up treatment strategies.

Zhang J, Ren X, Wang B, et al.
Effect of DACH1 on proliferation and invasion of laryngeal squamous cell carcinoma.
Head Face Med. 2018; 14(1):20 [PubMed] Article available free on PMC after 01/03/2020 Related Publications
BACKGROUND: To investigate the effect of DACH1 over-expression on proliferation and invasion of laryngeal squamous cell carcinoma (LSCC).
METHODS: The 120 cases of LSCC tumors and 114 adjacent non-neoplastic tissues were collected to detect the expression of DACH1 by immunohistochemistry. The changes of DACH1 expression from each group were assessed and correlated to the clinical parameters of the patients. Plasmid-DACH1 was transfected into Hep-2 cells to up-regulate the expression of DACH1C. Real-time PCR, Western blot, CCK8 and transwell assay were used to verify the cell proliferation and invasion after plasmid-DACH1 transfection.
RESULTS: The results indicated that DACH1 was downregulated in LSCC tissues as compared to corresponding adjacent non-neoplastic tissues. Decreased expression of DACH1 was found in the tumors upraglottic tumor, lymph node metastases, T3-4 stage and advanced clinical stage. In Hep-2 cells, transfection with plasmid-DACH1 could suppress cell proliferation, invasion and induce G1 phase extension in cell cycle.
CONCLUSIONS: DACH1 may act as a tumor suppressor gene and could be a potential target for therapeutic intervention of LSCC.

Zevallos JP, Mazul AL, Walter V, Hayes DN
Gene Expression Subtype Predicts Nodal Metastasis and Survival in Human Papillomavirus-Negative Head and Neck Cancer.
Laryngoscope. 2019; 129(1):154-161 [PubMed] Article available free on PMC after 01/01/2020 Related Publications
OBJECTIVES/HYPOTHESIS: Gene expression analyses of head and neck cancer have revealed four molecular subtypes: basal (BA), mesenchymal (MS), atypical (AT), and classical (CL). We evaluate whether gene expression subtypes in oral cavity squamous cell carcinoma (OCSCC) and laryngeal squamous cell carcinoma (LSCC) can be used to predict nodal metastasis and prognosticate survival.
STUDY DESIGN: Retrospective cohort study and genomic analysis.
METHODS: OCSCC and LSCC cases were identified from the The Cancer Genome Atlas (TCGA) head and neck cancer cohort. RNA-seq by expected maximization (RSEM) was used to quantify gene expression levels from TCGA RNA-seq data and to assign each case to one of four subtypes. Descriptive statistics were used to describe patient, disease, and treatment characteristics in each subtype. Cox regression and Kaplan-Meier analyses were used to determine associations with survival.
RESULTS: OCSCC cases were comprised primarily of the MS and BA subtypes, whereas LSCC was comprised primarily of CL and AT subtypes. In OCSCC, the MS subtype was significantly associated with higher risk of nodal metastasis. In a subset analysis of clinically T1-2N0M0 OCSCC, we demonstrate that the MS subtype was predictive of occult nodal metastasis (relative risk = 3.38, 95% confidence interval [CI]: 1.08-10.69). In LSCC, the CL subtype was associated with significantly worse overall survival (hazard ratio = 4.32, 95% CI: 1.77-10.54, P = .001).
CONCLUSIONS: Gene expression analysis reveals potential novel markers of nodal metastasis and survival in human papillomavirus-negative head and neck cancer. Future studies will continue to refine and validate these markers, with the goal of providing molecular risk assessments that guide therapy and improve patient outcomes.
LEVEL OF EVIDENCE: 2b Laryngoscope, 129:154-161, 2019.

Huang Q, Yang J, Zheng J, et al.
Characterization of selective exosomal microRNA expression profile derived from laryngeal squamous cell carcinoma detected by next generation sequencing.
Oncol Rep. 2018; 40(5):2584-2594 [PubMed] Article available free on PMC after 01/01/2020 Related Publications
Exosomes are nanometer‑scale extracellular vesicles derived from almost all types of cells and key signaling mediators between cancer cells and their microenvironment. Certain microRNAs (miRNAs) are selected for exosome packing and exclusion from parental cells, while other miRNAs are selectively retained by cells, suggesting a biological role for these miRNAs in tumor malignant progression. In the present study, we isolated and characterized the exosomes derived from the laryngeal squamous cell carcinoma (LSCC) cell line AMC‑HN‑8 for the first time, and identified a subset of miRNAs enriched in the exosomes compared with parental cells, such as miR‑1246, miR‑1290, miR‑335‑5p, miR‑127‑3p and miR‑122‑5p through small RNA sequencing combined with reverse transcription‑quantitative PCR (RT‑qPCR) analysis. Potential target prediction, Gene Ontology (GO) annotation and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis revealed possible functions associated with these selective exosomal miRNAs. In conclusion, the present study demonstrated that the LSCC cell line AMC‑HN‑8 can release exosomes and cells can selectively pack certain miRNAs into exosomes.

Zhang J, Hu H, Zhao Y, Zhao Y
CDR1as is overexpressed in laryngeal squamous cell carcinoma to promote the tumour's progression via miR-7 signals.
Cell Prolif. 2018; 51(6):e12521 [PubMed] Related Publications
OBJECTIVES: To investigate the roles played by the circular RNA (circRNA) molecule ciRS-7 (CDR1as) and tumour suppressor miRNA-7 (miR-7) in laryngeal squamous cell carcinoma (LSCC).
METHODS: Specimens of LSCC tissue (n = 30) and corresponding relative normal tissue (n = 30) were collected to determine their levels and clinical significance of CDR1as/mir-7 expression. The CDR1as and miR-7 were overexpressed in LSCC cells to investigate its function and mechanism in vitro and in vivo.
RESULTS: Patients with high TNM stages, poorly differentiated tumours, lymph node metastases and poor prognosis had high CDR1as levels but low miR-7 levels. CDR1 expression was negatively associated with miR-7 expression in LSCC. Overexpression of CDR1as in vitro enhanced cell vitality, and promoted the proliferation, migration, and invasion of two LSCC cell lines (Hep2 and AMC-HN-8.) However, these effects could be abrogated by knockdown of CDR1as or the forced expression of miR-7. Mechanistically, overexpressed CDR1 molecules functioned as miR-7 sponges and upregulated the key targets of miR-7, CCNE1, and PIK3CD in Hep2 and AMC-HN-8 cells. In vivo studies demonstrated the tumourigenic role of CDR1as. Overexpression of CDR1as alone promoted tumour growth and increased expression of the proliferation indices ki-67, CCNE1, and PIK3CD. Although the tumour suppressor miR-7 effectively inhibited the tumour growth, this effect could be counteracted by co-treatment with CDR1as in vivo.
CONCLUSION: CDR1as is an oncogene that promotes LSCC progression by regulating miR-7 signals.

Zhao R, Li FQ, Tian LL, et al.
Comprehensive analysis of the whole coding and non-coding RNA transcriptome expression profiles and construction of the circRNA-lncRNA co-regulated ceRNA network in laryngeal squamous cell carcinoma.
Funct Integr Genomics. 2019; 19(1):109-121 [PubMed] Related Publications
Recently, accumulating evidence has demonstrated that non-coding RNAs (ncRNAs) play a vital role in oncogenicity. Nevertheless, the regulatory mechanisms and functions remain poorly understood, especially for lncRNAs and circRNAs. In this study, we simultaneously detected, for the first time, the expression profiles of the whole transcriptome, including miRNA, circRNA and lncRNA + mRNA, in five pairs of laryngeal squamous cell carcinoma (LSCC) and matched non-carcinoma tissues by microarrays. Five miRNAs, four circRNAs, three lncRNAs and five mRNAs that were dysregulated were selected to confirm the verification of the microarray data by quantitative real-time PCR (qRT-PCR) in 20 pairs of LSCC samples. We constructed LSCC-related competing endogenous RNA (ceRNA) networks of lncRNAs and circRNAs (circRNA or lncRNA-miRNA-mRNA) respectively. Functional annotation revealed the lncRNA-mediated ceRNA network were enriched for genes involved in the tumor-associated pathways. Hsa_circ_0033988 with the highest degree in the circRNA-mediated ceRNA network was associated with fatty acid degradation, which was responsible for the depletion of fat in tumor-associated cachexia. Finally, to clarify the ncRNA co-regulation mechanism, we constructed a circRNA-lncRNA co-regulated network by integrating the above two networks and identified 9 modules for further study. A subnetwork of module 2 with the most dysregulated microRNAs was extracted to establish the ncRNA-involved TGF-β-associated pathway. In conclusion, our findings provide a high-throughput microarray data of the coding and non-coding RNAs and establish the foundation for further functional research on the ceRNA regulatory mechanism of non-coding RNAs in LSCC.

López F, Hunt JL, Nixon IJ, et al.
How phenotype guides management of the neuroendocrine carcinomas of the larynx.
J Laryngol Otol. 2018; 132(7):568-574 [PubMed] Related Publications
OBJECTIVE: This review aimed to critically analyse data pertaining to the clinical presentation and treatment of neuroendocrine carcinomas of the larynx.
METHOD: A PubMed search was performed using the term 'neuroendocrine carcinoma'. English-language articles on neuroendocrine carcinoma of the larynx were reviewed in detail.Results and conclusionWhile many historical classifications have been proposed, in contemporary practice these tumours are sub-classified into four subtypes: carcinoid, atypical carcinoid, small cell neuroendocrine carcinoma and large cell neuroendocrine carcinoma. These tumours exhibit a wide range of biological behaviour, ranging from the extremely aggressive nature of small and large cell neuroendocrine carcinomas, which usually have a fatal prognosis, to the less aggressive course of carcinoid tumours. In small and large cell neuroendocrine carcinomas, a combination of irradiation and chemotherapy is indicated, while carcinoid and atypical carcinoid tumour management entails conservation surgery.

Niu JT, Zhang LJ, Huang YW, et al.
MiR-154 inhibits the growth of laryngeal squamous cell carcinoma by targeting GALNT7.
Biochem Cell Biol. 2018; 96(6):752-760 [PubMed] Related Publications
MicroRNAs are critical regulators of the development and progression of laryngeal squamous cell carcinoma (LSCC). However, the role of microRNA-154 (miR-154) in the development and progression of LSCC has not been clarified. We found that down-regulated miR-154 expression in LSCC tissues was associated with poorer prognosis in LSCC patients. MiR-154 over-expression inhibited the proliferation, clonogenicity, and migration of LSCC cells and induced cell cycle arrest, which were reversed by miR-154 inhibition. MiR-154 targeted GALNT7 expression by reducing GALNT7-regulated luciferase activity in LSCC cells while up-regulating GALNT7 mRNA transcription in LSCC tissues and cells. GALNT7 silencing significantly attenuated the proliferation, clonogenicity, and migration of LSCC cells and induced cell cycle arrest. Finally, intravenous treatment with lentivirus for miR-154, but not scrambled control miRNA, significantly restrained the growth of implanted LSCC Hep-2 tumors and decreased the tumor mass by reducing GALNT7 expression in mice. Therefore, miR-154 may serve as a novel prognostic marker and therapeutic target for LSCC.

Hui L, Zhang J, Guo X
MiR-125b-5p suppressed the glycolysis of laryngeal squamous cell carcinoma by down-regulating hexokinase-2.
Biomed Pharmacother. 2018; 103:1194-1201 [PubMed] Related Publications
Laryngeal squamous cell carcinoma (LSCC) is the most common form of laryngeal carcinoma with poor prognosis. Exploring novel factors involved in the progression of LSCC is quite necessary for understanding the mechanisms and designing therapeutic strategies for LSCC. In this study, we showed that miR-125b-5p was significantly down-regulated in LSCC tissues and cell lines. The decreased expression of miR-125b-5p was associated with the tumor differentiation, metastasis and high clinical stage of the LSCC patients. Overexpression of miR-125b-5p suppressed the proliferation and induced apoptosis of LSCC cells. Bioinformatics analysis predicted hexokinase-2 (HK2), an essential enzyme involved in the glycolysis of cancer cells, as one of the downstream targets of miR-125b-5p. Further molecular studies showed that highly expressed miR-125b-5p bound the 3'-UTR of HK2 and decreased both the mRNA and protein levels of HK2. Consistent with the function of HK2 in glycolytic metabolism, overexpression of miR-125b-5p significantly suppressed the glucose consumption and lactate production of LSCC cells. Notably, restoration the expression of HK2 attenuated the inhibitory effect of miR-125b-5p on the glycolysis of LSCC cells. The inverse correlation between the expression of miR-125b-5p and HK2 in LSCC tissues further supported the involvement of miR-125b-5p-HK2 axis in the progression of LSCC. Collectively, these finding suggested the miR-125b-5p-HK2 pathway as a novel mechanism in regulating the glycolysis and progression of LSCC.

Chen X, Zhang L, Tang S
MicroRNA-4497 functions as a tumor suppressor in laryngeal squamous cell carcinoma via negatively modulation the GBX2.
Auris Nasus Larynx. 2019; 46(1):106-113 [PubMed] Related Publications
OBJECTIVE: MicroRNAs (miRNAs) are aberrantly expressed in various tumors and play a critical role in the progression and development of tumors. However, there is little information about the role of miR-4497 in laryngeal squamous cell carcinoma (LSCC). The aim of this study is to investigate the role of miR-4497 in LSCC.
METHODS: MiR-4497 expression in tumor tissues and adjacent normal tissues was measured by RT-PCR. The effects of miR-4497 on cell viability and apoptosis were evaluated by the MTT assay, Flow cytometry and caspase-3 activity assay. Western blot analysis was used to measure the expression of various proteins. Bioinformatic analysis and luciferase reporter assay were applied to investigate the relationship between miR-4497 and GBX2.
RESULTS: We found that miR-4497 expression was downregulated in LSCC tumor tissues and cell lines compared to the normal counterparts. Overexpression of miR-4497 inhibits the proliferation and induces apoptosis of LSCC cells accompanied by the down-regulation of anti-apoptotic Bcl-2 proteins. Mechanisms investigation revealed that GBX2 is a direct target of miR-4497. miR-4497 expression was inversely correlated with GBX2 expression in LSCC tissues. Moreover, overexpression of miR-4497 leads to the activation of ERK, JNK but not p38. Inhibition of ERK by specific inhibitor SCH772984 could interfere the apoptosis induced by overexpression of miR-4497.
CONCLUSION: Therefore, our results indicate that miR-4497 may play a suppressive role in LSCC by targeting GBX2, which offer new insights into the tumorigenesis of LSCC.

Liang XB, Lang JT, Liu YH
[Advances in the regulation of lncRNA on laryngeal squamous cell carcinoma].
Lin Chung Er Bi Yan Hou Tou Jing Wai Ke Za Zhi. 2018; 32(4):318-320 [PubMed] Related Publications
Laryngeal cancer (LC) is one of the most common malignant tumors that occur in the head and neck. Emerging evidence shows that coding RNAs and non-coding RNAs play key roles in the formation and progression of LC. In this review, we focus on the regulation of lncRNAs in LC. LncRNAs appear to be involved in laryngeal cancer growth, invasion, and metastasis and in establishment of the laryngeal tumor microenvironment through various mechanisms. Furthermore, we also discuss the possibilities of establishing lncRNAs as potential biomarkers and therapeutic targets for laryngeal cancer. Taken together, we summarize the emerging roles of lncRNAs in laryngeal cancer development and their possible clinical significance.

Zhao X, Zhang W, Ji W
miR-196b is a prognostic factor of human laryngeal squamous cell carcinoma and promotes tumor progression by targeting SOCS2.
Biochem Biophys Res Commun. 2018; 501(2):584-592 [PubMed] Related Publications
BACKGROUND: Laryngeal squamous cell carcinoma (LSCC) has the second highest incidence among the head and neck malignancies. Additionally, the incidence of LSCCs has been recently increasing. Therefore, understanding the mechanisms of LSCC tumorigenesis and identifying novel biomarkers to accurately predict and improve the prognosis of patients with LSCC is extremely important.
METHODS: miR-196b and SOCS2 expression was measured by qRT-PCR and western blot. Their correlation was analyzed with the Pearson test. TU212 and TU177 cells were cultured and transfected for MTT, Transwell, and apoptosis assays upon miR-196b knockdown, SOSC2 overexpression or SOCS2 silencing. Dual-luciferase reporter assay were conducted to identify the relationship between miR-196b and SOCS2. Moreover, the correlation between clinicopathological parameters and miR-196b/SOCS2 expression in patients was analyzed. Univariate and multivariate analysis and log-rank tests were used to determine if miR-196 was an independent LSCC prognostic factors.
RESULTS: We reported the aberrant expression and inverse correlation of miR-196b and SOCS2 in LSCC samples. miR-196b promoted LSCC cells proliferation and invasion, and suppressed apoptosis by directly inhibiting SOCS2 expression in vitro. Moreover, we also revealed that miR-196b/SOCS2 expression correlated with T stage and cervical metastasis. miR-196b was demonstrated to be an independent prognostic factor for overall survival of patients with LSCC.
CONCLUSIONS: Overexpression of miR-196b suppresses SOCS2 in human LSCC resulting in tumor progression and poor prognosis. miR-196b is a potential marker for prognosis assessment and targeting miR-196b may be a novel valuable strategy for the treatment of LSCC.

Lu C, Shi X, Wang AY, et al.
RNA-Seq profiling of circular RNAs in human laryngeal squamous cell carcinomas.
Mol Cancer. 2018; 17(1):86 [PubMed] Article available free on PMC after 01/01/2020 Related Publications
Abnormal expression of non-coding circular RNAs (circRNAs) have been reported in many types of tumors. circRNA have been suggested to be an ideal candidate biomarker for diagnostic and therapeutic implications in cancers. The aim of this study was to assess the circRNA expression profile of laryngeal squamous cell carcinomas (LSCC). The biopsy samples from patients with LSCC were obtained intra-operatively. The circRNA expression was performed using secondary sequencing. Among 10 patients with LSCC, 2 were well differentiated, 3 were moderately differentiated and 5 were adjunctive samples with normal and LSCC tissues. A total of 21,444 distinct circRNA candidates were detected. Among them, we defined the statistical criteria for selecting aberrant-expressed circRNA using a q-value of < 0.001 with a fold change of > 2.0 or < 0.5. A total of 29 circRNA were upregulated and 19 circRNA were downregulated significantly in the LSCC tissues. The intersection of these dysregulated circRNAs of normal-well differentiated set and normal-moderately differentiated set was then assessed to narrow the upregulated and downregulated circRNAs down to 18 and 5 respectively. Furthermore, an association of the circRNA-miRNA-mRNA was investigated, showing that 20 dysregulated circRNA successfully predicted an interaction with several cancer-related miRNAs. Finally, a further KEGG analysis showed that PPAR, Axon guidance, Wnt and Cell cycle signaling pathway were key putative pathways in the process of LSCC. hsa_circ:chr20:31876585-31,897,648 was found to be able to differentiate most of LSCC from the matching normal tissues. This observational study demonstrated dysregulation of circRNA in LSCC, which may have an impact on development of potential biomarkers in this disease. Validation of down-regulation of hsa_circ:chr20:31876585-31,897,648 in LSCC compared to each adjunctive tissue by Q-RT-PCR, indicating that hsa_circ:chr20:31876585-31,897,648 may be a novel promising tumor suppresser in LSCC.

Skalski M, Ustaszewski A, Jaskiewicz K, et al.
Single nucleotide polymorphism rs11614913 associated with CC genotype in miR-196a2 is overrepresented in laryngeal squamous cell carcinoma, but not salivary gland tumors in Polish population.
J Appl Genet. 2018; 59(3):301-304 [PubMed] Article available free on PMC after 01/01/2020 Related Publications
The miRNA-196a2 has shown significance in the development of various neoplasms, including head and neck squamous cell carcinoma (HNSCC). The oncogenic functionality of this miRNA is mediated via its potential to target annexin A1 mRNA, a tumor suppressor gene involved in inhibition of the NF-κB pathway. Interestingly, recent data indicate a susceptibility for aforementioned neoplasms in patients with the CC genotype vs the CT and TT genotypes of the rs11614913 SNP located within the DNA sequence of the miR-196a2 that results in elevated expression of the gene. To further investigate this phenomenon, we genotyped this SNP in 40 patients with laryngeal squamous cell carcinoma (LSCC), the most common tumor of the head and neck region and 60 patients with salivary gland tumors (SGT) that show a yet unexplained incidence increase in the last two decades. In agreement with previous reports, we have identified a statistically significant (p < 0.05) overrepresentation of the CC genotype in LSCC patients and demonstrated in LSCC cell lines that it results in elevated expression of miR-196a2 as compared to cell lines with the TT genotype of the respective SNP. Importantly, none of these correlations was found in patients with SGT. These findings underline the importance of the SNP rs11614913 for LSCC development in the Polish population and moreover highlight the different genetic background of the two studied neoplasms of the head and neck region.

Ekizoglu S, Seven D, Ulutin T, et al.
Investigation of the SLC22A23 gene in laryngeal squamous cell carcinoma.
BMC Cancer. 2018; 18(1):477 [PubMed] Article available free on PMC after 01/01/2020 Related Publications
BACKGROUND: Laryngeal squamous cell carcinoma (LSCC) is the second most common cancer of the head and neck. In order to identify differentially expressed genes which may have a role in LSCC carcinogenesis, we performed GeneFishing Assay. One of the differentially expressed genes was the SLC22A23 (solute carrier family 22, member 23) gene. SLC22A23 belongs to a family of organic ion transporters that are responsible for the absorption or excretion of many drugs, xenobiotics and endogenous compounds in a variety of tissues. SLC22A23 is expressed in a various tissues but no substrates or functions have been identified for it. Although the exact function is unknown, single nucleotide polymorphisms (SNPs) which are located in SLC22A23 gene were associated with inflammatory bowel disease (IBD), endometriosis-related infertility and the clearance of antipsychotic drugs. On the other hand SLC22A23 is identified as a prognostic gene to predict the recurrence of triple-negative breast cancer.
METHODS: To understand the role of the SLC22A23 gene in laryngeal carcinogenesis, we investigated its mRNA expression level in laryngeal tumor tissue and adjacent non-cancerous tissue samples obtained from 83 patients by quantitative real-time PCR. To understand the association between SNPs in SLC22A23 and LSCC, selected genetic variations (rs4959235, rs6923667, rs9503518) were genotyped.
RESULTS: We found that SLC22A23 expression was increased in 46 of 83 tumor tissues (55.4%) and was decreased in 30 of 83 (36.1%) tumor tissues compared to normal tissues. 77.2% of patients were homozygote for genotype rs9503518-AA and they most frequently had histological grade 2 and 3 tumors. We also found that rs9503518-AA genotype is associated with increased SLC22A23 expression.
CONCLUSIONS: Our results indicate that SLC22A23 may play a role in the development of laryngeal cancer.

Villaronga MÁ, Hermida-Prado F, Granda-Díaz R, et al.
Immunohistochemical Expression of Cortactin and Focal Adhesion Kinase Predicts Recurrence Risk and Laryngeal Cancer Risk Beyond Histologic Grading.
Cancer Epidemiol Biomarkers Prev. 2018; 27(7):805-813 [PubMed] Related Publications

Al-Otaibi SS, Al Zaher YN, Al Zaher NN, Khoja HA
Laryngeal carcinoma in a father and son. Possible familial risk?
Saudi Med J. 2018; 39(4):424-425 [PubMed] Article available free on PMC after 01/01/2020 Related Publications
[No Abstract Available].

Byzia E, Soloch N, Bodnar M, et al.
Recurrent transcriptional loss of the PCDH17 tumor suppressor in laryngeal squamous cell carcinoma is partially mediated by aberrant promoter DNA methylation.
Mol Carcinog. 2018; 57(7):878-885 [PubMed] Related Publications
Protocadherins are cell-cell adhesion molecules encoded by a large family of genes. Recent reports demonstrate recurrent silencing of protocadherin genes in tumors and provide strong arguments for their tumor supresor functionality. Loss of protocadherins may contribute to cancer development not only by altering cell-cell adhesion, that is a hallmark of cancer, but also by enhancing proliferation and epithelial mesenchymal transition of cells via deregulation of the WNT signaling pathway. In this study we have further corroborated our previous findings on the involvement of PCDH17 in laryngeal squamous cell carcinoma (LSCC). We used bisulfite pyrosequencing to analyze a cohort of primary LSCC tumors for alterations in PCDH17 promoter DNA methylation as an alternative gene inactivation mechanism to the homozygous deletions reported earlier. Moreover, we analyzed primary LSCC samples by immunohistochemistry for PCDH17 protein loss. We identified recurrent elevation of PCDH17 promoter DNA methylation in 32/81 (40%) primary tumors (P < 0.001) and therein hypermethylation of 12 (15%) cases in contrast to no tumor controls (n = 24) that were all unmethylated. Importantly, DNA demethylation by decitabine has restored low level PCDH17 expression in LSCC cell lines. In conclusion, we provide a mechanistic explanation of recurrently observed PCDH17 silencing in LSCC by demonstrating the role of promoter methylation in this process. In light of these findings and recent reports showing that PCDH17 methylation is detectable in serum of cancer patients we suggest that testing PCDH17 DNA methylation might serve as a potential biomarker in LSCC.

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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