Multi-ethnic variations in the practice of oral cancer risk habits in a developing country.

OBJECTIVE: To elucidate ethnic variations in the practice of oral cancer risk habits in a selected Malaysian population. METHODS: This retrospective case-control study involves 790 cases of cancers of the oral cavity and 450 controls presenting with non-malignant oral diseases, recruited from seven hospital-based centres nationwide. Data on risk habits (smoking, drinking, chewing) were obtained using a structured questionnaire via face-to-face interviews. Multiple logistic regression was used to determine association between risk habits and oral cancer risk; chi-square test was used to assess association between risk habits and ethnicity. Population attributable risks were calculated for all habits. RESULTS: Except for alcohol consumption, increased risk was observed for all habits; the highest risk was for smoking + chewing + drinking (aOR 22.37 95% CI 5.06, 98.95). Significant ethnic differences were observed in the practice of habits. The most common habit among Malays was smoking (24.2%); smoking + drinking were most common among Chinese (16.8%), whereas chewing was the most prevalent among Indians (45.2%) and Indigenous people (24.8%). Cessation of chewing, smoking and drinking is estimated to reduce cancer incidence by 22.6%, 8.5% and 6.9%, respectively. CONCLUSION: Ethnic variations in the practice of oral cancer risk habits are evident. Betel quid chewing is the biggest attributable factor for this population.

Genome wide profiling in oral squamous cell carcinoma identifies a four genetic marker signature of prognostic significance.

BACKGROUND: Cancers of the oral cavity are primarily oral squamous cell carcinomas (OSCCs). Many of the OSCCs present at late stages with an exceptionally poor prognosis. A probable limitation in management of patients with OSCC lies in the insufficient knowledge pertaining to the linkage between copy number alterations in OSCC and oral tumourigenesis thereby resulting in an inability to deliver targeted therapy. OBJECTIVES: The current study aimed to identify copy number alterations (CNAs) in OSCC using array comparative genomic hybridization (array CGH) and to correlate the CNAs with clinico-pathologic parameters and clinical outcomes. MATERIALS AND METHODS: Using array CGH, genome-wide profiling was performed on 75 OSCCs. Selected genes that were harboured in the frequently amplified and deleted regions were validated using quantitative polymerase chain reaction (qPCR). Thereafter, pathway and network functional analysis were carried out using Ingenuity Pathway Analysis (IPA) software. RESULTS: Multiple chromosomal regions including 3q, 5p, 7p, 8q, 9p, 10p, 11q were frequently amplified, while 3p and 8p chromosomal regions were frequently deleted. These findings were in confirmation with our previous study using ultra-dense array CGH. In addition, amplification of 8q, 11q, 7p and 9p and deletion of 8p chromosomal regions showed a significant correlation with clinico-pathologic parameters such as the size of the tumour, metastatic lymph nodes and pathological staging. Co-amplification of 7p, 8q, 9p and 11q regions that harbored amplified genes namely CCND1, EGFR, TPM2 and LRP12 respectively, when combined, continues to be an independent prognostic factor in OSCC. CONCLUSION: Amplification of 3q, 5p, 7p, 8q, 9p, 10p, 11q and deletion of 3p and 8p chromosomal regions were recurrent among OSCC patients. Co-alteration of 7p, 8q, 9p and 11q was found to be associated with clinico-pathologic parameters and poor survival. These regions contain genes that play critical roles in tumourigenesis pathways.

Co-Expression of TWIST1 and ZEB2 in Oral Squamous Cell Carcinoma Is Associated with Poor Survival.

Oral squamous cell carcinoma (OSCC) is an aggressive disease accounting for more than 260,000 cancer cases diagnosed and 128,000 deaths worldwide. A large majority of cancer deaths result from cancers that have metastasized beyond the primary tumor. The relationship between genetic changes and clinical outcome can reflect the biological events that promote cancer's aggressive behavior, and these can serve as molecular markers for improved patient management and survival. To this end, epithelial-mesenchymal transition (EMT) is a major process that promotes tumor invasion and metastasis, making EMT-related proteins attractive diagnostic biomarkers and therapeutic targets. In this study, we used immunohistochemistry to study the expression of a panel of transcription factors (TWIST1, SNAI1/2, ZEB1 and ZEB2) and other genes intimately related to EMT (CDH1 and LAMC2) at the invasive tumor front of OSCC tissues. The association between the expression of these proteins and clinico-pathological parameters were examined with Pearson Chi-square and correlation with survival was analyzed using Kaplan Meier analysis. Our results demonstrate that there was a significant differential expression of CDH1, LAMC2, SNAI1/2 and TWIST1 between OSCC and normal oral mucosa (NOM). Specifically, CDH1 loss was significantly associated with Broder's grading, while diffused LAMC2 was similarly associated with non-cohesive pattern of invasion. Notably, co-expression of TWIST1 and ZEB2 in OSCC was significantly associated with poorer overall survival, particularly in patients without detectable lymph node metastasis. This study demonstrates that EMT-related proteins are differentially expressed in OSCC and that the co-expression of TWIST1 and ZEB2 could be of clinical value in identifying patients with poor survival for appropriate patient management.

Valproic acid: growth inhibition of head and neck cancer by induction of terminal differentiation and senescence.

BACKGROUND: There are limited studies on the effects of drugs that modulate epigenetic regulation for head and neck squamous cell carcinoma (HNSCC). This study determined the effect of valproic acid (VPA) on HNSCC. METHODS: Growth inhibition effects of VPA alone or in combination with 5-aza-2'deoxycytidine (5-aza-dC) or all-trans retinoic acid (ATRA) was evaluated with MTT and clonogenic assays on 5 HNSCC cell lines. The mechanism of growth inhibition was investigated by looking at markers of terminal differentiation and senescence. RESULTS: Growth inhibition profiles of HNSCC cell lines varied in response to VPA. Inhibition of clonogenic survival in response to VPA was associated with an upregulation of p21, expression of terminal differentiation markers, and cellular senescence. Notably, a combination treatment of 5-Aza-dC-VPA-ATRA enhanced growth inhibition in cells resistant to VPA. CONCLUSION: VPA is a potent inhibitor of proliferation in some HNSCC cell lines, and may be used to treat HNSCC.

MDM2 SNP309 does not confer an increased risk to oral squamous cell carcinoma but may modulate the age of disease onset.

The MDM2 SNP309 has been associated with increased expression of the protein which could suppress p53 function, and has been shown to modulate risk to cancer. We have previously shown that overexpression of MDM2 is a common event in oral cancers. In the present study, we determined the association between the MDM2 SNP309 polymorphism and oral cancer in 207 oral cancer patients and 116 normal subjects. We genotyped the MDM2 SNP309 by PCR-RFLP. Logistic regression was adapted to calculate odds ratios for MDM2 SNP309 polymorphism from univariate and multivariable adjusted models. Our results suggest that MDM2 SNP309 does not confer increased risk to oral cancer (OR=1.55, 95% CI=0.77-3.11). However, the GG/TG genotype was associated with later disease onset in women above 55 years of age. Collectively, our data suggests that MDM2 SNP309 may modulate the risk to oral cancer and is a modifier of the age at oral cancer onset in women above the age of 55 years.