Chromosomal Alterations and Gene Expression Changes Associated with the Progression of Leukoplakia to Advanced Gingivobuccal Cancer

We present an integrative genome-wide analysis that can be used to predict the risk of progression from leukoplakia to oral squamous cell carcinoma (OSCC) arising in the gingivobuccal complex (GBC). We find that the genomic and transcriptomic profiles of leukoplakia resemble those observed in later stages of OSCC and that several changes are associated with this progression, including amplification of 8q24.3, deletion of 8p23.2, and dysregulation of DERL3, EIF5A2, ECT2, HOXC9, HOXC13, MAL, MFAP5 and NELL2. Comparing copy number profiles of primary tumors with and without lymph-node metastasis, we identify alterations associated with metastasis, including amplifications of 3p26.3, 8q24.21, 11q22.1, 11q22.3 and deletion of 8p23.2. Integrative analysis reveals several biomarkers that have never or rarely been reported in previous OSCC studies, including amplifications of 1p36.33 (attributable to MXRA8), 3q26.31 (EIF5A2), 9p24.1 (CD274), and 12q13.2 (HOXC9 and HOXC13). Additionally, we find that amplifications of 1p36.33 and 11q22.1 are strongly correlated with poor clinical outcome. Overall, our findings delineate genomic changes that can be used in treatment management for patients with potentially malignant leukoplakia and OSCC patients with higher risk of lymph-node metastasis

Chromosomal Alterations and Gene Expression Changes Associated with the Progression of Leukoplakia to Advanced Gingivobuccal Cancer

We present an integrative genome-wide analysis that can be used to predict the risk of progression from leukoplakia to oral squamous cell carcinoma (OSCC) arising in the gingivobuccal complex (GBC). We find that the genomic and transcriptomic profiles of leukoplakia resemble those observed in later stages of OSCC and that several changes are associated with this progression, including amplification of 8q24.3, deletion of 8p23.2, and dysregulation of DERL3, EIF5A2, ECT2, HOXC9, HOXC13, MAL, MFAP5 and NELL2. Comparing copy number profiles of primary tumors with and without lymph-node metastasis, we identify alterations associated with metastasis, including amplifications of 3p26.3, 8q24.21, 11q22.1, 11q22.3 and deletion of 8p23.2. Integrative analysis reveals several biomarkers that have never or rarely been reported in previous OSCC studies, including amplifications of 1p36.33 (attributable to MXRA8), 3q26.31 (EIF5A2), 9p24.1 (CD274), and 12q13.2 (HOXC9 and HOXC13). Additionally, we find that amplifications of 1p36.33 and 11q22.1 are strongly correlated with poor clinical outcome. Overall, our findings delineate genomic changes that can be used in treatment management for patients with potentially malignant leukoplakia and OSCC patients with higher risk of lymph-node metastasis

Genomic Profiling of Advanced-Stage Oral Cancers Reveals Chromosome 11q Alterations as Markers of Poor Clinical Outcome

Identifying oral cancer lesions associated with high risk of relapse and predicting clinical outcome remain challenging questions in clinical practice. Genomic alterations may add prognostic information and indicate biological aggressiveness thereby emphasizing the need for genome-wide profiling of oral cancers. High-resolution array comparative genomic hybridization was performed to delineate the genomic alterations in clinically annotated primary gingivo-buccal complex and tongue cancers (n = 60). The specific genomic alterations so identified were evaluated for their potential clinical relevance. Copy-number changes were observed on chromosomal arms with most frequent gains on 3q (60%), 5p (50%), 7p (50%), 8q (73%), 11q13 (47%), 14q11.2 (47%), and 19p13.3 (58%) and losses on 3p14.2 (55%) and 8p (83%). Univariate statistical analysis with correction for multiple testing revealed chromosomal gain of region 11q22.1–q22.2 and losses of 17p13.3 and 11q23–q25 to be associated with loco-regional recurrence (P = 0.004, P = 0.003, and P = 0.0003) and shorter survival (P = 0.009, P = 0.003, and P 0.0001) respectively. The gain of 11q22 and loss of 11q23-q25 were validated by interphase fluorescent in situ hybridization (I-FISH). This study identifies a tractable number of genomic alterations with few underlying genes that may potentially be utilized as biological markers for prognosis and treatment decisions in oral cancers

A rare truncating BRCA2 variant and genetic susceptibility to upper aerodigestive tract cancer

© The Author 2015. Published by Oxford University Press. This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0/), which permits non-commercial re-use, distribution, and reproduction in any medium, provided the original work is properly cited. For commercial re-use, please contact [email protected] Funding This work was supported the National Institutes of Health (R01CA092039 05/05S1) and the National Institute of Dental and Craniofacial Research (1R03DE020116). Notes The authors thank all of the participants who took part in this research and the funders and technical staff who made this study possible. We acknowledge and thank Simone Benhamou (INSERM, France) for sample contributions. We also acknowledge and thank The Cancer Genome Atlas initiative, whose data contributed heavily to this study.Peer reviewedPublisher PD

The 12p13.33/RAD52 locus and genetic susceptibility to squamous cell cancers of upper aerodigestive tract

Acknowledgments: The authors thank all of the participants who took part in this research and the funders and support and technical staff who made this study possible. We also acknowledge and thank The Cancer Genome Atlas initiative whose data contributed heavily to this study. Funding: Funding for study coordination, genotyping of replication studies and statistical analysis was provided by the US National Institutes of Health (R01 CA092039 05/05S1) and the National Institute of Dental and Craniofacial Research (1R03DE020116). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.Peer reviewedPublisher PD

Occupational exposure to bidi tobacco increases chromosomal aberrations in tobacco processors

In India, workers engaged in processing of tobacco for the manufacture of bidis (the indogenous substitute for cigarettes) are chronically exposed to tobacco flakes and dust via the cutaneous and nasopharyngeal routes. Hence, workers in a tobacco processing factory were monitored for chromosomal aberrations (CA) using peripheral blood lymphocytes as the test system. Cytogenetic analysis revealed a significant increase in deletion fragments and chromatid gaps in the exposed group. The frequency of aberrant metaphases and the proportion of individuals with CA were significantly higher in workers than in controls, indicating that occupational exposure to tobacco imposes considerable genotoxicity among tobacco processors

Biological monitoring of bidi industry workers occupationally exposed to tobacco

Ambient and biological monitoring was undertaken among tobacco processors who are chronically exposed to tobacco particulates via nasopharyngeal and cutaneous routes. Ambient monitoring revealed that the inspirable dust concentration was 150-fold higher in the tobacco factory than in the control environment, and was associated with chronic bronchitis in workers. Increased systemic exposure to tobacco constituents was evident from the high levels of cotinine, thioethers, promutagens and direct acting mutagens in workers' urine. The mean glutathione level and glutathione S-transferase activity were significantly lower in the peripheral blood lymphocytes of workers; however, the frequency of the GSTM1 null allele was similar to that in controls. A significant increase in chromosomal damage was noted in target and non-target cells of tobacco processors. In view of the association between tobacco use and several non-communicable diseases, the findings of the present study indicate an urgent need to minimize tobacco exposure among the processors

Susceptibility to oral cancer by genetic polymorphisms at CYP1A1, GSTM1 and GSTT1 loci among Indians: tobacco exposure as a risk modulator

Oral cancer is the leading cancer type among Southeast Asian men and is causally associated with the use of tobacco. Genetic polymorphisms in xenobiotic-metabolizing enzymes modify the effect of environmental exposures, thereby playing a significant role in gene-environment interactions and hence contribute to the high degree of variance in individual susceptibility to cancer risk. This study investigates the role of polymorphisms at CYP1A1, GSTM1 and GSTT1 to oral squamous cell carcinoma (OSCC) in a case-control study involving 155 patients with precancerous lesions, 458 cancer patients and 729 age and habit-matched controls. Genotypes at these loci were determined by polymerase chain reaction (PCR) and PCR-restriction fragment length polymorphism performed on genomic DNA extracted from peripheral blood lymphocytes. Risk to oral cancer was estimated among different tobacco exposure groups and doses using logistic regression analysis. GSTM1 null genotype conferred 1.29-fold increased risk [95% confidence interval (CI), 1.04-1.65] to OSCC. GSTT1 null genotype, however, conferred 0.57 times reduced risk to OSCC (95% CI, 0.39-0.83), specifically among tobacco chewers (odds ratio 0.27; 95% CI, 0.14-0.53). This risk was further reduced to 0.13 times (95% CI, 0.04-0.46) with increase in lifetime exposure to tobacco. We also investigated risk conferred by these genotypes at two different intra-oral sites, buccal mucosa and tongue. We found increased susceptibility to buccal mucosa cancer among individuals carrying these genetic markers. These results support the finding that GSTM1 null genotype is a risk factor to OSCC among Indian tobacco habits; GSTT1 null genotype, however, emerged as a protective factor

Influence of smokeless tobacco exposure on detoxification status and chromosomal damage in male and female habitues

In India, a large number of tobacco chewers and masheri users are chronically exposed to tobacco genotoxicants. Detoxification processes involving cellular glutathione (GSH) and glutathione S-transferases (GST) determine the outcome of exposure to environmental mutagens including those present in tobacco. Hence, in this study, GSH levels, GST activity, GSTM1 genotype and cytogenetic damage were determined using lymphocytes from 114 smokeless tobacco habitues and controls. The study groups comprised of male tobacco chewers, female masheri users, and age- and sex-matched controls. Irrespective of the tobacco habit, GSH levels and GST activity were higher in females than in males. In both the groups of habitues, GSH levels were similar to those in controls, while a significant reduction in GST activity was observed in tobacco chewers only. The frequency of cytogenetic alterations was significantly elevated in both the groups of habitues with respect to controls. However, break-type aberrations were more frequent in tobacco chewers while gaps were commonly observed in masheri users. Differences in the nature of chromosomal alterations in the two groups of habitues appeared to be related to variation in total tobacco exposure and gender-related differences in the efficacy of the GSH/GST detoxification system

Recurring Amplification at 11q22.1-q22.2 Locus Plays an Important Role in Lymph Node Metastasis and Radioresistance in OSCC

A key feature in the pathogenesis of OSCC is genetic instability, which results in altered expression of genes located in amplified/deleted chromosomal regions. In a previous study we have shown that the amplification of the 11q22.1-q22.2 region, encoding cIAP1 and cIAP2, is associated with lymph node metastasis and poor clinical outcome in OSCC. Here, we validate the aCGH results by nuc ish and detect a weak amplification at the 11q22.1-q22.2 locus in 37% of the 182 samples tested. We find positive correlation of 11q22.1-q22.2 amplification with lymph node metastasis, reduced survival, and increased cancer recurrence, and we observe that patients with 11q22.1-q22.2 amplification fail to respond to radiotherapy. We confirm the concurrent overexpression of cIAP1 and cIAP2 and observe differential subcellular localization of the two proteins in OSCC. To ascertain the roles of cIAP1/cIAP2 in lymph node metastasis and radioresistance, we use an in vitro pre-clinical model and confirm the role of cIAP1 in invasion and the role of cIAP2 in invasion and migration. Studies of other tumor types in which cIAP1 is overexpressed suggest that multi-regimen treatments including SMAC mimetics may be effective. Thus, the evaluation of 11q22.1-q22.2 amplifications in OSCC patients may help choose the most effective treatment