Squamous Cell Carcinoma Susceptibility Research Articles

Evaluating the Role of KRAS and NRAS 3' Untranslated Region Polymorphisms in Susceptibility and Clinical Features of Laryngeal Squamous Cell Carcinoma.

Laryngeal squamous cell cancer (LSCC) is one of the most common head and neck cancers in which genetic factors play an important role in its occurrence. This study investigated the association of KRAS and NRAS gene polymorphisms with the risk of LSCC. KRAS polymorphisms including rs712, rs61764370, rs8720, and rs9266, as well as NRAS rs14804, were compared in the patient group (n=120) and the control group (n=100). The Sanger sequencing method was used to identify these polymorphisms. The results showed that KRAS rs8720 is associated with an increased risk of LSCC; consequently, those with the CT genotype were at a higher risk than those with the CC genotype. Also, the CC genotype had a protective effect on rs14804 polymorphism of theNRAS gene. These findings show that some KRAS and NRAS polymorphisms can be used as diagnostic and prognostic biomarkers in LSCC, and their accurate identification by Sanger sequencing is of great importance in research related to cancer genetics.

The Association of TP53, BCL2, BAX and NOXA SNPs and Laryngeal Squamous Cell Carcinoma Development.

Head and neck cancer is the seventh leading cancer diagnosis worldwide. One of the most common cancers in the head and neck region is laryngeal cancer. In past years, the incidence of laryngeal squamous cell carcinoma has risen by 23%, and despite progress in treatment modalities, the survival rate has not changed. It is well known that genetic alterations may contribute to individuals' susceptibility to cancer. Research of genetic alterations, such as single nucleotide polymorphisms, is essential to understanding carcinogenesis and susceptibility of laryngeal squamous cell carcinoma. A total of 200 LSCC patients and 200 controls were included in this retrospective case-control study; both groups were matched by age and sex. In the present study, we analyzed six SNPs in genes essential for apoptosis regulation: TP53 (rs9895829, rs17884306), BCL2 (rs1564483, rs4987855), BAX (rs704243), NOXA (PMAIP1) (rs1041978, rs78800940). We evaluated their associations with the risk of LSCC development, its pathomorphological manifestation, and patients' overall survival rate. Genotyping was carried out using RT-PCR. The AG genotype of rs9895829 was more prevalent in controls than in cancer patients, leading to lower susceptibility to LSCC (OR = 0.301; 95%CI 0.096-0.940; p = 0.039). None of the analyzed SNPs showed an association with pathomorphological features of LSCC, but NOXA rs1041978 T allele carriers were found to be diagnosed with LSCC at an older age (OR = 1.962; 95%CI 1.072-3.592; p = 0.031). There was no statistically significant association between investigated SNPs and patient OS. The present study indicates that the AG genotype of rs9895829 provides a protective effect against LSCC development.

The Role of Ryanodine Receptor 2 Polymorphisms in Oral Squamous Cell Carcinoma Susceptibility and Clinicopathological Features.

Head and neck squamous cell carcinoma (HNSCC) is the sixth most common malignancy worldwide, and oral squamous cell carcinoma (OSCC) is one of the most common types. There is strong evidence that ryanodine receptor 2 (RYR2) plays an important role in different types of cancer according to previous studies. Its expression is associated with survival in patients with HNSCC, but it is unknown whether altered RYR2 expression contributes to tumorigenesis. Therefore, we examined how RYR2 polymorphisms affect OSCC susceptibility and clinicopathological characteristics. Five single nucleotide polymorphisms (SNPs) of RYR2, rs12594, rs16835904, rs2779359, rs3765097, and rs3820216, were analyzed in 562 cases of OSCC and 332 healthy controls using real-time PCR. We demonstrated that RYR2 SNP rs12594 was significantly different between the case and control groups, but this difference was not significant after adjusting for personal habits. In contrast, we found that different genotypes of SNP rs2779359 were significantly associated with the characteristics of clinical stage and tumor size in OSCC patients, according to the odds ratios and the adjusted odds ratios; specifically, patients with the T genotype had 1.477-fold (95% CI, 1.043 to 2.091; p = 0.028) and 1.533-fold (95% CI, 1.087-2.162; p = 0.015) increases in clinical stage and tumor size, respectively, compared with patients with the C allele. The results of our study, in which RYR2 SNPs associated with OSCC progression and development were examined for the first time, suggest that clinicopathological characteristics may alter OSCC susceptibility. Finally, RYR2 SNP rs2779359 not only plays a role in both the prognosis and diagnosis of oral cancer but is also likely an important predictive factor for recurrence, response to treatment, and medication toxicity.

Association of CTLA-4 (AT)n Variants in Basal Cell Carcinoma and Squamous Cell Carcinoma Patients from Western Mexico.

The incidence of basal cell carcinoma (BCC) and squamous cell carcinoma (SCC) is constantly increasing, becoming a significant health problem. CTLA-4 is a critical immune checkpoint, and it has been suggested that a variant of variable-number tandem repeat in the 3'-UTR of its gene, known as (AT)n, may be associated with a higher susceptibility to some cancers; however, little is known about genetic variants of the CTLA-4 gene in NMSC. To establish the association of this genetic variant in the CTLA-4 gene with the susceptibility of NMSC carcinogenesis in the Western Mexican population, samples from 150 BCC patients, 150 SCC patients, and 150 healthy individuals as the reference group (RG) were analyzed by endpoint PCR, followed by electrophoresis to genotype the samples. We found that the short-repeat 104/104 bp genotype may be a risk factor for BBC carcinogens (OR = 2.92, p = 0.03), whereas the long-repeat 106/106 bp genotype may be a protective factor for both BCC (OR = 0.13, p = 0.01) and SCC (OR = 0.32, p = 0.01) susceptibility. Our results show that in the Western Mexican population, long-repeat (AT)n variants in the CTLA-4 gene are associated with a protective factor in BCC and SCC. In contrast, short repeats are associated with a risk factor.

Abstract LB379: HLA-DQB1*05:02: An independent genetic marker for oral cavity squamous cell carcinoma susceptibility

Abstract Environmental exposure to carcinogens causes mucosal damage in the upper aerodigestive tract, which can lead to cancers. The genetic basis of head and neck cancer is controversial. To identify susceptibility genes in head and neck cancers, we enrolled patients with early-onset disease in Taiwan. This case-control study included 54 young male patients with oral squamous cell carcinoma (OSCC) who were treated between March 1996 and December 2016, as well as 2,400 healthy controls. A single-nucleotide polymorphism (SNP) array was used to determine genetic loci that increase susceptibility to OSCC. Sequencing-based typing (TBG Biotechnology Corp., Taipei, Taiwan) was used to determine the HLA-DQB1 genotype in another cohort of 147 OSCC patients. We analyzed the allele frequencies of 664,994 autosomal SNPs in the 54 OSCC cases. In a genome-wide association analysis, four SNPs within loci on chromosomes 6, 7, 9, and 12 were significantly different between OSCC patients and controls (corrected P < 1.0 × 10−6). HLA-DQB1 was closest to rs28451423 on chromosome 6. HLA-DQB1*05:02 in OSCC (18.5%) was significantly different from normal population (7.0%) (P = 0.009). The influence of disease onset was independently significant after adjusting cigarette smoking, alcohol drinking and areca-quid chewing (P = 0.015, OR: 3.922, 95% confidence interval: 1.311 - 11.734). Furthermore, HLA-DQB1*05:02 was associated with early-onset OSCC (P = 0.004). HLA-DQB1*05:02 is associated with OSCC independent of environmental exposures. HLA-DQB1*05:02 is also related with early onset of OSCC. It provides evidence of a genetic basis for OSCC. Citation Format: Shiang-Fu Huang, Huei-Tzu Chien, Chi-Kuan Young, Yun-Shien Lee, Chun-Ta Liao, Kai-Lun Cho, Ching-Han Chen. HLA-DQB1*05:02: An independent genetic marker for oral cavity squamous cell carcinoma susceptibility [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(7_Suppl):Abstract nr LB379.

RESISTIN GENE POLYMORPHISMS: POTENTIAL BIOMARKER FOR ORAL SQUAMOUS CELL CARCINOMA

Objective: The objective of the work is to study the association between Resistin Gene polymorphisms and susceptibility of Oral Squamous Cell carcinoma. Methods: In the present study, we scrutinize the connection between four genetic polymorphisms present in RETN gene with the susceptibility, progression, and clinical outcome of OSCC among 200 OSCC patients and 200 healthy controls. Results: The results of the study reveal that among 260 smokers, the risk of developing OSCC is significantly more among the subjects having history of using betel quid in comparison to those who are not habitual users of betel quid. Conclusion: The study reveals that patients with OSCC exhibiting G/A heterozygous genotype of RETN rs3219175 polymorphism have lesser risk for developing high-grade tumor compared to the patients with G/G homozygotes in North Indian population.

Functional polymorphisms in Benzo(a)Pyrene-induced toxicity pathways associated with the risk on laryngeal squamous cell carcinoma

Benzo(a)Pyrene (BaP) is a well-known environmental carcinogen that poses a significant risk to human health. The pivotal genes and toxicity pathways have been identified as key events to construct the mode of action (MOA) of BaP. In this study, we focused on evaluating the association between genetic variants in BaP-disturbed toxicity pathways and the susceptibility of laryngeal squamous cell carcinoma (LSCC), based on the data of our previous genome-wide association analysis (GWAS). In addition, we investigated the biological roles of these significant polymorphisms by integrating bioinformatic annotation and experimental validation. Our findings revealed that 15 functional polymorphisms in AHR signaling, p53 signaling, NRF2 signaling, TGF-β signaling, STAT3 signaling, and IL-8 signaling pathways were significantly associated with susceptibility to LSCC. Our study provides a novel approach for identifying novel risk genetic loci utilizing GWAS data, and suggests potential targets for early detection of LSCC in the future.

AIF-1 GENE AS STRONG PROGNOSTIC BIOMARKER FOR ORAL CANCER

Objective: Oral Squamous Cell Carcinoma (OSCC), which is the sixth most prevalent type of cancer across the globe caused by cigarette smoking, smokeless tobacco use, excessive and extreme alcohol use, oral trauma, HPV (Human Papilloma Virus) infection as well as genetic mutations. AIF-1(Allograft Inflammatory Factor) has been identified as an inflammatory response modulator, and its increased expression has been linked to carcinogenesis. Methods: In this study, 200 OSCC patients and 200 matched controls were compared to investigate if there was any association between the AIF-1(Allograft Inflammatory Factor) gene and the risk of cancer of oral cavity in the North Indian population. AIF-1(Allograft Inflammatory Factor) gene polymorphism rs2857595 were detected using TaqMan probe assay. Results: The findings of our study revealed that AA genotype of AIF-1(Allograft Inflammatory Factor) Gene increases the susceptibility of Oral Squamous Cell Carcinoma. The association of AA genotype with Oral Squamous Cell Carcinoma is more in co-dominant model and the combination of both the mutant genotypes (AA+AG) is more significantly associated with Oral Squamous Cell Carcinoma in recessive model. GG genotype of AIF-1 (Allograft Inflammatory Factor) gene comes out with a protective effect against the risk of (OSCC Squamous Cell Carcinoma). To further understand the role of AIF-1(Allograft Inflammatory Factor) polymorphism, we compared the association of genotypes with various clinicopathological characteristics of Oral Squamous Cell Carcinoma patients. And we found that the patients with AA genotype have a significantly higher risk of developing high-grade tumors and more nodal involvement. Conclusion: Thus, rs2857595 locus AA genotype of AIF-1(Allograft Inflammatory Factor) can be considered as important point in the development of accurate preventive approach and a prognostic indicator for oral cancer.

Haplotypes of [-794(CATT)5-8 /-173G>C] MIF gene polymorphisms and its soluble levels in cutaneous squamous cell carcinoma in western Mexican population.

Some cytokines are strongly implicated in the development of squamous cell carcinoma (SCC) such as the Macrophage migration inhibitory factor (MIF). The haplotype -794 (CATT)5-8 /-173G>C in MIF gene polymorphisms has been associated with some types of cancer. The aim of this study is to establish the possible association between the presence of this haplotype in the MIF gene and its subsequent soluble levels with the susceptibility of SCC in western Mexican population. This study included 175 SCC patients and 175 age-sex-matched individuals as a reference group (RG) from western Mexico. Genomic DNA was extracted from peripheral blood leukocytes. Polymorphisms were genotyped by endpoint PCR and PCR-RFLP, and the determination of MIF serum levels was measured by ELISA. Clinical characteristics were evaluated by a group of dermatologists. Analysis of [-794(CATT)5-8 /-173G>C] MIF gene polymorphisms showed that the 5C (OR = 2.7, p = 0.02) and the 7G (OR = 3.39, p < 0.01) haplotypes are associated with susceptibility in SCC. MIF soluble levels in SCC patients showed a median of 13.93 ng/mL, whereas the reference group showed 6.000 ng/mL. Our findings suggest that 5C and 7G [-794(CATT)5-8 /-173G>C] MIF gene haplotypes are associated with susceptibility to SCC and that SCC patients present increased soluble levels of MIF.

Effect of CDH1 and CDH2 genes polymorphisms in oral squamous cell carcinoma susceptibility in a sample of Iranian population: A case-control study.

Oral squamous cell carcinoma (OSCC) is a global malignant epithelial neoplasm affecting the oral cavity. Cadherins, as an adhesion molecule, are involved in cell-cell interaction. We aim to study the effect of two cadherin polymorphisms on OSCC risk in southeast of Iran. In this case-control study, 94 individuals (47 OSCC cases and 47 controls), that referred to the Department of Oral Pathology, Faculty of Dentistry, Zahedan University of Medical Sciences, Iran were included. Cadherin single nucleotide polymorphisms CDH1 (rs16260) and CDH2 (rs11564299) were genotyped by the tetra-Amplification Refractory Mutation System-PCR technique. N-cadherin genotyping showed that the AA, AG, and AG + GG were presented 78.7%, 17%, 21.3% versus 66%, 29.7%, 34% in the cases and the control group, respectively. AG genotype was more common in control than case (OR = 0.47, 95% CI: 0.17-1.29, p = 0.14). G allele was more prevalent in control (19.1%) than the case group (12.8%) (OR = 0.61, 95% CI: 0.27-1.36, p = 0.23). In E-cadherin, AC, AA, and AC + AA genotypes frequency were 17%, 12.8%, and 29.8% in case versus 8.5%, 8.5%, and 17% in the control group. Allele A was more common in the case than the control group (OR = 1.84, 95% CI: 0.84-4.03, p = 0.12). Also, AA and CC, the codominant genotypes were common in CDH2 and CDH1 respectively in all histopathological grades, and no statically significant association was observed between OSCC different histopathological grades and cadherin genotypes (p = 0.39 in N-cadherin, p = 0.74 in E-cadherin). Our results showed a lack of association between CDH1 and CDH2 gene polymorphisms with OSCC risk in a population of Southeastern of Iran.

The XRCC1 Arg194Trp polymorphism was associated with the risk of head and neck squamous cell carcinoma development: Results from a systematic review and meta-analysis.

The X-ray repair cross complementing group 1 (XRCC1) is a DNA repair gene. Various studies have examined the association between XRCC1 Arg194Trp polymorphism and head and neck squamous cell carcinoma (HNSCC) susceptibility with contradictory results. So, this systematic review and meta-analysis aimed to assess whether variants of this polymorphism increase the HNSCC risk or not. Thirty three studies consisting of 14282 subjects (6012 cases and 8270 controls) were included in this meta-analysis. Variants of XRCC1 Arg194Trp polymorphism were associated with increased HNSCC risk and the associations were significant based on heterozygous and dominant models (heterozygous model: OR = 1.182, 95%CI = 1.015-1.377, P = 0.032; homozygous model: OR = 1.274, 95%CI = 0.940-1.727, P = 0.119; dominant model: OR = 1.194, 95%CI = 1.027-1.388, P = 0.021; recessive model: OR = 1.181, 95%CI = 0.885-1.576, P = 0.119). There were significant associations between variants of this polymorphism and HNSCC risk based on Asian ethnicity under dominant model, hospital control source under different genetic models, PCR-RFLP genotyping method under dominant model and oral cavity tumor site under heterozygous and dominant models. The X-ray repair cross complementing group 1 (XRCC1) is a DNA repair gene. Various studies have examined the association between XRCC1 Arg194Trp polymorphism and head and neck squamous cell carcinoma (HNSCC) susceptibility with contradictory results. So, this systematic review and meta-analysis aimed to assess whether variants of this polymorphism increase the HNSCC risk or not. A systematic search of the literatures published till April 2022 was conducted using Google Scholar, Scopus, PubMed, Web of Science, Cochrane Library and Embase databases. The heterogeneity was assessed with the I-Square statistic. A random effects model or fixed effects model was used to analyze the data. Data were reported by odds ratio (OR) and 95% confidence interval (CI). The p value was considered significant if p < .05. Thirty three studies consisting of 14 282 subjects (6012 cases and 8270 controls) were included in this meta-analysis. Variants of XRCC1 Arg194Trp polymorphism were associated with increased HNSCC risk and the associations were significant based on heterozygous and dominant models (heterozygous model: OR=1.182, 95%CI=1.015-1.377, p=.032; homozygous model: OR=1.274, 95%CI=0.940-1.727, p=.119; dominant model: OR=1.194, 95%CI=1.027-1.388, p=.021; recessive model: OR=1.181, 95%CI=0.885-1.576, p=.119). There were significant associations between variants of this polymorphism and HNSCC risk based on Asian ethnicity under dominant model, hospital control source under different genetic models, PCR-RFLP genotyping method under dominant model and oral cavity tumor site under heterozygous and dominant models. Variants of XRCC1 Arg194Trp polymorphism were significantly associated with increased risk of HNSCC development based on heterozygous and dominant genetic models.

Genetic variant of ADH1C for predicting survival in esophageal squamous cell cancer patients who underwent postoperative radiotherapy.

Background: Single nucleotide polymorphisms (SNPs) of essential enzymes for alcohol metabolism ADH1B, ADH1C, and ALDH2 are commonly regarded as genetic biomarkers for esophageal squamous cell carcinoma (ESCC) susceptibility. However, there have not been any reports on relations between SNPs of these genes and the prognosis of postoperative radiotherapy in ESCC. The current study aimed to understand the associations between gene variants of alcohol metabolism and adjuvant radiotherapy’s prognosis in ESCC. Methods: This study retrospectively analyzed 110 ESCC patients from our institution who received adjuvant radiotherapy after surgery. The SNPs of ADH1B rs1229984, ADH1C rs1789924, and ALDH2 rs671 were detected by Sanger sequencing using formalin-fixed paraffin-embedded tumor samples. A nomogram was drawn based on prognostic factors associated with overall survival (OS). Results: ADH1C rs1789924 (C>T) was associated with poor DFS and OS in ESCC patients undergoing adjuvant radiotherapy. Multivariate analysis showed that ADH1C rs1789924 (C>T) was one of the independent prognosis factors of DFS and OS. However, the genotypes of ADH1B SNP rs1229984 and ALDH2 rs671 were not associated with differences in the PFS and OS of these patients. Compared with the AJCC staging system, the nomogram containing the ADH1C genotype can more effectively and accurately predict the survival time of ESCC after surgery and adjuvant radiotherapy. Conclusion: ADH1C rs1789924 might be a prognostic genetic biomarker for ESCC patients undergoing surgery and postoperative radiotherapy.

RSPO1-mutated keratinocytes from palmoplantar keratoderma display impaired differentiation, alteration of cell–cell adhesion, EMT-like phenotype and invasiveness properties: implications for squamous cell carcinoma susceptibility in patients with 46XX disorder of sexual development

BackgroundSecreted R-spondin (RSPO) proteins play a key role in reproductive organ development, epithelial stem cell renewal and cancer induction by reinforcing canonical Wnt signaling. We have previously reported that palmoplantar keratoderma (PPK), predisposition to cutaneous squamous cell carcinoma (SCC) development and sex reversal segregate as autosomal recessive trait in patients carrying RSPO1-mutations.Although our previous findings suggested that RSPO1 secreted from fibroblasts regulates keratinocyte growth or differentiation, the role of this protein in the epidermis remains largely unexplored. Our study was aimed at expanding the phenotypic, molecular and functional characterization of RSPO1-mutated skin and keratinocytes.ResultsCultured primary keratinocytes from PPK skin of a RSPO1-mutated XX-sex reversed patient displayed highly impaired differentiation and epithelial-mesenchymal transition (EMT)-like phenotype. Interestingly, RSPO1-mutated PPK skin expressed markers of increased proliferation, dedifferentiation and altered cell–cell adhesion. Furthermore, all these signs were more evident in SCC specimens of the patient. Cultured PPK patient’s keratinocytes exhibited increased expression of cell‒matrix adhesion proteins and extracellular matrix remodeling enzymes. Moreover, they showed invasiveness properties in an organotypic skin model in presence of PPK fibroblasts, which behave like cancer-associated fibroblasts. However, the co-culture with normal fibroblasts or treatment with the recombinant RSPO1 protein did not revert or reduce the EMT-like phenotype and invasion capability of PPK keratinocytes. Notably, RSPO1-mutated PPK fibroblasts induced a hyperproliferative and dedifferentiated phenotype of age-matched normal control plantar keratinocytes. Wnt signaling has a key role in both PPK promotion and SCC development. Accordingly, Wnt mediators were differentially expressed in both PPK keratinocytes and skin specimens of RSPO1-mutated patient compared to control.ConclusionsAltogether our data indicate that the absence of RSPO1 in patients with 46XX disorder of sexual development affects the skin microenvironment and epidermal integrity, thus contributing to the risk of SCC tumorigenesis in palmoplantar regions exposed to major frictional stresses.

Defective expression of C20orf54 in esophageal dysplasia: a possible biomarker of esophageal carcinoma for early detection

BackgroundC20orf54 has been identified as an esophageal squamous cell carcinoma (ESCC) susceptibility gene in previous genome-wide association studies. Here, we attempted to clarify the expression level of C20orf54 in ESCC, non-tumoral esophageal tissues, and esophageal squamous intraepithelial neoplasia (ESIN).MethodsWe assessed C20orf54 expression in 146 ESCC, 108 non-tumoral esophageal tissues, and 148 ESIN using immunohistochemistry on tissue microarrays. We also evaluated the possible correlations of C20orf54 expression with clinicopathological characteristics. The survival rates were analyzed using the Kaplan-Meier method and log-rank test.ResultsC20orf54 expression was significantly lower in ESCC, high-grade ESIN, and low-grade ESIN than in the non-tumoral esophageal tissues. The level observed for ESCC was also significantly lower than that in low-grade ESIN and high-grade ESIN, whereas no difference was observed between high-grade ESIN and low-grade ESIN. Furthermore, the C20orf54 defective expression correlated significantly with differentiation, lymph node metastasis, and invasion depth. The overall survival time was inversely associated with lymph node metastasis, an advanced TNM stage (III + IV), and deeper invasion.ConclusionsThis study provides the first evidence of C20orf54 defective expression in ESCC and precancerous lesions, demonstrating a potential role in tumor progression and metastasis. C20orf54 could be used as a potential biomarker for the early detection of ESCC.

The Association of CCL4 rs1634507 and rs10491121 Polymorphisms with Susceptibility of Oral Squamous Cell Carcinoma in an Iranian Population: A Case-Control Study.

Background & Objective:CCL4 (C-C chemokine ligand4) is a chemoattractant involved in tumors' development, progression, and metastasis. The relationship between the ccl4 gene polymorphisms and the risk of OSCC has not been studied in Iran. This study aimed to identify the effect of ccl4 gene polymorphism on OSCC susceptibility in the population of Southeastern Iran. Methods:In this case-control study, a total of 100 participants, 50 patients with OSCC who were referred to the Department of Oral Pathology, Faculty of Dentistry, Zahedan University of Medical Sciences, Iran, and 50 healthy people were included. The DNA was extracted from the tissue blocks of OSCC patients. The rs10491121 and rs1634507 in the ccl4 gene were evaluated by the tetra-ARMS (Amplification Refractory Mutation System)- PCR technique. Data were analyzed in SPSS (version 21) using the Chi-square and logistic regression test.Results:CCL4 genotyping showed that AA+AG genotype in rs10491121 and AA+CA genotype in rs1634507 were slightly higher in control than in the case. Still, the risk of OSCC in both polymorphisms was not significantly different. The minor allele (A) in the rs10491121 and rs1634507 polymorphisms were more common in OSCC compared to the control group (OR = 1.2, 95% CI: 0.66 – 2.22, P=0.54) (OR = 1.6, 95% CI: 0.85-3.07, P=0.15). There was no association between OSCC histopathological grades and CCL4 genotypes at these two sites. Conclusion:Our results showed no association between ccl4 gene polymorphism and the risk of oral cancer in the population of Southeastern Iran.

72 Increasing Radiotherapy Induced DNA Damage by Inhibiting Repair Proteins

Abstract Introduction Fanconi anaemia (FA) is a rare genetic disorder displaying higher incidences of head and neck squamous cell carcinoma (SCC). The surgical excision of these cancers is challenging and often supplemented with radiotherapy. One novel concept to improve survival rates is to increase the susceptibility of SCCs to radiotherapy. ATR is a protein responsible for homologous recombination repair (HRR) within the FA pathway and has been identified as a possible target for cancer therapy. Inhibition of ATR induces subsequent DNA damage. The primary objective of this study was to identify whether the inhibition of ATR can be achieved by exposing SCCs to mild hyperthermia. This novel concept aims to improve survival rates of patients with SCCs who require surgical excision and subsequent radiotherapy. Method By using a HRR assay it was possible to examine levels of DNA repair in various SCC cell lines following the exposure to radiation. These were compared to cells treated with heat, an ATR inhibitor and a mixture of both to determine whether heat reduces HRR. Results Repeated HRR assay’s showed SCC’s treated with heat, ATR inhibitor and a mixture of both before exposure to radiation underwent significantly lower levels of HRR compared to cells within the control. Conclusions Reduced HRR following exposure to heat increases the susceptibility of SCCs to radiotherapy. It is hoped that in combination with the surgical excision, this study will help to improve the outcomes of patients with head and neck carcinomas by improving the efficacy of radiotherapy.

Systems genetics analysis of oral squamous cell carcinoma susceptibility using the mouse model: current position and new perspective.

Oral squamous cell carcinoma (OSCC) is one of the most common human malignancies with complex etiology and poor prognosis. Although environmental carcinogens and carcinogenic viruses are still considered the main etiologic factors for OSCC development, genetic factors obviously play a key role in the initiation and progression of this neoplasm, given that not all individuals exposed to carcinogens develop the same severity of the disease, if any. Identifying genetic loci modulating OSCC risk may have several important clinical implications, including early detection, prevention and developing new treatment strategies. Due to limitations in controlled and standardized genetic studies in humans, genetic components underlying susceptibility of OSCC development remain largely unknown. A combination of quantitative trait loci mapping in mice, with complementary association studies in humans, has the potential to discover novel cancer risk loci. As of today, a limited number of genetic analyses were applied on rodent models to locate novel genetic loci associated with human OSCC. Here, we discuss the current status of the mouse models use for dissecting the genetic basis of OSCC and highlight how systems genetics analysis using mouse models, may increase our understanding of human OSCC susceptibility.

A Functional Variant rs2072915 is Associated with the Susceptibility and Mortality of Cervical Squamous Cell Carcinoma.

PurposeGenetic variant has been demonstrated to be a risk factor for the occurrence and outcome of cervical squamous cell carcinoma (CSCC). From previous genome wide association studies, 6p21.32 has been identified as a susceptibility locus of CSCC. The purpose of this study was to investigate the association of a polymorphism rs2072915 located in 6p21.32 with the risk of CSCC and examine the potential mechanism of the rs2072915 in CSCC pathogenesis.Patients and MethodsThe rs2072915 was genotyped using polymerase chain reaction (PCR)-restriction fragment length polymorphism. miR-637 and RXRB mRNA expression levels in CSCC patients were examined using quantitative PCR. miR-637 target site was determined using the dual-luciferase reporter assay.ResultsThe rs2072915 was associated with a significantly increased risk (AA vs TT: adjusted OR = 2.48, 95% CI, 1.57–3.94, P < 0.001; AT/AA vs TT: adjusted OR = 1.38, 95% CI, 1.06–1.80, P = 0.018; A vs T: adjusted OR = 1.49, 95% CI, 1.21–1.84, P < 0.001, respectively) and shorter survival time of CSCC (P = 0.03). Patients with the rs2072915 AA genotype displayed lower levels of RXRB that is a target of miR-637.ConclusionThese findings suggest that the rs2072915 T > A change might augment the binding energy of miR-637 to RXRB, result in lower levels of RXRB, and thus contribute to the risk of CSCC.

Associations of interleukin-4 and interleukin-4 receptor loci with esophageal squamous cell carcinoma susceptibility

Some functional polymorphisms in immune-regulating genes could affect the development of esophageal squamous cell carcinoma (ESCC). We enrolled 721 patients with ESCC and 1,208 healthy controls to explore the roles of rs2227282 (C > G) and rs2243283 (C > G) loci in the interleukin-4 (IL4) gene and rs1801275 loci in the interleukin-4 receptor (IL4R) gene for the occurrence of ESCC. As for IL4, the single nucleotide polymorphism rs2227282 (C > G) conferred an overall decreased risk for ESCC (adjusted P = 0.005, power = 0.816 in GG vs. CC genetic models). A stratification analysis of IL4 rs2227282 (C > G) and rs2243283 (C > G) and IL4R rs1801275 (A > G) loci with the ESCC risk revealed that the IL4 rs2243283 (C > G) polymorphism was a protective factor for the susceptibility to ESCC in some subgroups (women: power = 0.932 in CG vs. CC and 0.956 in CG/GG vs. CC; subjects aged ≥63 years: power = 0.844 in CG/GG vs. CC; never-smokers: power = 0.893 in CG vs. CC and 0.882 in CG/GG vs. CC; never-drinkers: power = 0.904 in CG vs. CC and 0.862 in CG/GG vs. CC). We also investigated the association of IL4 rs2227282 and rs2243283 and IL4R rs1801275 loci with the lymph node status. However, a null relationship was found. In conclusion, the present study highlighted that IL4 rs2227282 (C > G) and rs2243283 (C > G) loci are protective factors for the occurrence of ESCC.

TIM-3 polymorphism is involved in the progression of esophageal squamous cell carcinoma by regulating gene expression.

The T-cell immunoglobulin and mucin domain containing molecule 3 (TIM-3), a crucial immune regulatory molecule, is an emerging immune checkpoint target for cancer therapy. Our study aimed to investigate the association between TIM-3 polymorphisms (rs10053538 C > A, rs10515746 C > A, and rs1036199 A > C) and the susceptibility and prognosis of esophageal squamous cell carcinoma (ESCC). We further detect the effects of polymorphisms on TIM-3 expression. Two independent case-control sets (population-based and hospital-based sets) were performed in total 994 ESCC patients and 998 controls. TIM-3 polymorphisms were genotyped by polymerase chain reaction-ligase detection reaction (PCR). Survival data were available for 198 patients who received platinum-based chemotherapy after surgery. The regulation on TIM-3 expression by the polymorphisms was investigated in 35 patients using real-time quantitative PCR. The association between mRNA level of TIM-3 and survival was detected by using Kaplan-Meier plotter database. We found that for rs10053538 C > A polymorphisms, A allele was associated with significant increased risk of ESCC (odds ratios [OR] = 1.34, 95%CI = 1.05-1.72), and CA/AA genotypes enhanced susceptibility to ESCC for smokers (adjusted OR = 1.61, 95%CI = 1.00-2.59). The patients with AA genotypes had significantly poor prognosis (adjusted HR = 4.98, 95%CI = 1.14-21.71). The patients carrying CA/AA genotypes had significantly higher mRNA levels of TIM-3 than those carrying the CC genotype. Furthermore, high mRNA level of TIM-3 had a shorter overall survival in patients (HR = 2.56, 95%CI = 1.04-6.28). For rs10515746 C > A and rs1036199 A > C polymorphisms, there were no statistical correlation with the progression of ESCC. These data demonstrate that rs10053538 C > A polymorphisms may be associated with the susceptibility and prognosis of ESCC patients through regulating expression of TIM-3.