For a better understanding of genetic alterations in head and neck squamous cell carcinoma (HNSCC), we applied comparative genomic hybridization (CGH) in the analysis of 75 HNSCCs, comprised of 18 pharyngeal squamous cell carcinomas (PSCCs), 23 laryngeal squamous cell carcinomas (LSCCs), and 34 oral squamous cell carcinomas (OSCCs). The three subgroups of HNSCC showed significant differences in genetic alteration patterns. Overall, PSCC and LSCC had more copy number aberrations (CNAs) per tumor than did OSCC. Apparent differing patterns of high-level amplification were also observed. The smallest recurrent chromosomal regions of high-level amplification (Ն15% of cases) were 7q22, 8q24.1, and 11q12-13 in PSCC and 3q26.1-29 in OSCC. According to single frequency and combined frequencies of CNAs, we concluded that the most important chromosomal events for progression of head and neck cancer were ϩ3q, ϩ5p, ϩ8q, and Ϫ3p for all subgroups of HNSCC; additionally, ϩ7q, ϩ17q, Ϫ9p, and Ϫ13q for PSCC; ϩ7p, ϩ9q, ϩ11q12-13, ϩ14q, and ϩ17q for LSCC; and ϩ1p and ϩ11q12-13 for OSCC. To identify further important genetic alterations and the relationships among the alterations, we constructed oncogenetic tree models for tumor progression of HNSCC from CGH data using branching and distance-based tree models. The tree models predicted that: (1) ϩ3q21-29 was the most important early chromosomal event, and Ϫ3p, which occurred after ϩ3q21-29, was also an important chromosomal event for all subsites of HNSCC; (2) ϩ8q is the second most important early chromosomal event; (3) there may be at least three subgroups of HNSCC: one characterized by Ϫ3p, Ϫ9p, ϩ7p, and Ϫ13q; another by ϩ5p, ϩ9qter, and ϩ17p; and the other by ϩ8q and ϩ18p. These results suggest that different chromosomal aberrations may play a role in the initiation and/or progression of different subgroups of HNSCC.

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.

BACKGROUND:Because the addition of nimotuzumab to chemoradiation in patients with locally advanced head and neck cancer improved outcomes in a phase 2 study, the authors conducted a phase 3 study to confirm these findings. METHODS: This openlabel, investigator-initiated, phase 3, randomized trial was conducted from 2012 to 2018. Adult patients with locally advanced head and neck cancer who were fit for radical chemoradiation were randomized 1:1 to receive either radical radiotherapy (66-70 grays) with concurrent weekly cisplatin (30 mg/m 2 ) (CRT) or the same schedule of CRT with weekly nimotuzumab (200 mg) (NCRT). The primary endpoint was progression-free survival (PFS); key secondary endpoints were disease-free survival (DFS), duration of locoregional control (LRC), and overall survival (OS). An intent-to-treat analysis also was performed. RESULTS: In total, 536 patients were allocated equally to both treatment arms. The median follow-up was 39.13 months. The addition of nimotuzumab improved PFS (hazard ratio [HR], 0.69; 95% CI, 0.53-0.89; P = .004), LRC (HR, 0.67; 95% CI, 0.50-0.89; P = .006), and DFS (HR, 0.71; 95% CI, 0.55-0.92; P = .008) and had a trend toward improved OS (HR, 0.84; 95% CI, 0.65-1.08; P = .163). Grade 3 through 5 adverse events were similar between the 2 arms, except for a higher incidence of mucositis in the NCRT arm (66.7% vs 55.8%; P = .01). CONCLUSIONS: The addition of nimotuzumab to concurrent weekly CRT improves PFS, LRC, and DFS. This combination provides a novel alternative therapeutic option to a 3-weekly schedule of 100 mg/m 2 cisplatin in patients with locally advanced head and neck cancer who are treated with radical-intent CRT. Cancer 2019;125:3184-3197.

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.

The International Head and Neck Cancer Epidemiology (INHANCE) consortium is a collaboration of research groups leading large epidemiology studies to improve the understanding of the causes and mechanisms of head and neck cancer. The consortium includes investigators of 35 studies who have pooled their data on 25 500 patients with head and neck cancer (i.e., cancers of the oral cavity, oropharynx, hypopharynx, and larynx) and 37 100 controls. The INHANCE analyses have confirmed that tobacco use and alcohol intake are key risk factors of these diseases and have provided precise estimates of risk and dose response, the benefit of quitting, and the hazard of smoking even a few cigarettes per day. Other risk factors include short height, lean body mass, low education and income, and a family history of head and neck cancer. Risk factors are generally similar for oral cavity, pharynx, and larynx, although the magnitude of risk may vary. Some major strengths of pooling data across studies include more precise estimates of risk and the ability to control for potentially confounding factors and to examine factors that may interact with each other. The INHANCE consortium provides evidence of the scientific productivity and discoveries that can be obtained from data pooling projects.

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The association of GSTM1 and CYP1A1 polymorphisms and oral and pharyngeal cancers was assessed through a metaanalysis of published case-control studies and a pooled analysis of both published and unpublished case-control studies from the Genetic Susceptibility to Environmental Carcinogens database (http://www.upci.upmc.edu/research/ccps/ccontrol/ index.html). Thirty publications used in the meta-analysis included a total of 7783 subjects (3177 cases and 4606 controls); 21 datasets, 9397 subjects (3130 cases and 6267 controls) were included in the pooled analysis. The GSTM1 deletion was 2-fold more likely to occur in African American and African cases than controls (odds ratio: 1.7, 95% confidence interval: 0.9-3.3), although this was not observed among whites (odds ratio: 1.0, 95% confidence interval: 0.9-1.1). The metaanalysis and pooled analysis showed a significant association between oral and pharyngeal cancer and the CYP1A1 MspI homozygous variant (meta-OR m2/m2 : 1.9, 95% confidence interval: 1.4-2.7; Pooled OR m2m2 : 2.0, 95% confidence interval:1.3-3.1; OR m1m2 or [infi]m2m2 : 1.3, 95% confidence interval: 1.1-1.6). The association was present for the CYP1A1 (exon 7) polymorphism (OR Val/Val : 2.2, 95% confidence interval: 1.1-4.5) in ever smokers. A joint effect was observed for GSTM1 homozygous deletion and the CYP1A1 m1m2 variant on cancer risk. Our findings suggest that tobacco use and genetic factors play a significant role in oral and pharyngeal cancer. Genet Med 2008:10(6):369-384. Key Words: GSTM1, CYP1A1, oral and pharyngeal cancers, epidemiology, meta-analysis and pooled analysis Glutathione S-transferasesThe Glutathione S-transferases (GSTs) comprise a family of phase II detoxifying enzymes that catalyze a large number of reactions taking place between the cytosolic glutathione and compounds containing an electrophilic center. 1 These enzymes are involved in the elimination of xenobiotics and endogenous products of oxidative stress formed as a result of aerobic metabolism, exposure to ionizing radiation or any other process that causes cellular damage. Substrates for GSTs include acetaldehyde and several polyaromatic hydrocarbons (PAHs) found in tobacco smoke. The main steps for GST catalysis includes the formation of a complex with the cytosolic glutathione and the ionization of the sulfydryl group of this enzyme bound to glutathione to yield a highly reactive thiolate anion through hydrogen bonding with the adjacent hydroxyl

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.