Philip Lazarus

Interaction between tobacco and alcohol use and the risk of head and neck cancer: Pooled analysis in the international head and neck cancer Epidemiology consortium

Background: The magnitude of risk conferred by the interaction between tobacco and alcohol use on the risk of head and neck cancers is not clear because studies have used various methods to quantify the excess head and neck cancer burden. Methods: We analyzed individual-level pooled data from 17 European and American case-control studies (11,221 cases and 16,168 controls) participating in the International Head and Neck Cancer Epidemiology consortium. We estimated the multiplicative interaction parameter (ψ) and population attributable risks (PAR). Results: A greater than multiplicative joint effect between ever tobacco and alcohol use was observed for head and neck cancer risk (ψ = 2.15; 95% confidence interval, 1.53-3.04). The PAR for tobacco or alcohol was 72% (95% confidence interval, 61-79%) for head and neck cancer, of which 4% was due to alcohol alone, 33% was due to tobacco alone, and 35% was due to tobacco and alcohol combined. The total PAR differed by subsite (64% for oral cavity cancer, 72% for pharyngeal cancer, 89% for laryngeal cancer), by sex (74% for men, 57% for women), by age (33% for cases <45 years, 73% for cases >60 years), and by region (84% in Europe, 51% in North America, 83% in Latin America). Conclusions: Our results confirm that the joint effect between tobacco and alcohol use is greater than multiplicative on head and neck cancer risk. However, a substantial proportion of head and neck cancers cannot be attributed to tobacco or alcohol use, particularly for oral cavity cancer and for head and neck cancer among women and among young-onset cases. (Cancer Epidemiol Biomarkers Prev 2009;18(2):541–50)

Genetic differences detected by comparative genomic hybridization in head and neck squamous cell carcinomas from different tumor sites: construction of oncogenetic trees for tumor progression

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 (≥15% 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 +3q, +5p, +8q, and −3p for all subgroups of HNSCC; additionally, +7q, +17q, −9p, and −13q for PSCC; +7p, +9q, +11q12–13, +14q, and +17q for LSCC; and +1p and +11q12–13 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) +3q21–29 was the most important early chromosomal event, and −3p, which occurred after +3q21–29, was also an important chromosomal event for all subsites of HNSCC; (2) +8q is the second most important early chromosomal event; (3) there may be at least three subgroups of HNSCC: one characterized by −3p, −9p, +7p, and −13q; another by +5p, +9qter, and +17p; and the other by +8q and +18p. These results suggest that different chromosomal aberrations may play a role in the initiation and/or progression of different subgroups of HNSCC.

Cessation of alcohol drinking, tobacco smoking and the reversal of head and neck cancer risk

BACKGROUND Quitting tobacco or alcohol use has been reported to reduce the head and neck cancer risk in previous studies. However, it is unclear how many years must pass following cessation of these habits before the risk is reduced, and whether the risk ultimately declines to the level of never smokers or never drinkers. METHODS We pooled individual-level data from case-control studies in the International Head and Neck Cancer Epidemiology Consortium. Data were available from 13 studies on drinking cessation (9167 cases and 12 593 controls), and from 17 studies on smoking cessation (12 040 cases and 16 884 controls). We estimated the effect of quitting smoking and drinking on the risk of head and neck cancer and its subsites, by calculating odds ratios (ORs) using logistic regression models. RESULTS Quitting tobacco smoking for 1-4 years resulted in a head and neck cancer risk reduction [OR 0.70, confidence interval (CI) 0.61-0.81 compared with current smoking], with the risk reduction due to smoking cessation after > or =20 years (OR 0.23, CI 0.18-0.31), reaching the level of never smokers. For alcohol use, a beneficial effect on the risk of head and neck cancer was only observed after > or =20 years of quitting (OR 0.60, CI 0.40-0.89 compared with current drinking), reaching the level of never drinkers. CONCLUSIONS Our results support that cessation of tobacco smoking and cessation of alcohol drinking protect against the development of head and neck cancer.

Family history of cancer: Pooled analysis in the International Head and Neck Cancer Epidemiology consortium

Alcohol and tobacco consumption are well‐recognized risk factors for head and neck cancer (HNC). Evidence suggests that genetic predisposition may also play a role. Only a few epidemiologic studies, however, have considered the relation between HNC risk and family history of HNC and other cancers. We pooled individual‐level data across 12 case–control studies including 8,967 HNC cases and 13,627 controls. We obtained pooled odds ratios (OR) using fixed and random effect models and adjusting for potential confounding factors. All statistical tests were two‐sided. A family history of HNC in first‐degree relatives increased the risk of HNC (OR = 1.7, 95% confidence interval, CI, 1.2–2.3). The risk was higher when the affected relative was a sibling (OR = 2.2, 95% CI 1.6–3.1) rather than a parent (OR = 1.5, 95% CI 1.1–1.8) and for more distal HNC anatomic sites (hypopharynx and larynx). The risk was also higher, or limited to, in subjects exposed to tobacco. The OR rose to 7.2 (95% CI 5.5–9.5) among subjects with family history, who were alcohol and tobacco users. A weak but significant association (OR = 1.1, 95% CI 1.0–1.2) emerged for family history of other tobacco‐related neoplasms, particularly with laryngeal cancer (OR = 1.3, 95% CI 1.1–1.5). No association was observed for family history of nontobacco‐related neoplasms and the risk of HNC (OR = 1.0, 95% CI 0.9–1.1). Familial factors play a role in the etiology of HNC. In both subjects with and without family history of HNC, avoidance of tobacco and alcohol exposure may be the best way to avoid HNC.

Obesity, metabolic factors and risk of different histological types of lung cancer: A Mendelian randomization study.

Background Assessing the relationship between lung cancer and metabolic conditions is challenging because of the confounding effect of tobacco. Mendelian randomization (MR), or the use of genetic instrumental variables to assess causality, may help to identify the metabolic drivers of lung cancer. Methods and findings We identified genetic instruments for potential metabolic risk factors and evaluated these in relation to risk using 29,266 lung cancer cases (including 11,273 adenocarcinomas, 7,426 squamous cell and 2,664 small cell cases) and 56,450 controls. The MR risk analysis suggested a causal effect of body mass index (BMI) on lung cancer risk for two of the three major histological subtypes, with evidence of a risk increase for squamous cell carcinoma (odds ratio (OR) [95% confidence interval (CI)] = 1.20 [1.01–1.43] and for small cell lung cancer (OR [95%CI] = 1.52 [1.15–2.00]) for each standard deviation (SD) increase in BMI [4.6 kg/m2]), but not for adenocarcinoma (OR [95%CI] = 0.93 [0.79–1.08]) (Pheterogeneity = 4.3x10-3). Additional analysis using a genetic instrument for BMI showed that each SD increase in BMI increased cigarette consumption by 1.27 cigarettes per day (P = 2.1x10-3), providing novel evidence that a genetic susceptibility to obesity influences smoking patterns. There was also evidence that low-density lipoprotein cholesterol was inversely associated with lung cancer overall risk (OR [95%CI] = 0.90 [0.84–0.97] per SD of 38 mg/dl), while fasting insulin was positively associated (OR [95%CI] = 1.63 [1.25–2.13] per SD of 44.4 pmol/l). Sensitivity analyses including a weighted-median approach and MR-Egger test did not detect other pleiotropic effects biasing the main results. Conclusions Our results are consistent with a causal role of fasting insulin and low-density lipoprotein cholesterol in lung cancer etiology, as well as for BMI in squamous cell and small cell carcinoma. The latter relation may be mediated by a previously unrecognized effect of obesity on smoking behavior.

International Lung Cancer Consortium: Pooled Analysis of Sequence Variants in DNA Repair and Cell Cycle Pathways

Background: The International Lung Cancer Consortium was established in 2004. To clarify the role of DNA repair genes in lung cancer susceptibility, we conducted a pooled analysis of genetic variants in DNA repair pathways, whose associations have been investigated by at least 3 individual studies. Methods: Data from 14 studies were pooled for 18 sequence variants in 12 DNA repair genes, including APEX1, OGG1, XRCC1, XRCC2, XRCC3, ERCC1, XPD, XPF, XPG, XPA, MGMT, and TP53. The total number of subjects included in the analysis for each variant ranged from 2,073 to 13,955 subjects. Results: Four of the variants were found to be weakly associated with lung cancer risk with borderline significance: these were XRCC3 T241M [heterozygote odds ratio (OR), 0.89; 95% confidence interval (95% CI), 0.79-0.99 and homozygote OR, 0.84; 95% CI, 0.71-1.00] based on 3,467 cases and 5,021 controls from 8 studies, XPD K751Q (heterozygote OR, 0.99; 95% CI, 0.89-1.10 and homozygote OR, 1.19; 95% CI, 1.02-1.39) based on 6,463 cases and 6,603 controls from 9 studies, and TP53 R72P (heterozygote OR, 1.14; 95% CI, 1.00-1.29 and homozygote OR, 1.20; 95% CI, 1.02-1.42) based on 3,610 cases and 5,293 controls from 6 studies. OGG1 S326C homozygote was suggested to be associated with lung cancer risk in Caucasians (homozygote OR, 1.34; 95% CI, 1.01-1.79) based on 2,569 cases and 4,178 controls from 4 studies but not in Asians. The other 14 variants did not exhibit main effects on lung cancer risk. Discussion: In addition to data pooling, future priorities of International Lung Cancer Consortium include coordinated genotyping and multistage validation for ongoing genome-wide association studies. (Cancer Epidemiol Biomarkers Prev 2008;17(11):3081–9)

Lung Cancer Risk in White and Black Americans

PURPOSE To test whether differences in smoking-related lung cancer risks in blacks and whites can explain why lung cancer incidence is greater in black males than in white males but about equal in black and white females, given that a greater proportion of blacks are smokers, but smoke far fewer cigarettes per day than do whites. METHODS A hospital-based case-control study was conducted between 1984 and 1998 that included interviews with 1,710 white male and 1,321 white female cases of histologically confirmed lung cancer, 254 black male and 163 black female cases, and 8,151 controls. Relative risks were estimated via odds ratios using logistic regression, adjusted for age, education, and body mass index. RESULTS We confirmed prior reports that smoking prevalence is higher but overall dosage is lower among blacks. Overall ORs were similar for blacks and whites, except among the heaviest smoking males (21+ cigarettes per day or 37.5 pack-years), in whom ORs for blacks were considerably greater than for whites. Long-term benefits of cessation were similar for white and black ex-smokers. Smokers of menthol flavored cigarettes were at no greater risk for lung cancer than were smokers of unflavored brands. CONCLUSIONS Lung cancer risks were similar for whites and blacks with similar smoking habits, except possibly for blacks who were very heavy smokers; this sub-group is unusual in the general population of African American smokers. Explanations of racial disparities in lung cancer risk may need to account for modifying factors including type of cigarette (yield, mentholation), diet, occupation, and host factors such as ability to metabolize mainstream smoke carcinogens.

The human 8-oxoguanine DNA N-glycosylase 1 (hOGG1) DNA repair enzyme and its association with lung cancer risk.

OBJECTIVE The human 8-oxoguanine DNA N-glycosylase 1 gene encodes a DNA glycosylase that is involved in the base excision repair of 8-hydroxy-2-deoxyguanine from oxidatively-damaged DNA and expressed in lung tissue. The codon 326 polymorphism in the hOGG1 gene has been suggested to reduce DNA repair enzyme activity based on in vitro functional analysis. The goal of the present study is to determine whether the codon 326 polymorphism was significantly associated with alterations in individual risk for lung cancer. METHODS To determine whether hOGG1 plays a role in risk for lung cancer, we measured the prevalence of the Ser326Cys polymorphism in incident lung cancer patients and matched non-cancer controls. hOGG1 genotyping was performed by PCR-restriction fragment length polymorphism analysis of genomic DNA isolated from 179 Caucasian lung cancer cases and 358 controls individually matched in a 1:2 ratio by race-, sex- and age (+/- 5 years). RESULTS Significantly increased risk for lung cancer was observed for both the hOGG1 326 (odds ratio [OR] = 1.9, 95% confidence interval [CI] = 1.2-2.9) and hOGG1 326 genotypes (OR = 3.8, 95% CI = 1.4-10.6). The increased risk for lung cancer was observed for subjects with both the hOGG1 326 (OR = 1.7, 95% CI = 1.1-2.8) and hOGG1 326 genotypes (OR = 4.9, 95% CI = 1.5-16.1) in ever-smokers. A significant association was found between hOGG1 genotypes and lung cancer risk with a dose-dependent effect with smoking. Significantly increased risk for variant hOGG1 genotypes was observed for all non-small cell lung cancer patients. CONCLUSION These results suggest that the hOGG1 Ser326Cys polymorphism plays an important role in the risk for lung cancer and is linked to exposure to tobacco smoke.

Glucuronidation of Active Tamoxifen Metabolites by the Human UDP Glucuronosyltransferases

Tamoxifen (TAM) is an antiestrogen that has been widely used in the treatment and prevention of breast cancer in women. One of the major mechanisms of metabolism and elimination of TAM and its major active metabolites 4-hydroxytamoxifen (4-OH-TAM) and 4-OH-N-desmethyl-TAM (endoxifen; 4-hydroxy-N-desmethyl-tamoxifen) is via glucuronidation. Although limited studies have been performed characterizing the glucuronidation of 4-OH-TAM, no studies have been performed on endoxifen. In the present study, characterization of the glucuronidating activities of human UDP glucuronosyltransferases (UGTs) against isomers of 4-OH-TAM and endoxifen was performed. Using homogenates of individual UGT-overexpressing cell lines, UGTs 2B7 ∼ 1A8 > UGT1A10 exhibited the highest overall O-glucuronidating activity against trans-4-OH-TAM as determined by Vmax/KM, with the hepatic enzyme UGT2B7 exhibiting the highest binding affinity and lowest KM (3.7 μM). As determined by Vmax/KM, UGT1A10 exhibited the highest overall O-glucuronidating activity against cis-4-OH-TAM, 10-fold higher than the next-most active UGTs 1A1 and 2B7, but with UGT1A7 exhibiting the lowest KM. Although both N- and O-glucuronidation occurred for 4-OH-TAM in human liver microsomes, only O-glucuronidating activity was observed for endoxifen; no endoxifen-N-glucuronidation was observed for any UGT tested. UGTs 1A10 ∼ 1A8 > UGT2B7 exhibited the highest overall glucuronidating activities as determined by Vmax/KM for trans-endoxifen, with the extrahepatic enzyme UGT1A10 exhibiting the highest binding affinity and lowest KM (39.9 μM). Similar to that observed for cis-4-OH-TAM, UGT1A10 also exhibited the highest activity for cis-endoxifen. These data suggest that several UGTs, including UGTs 1A10, 2B7, and 1A8 play an important role in the metabolism of 4-OH-TAM and endoxifen.

Role of Polymorphisms in Codons 143 and 160 of the O6-Alkylguanine DNA Alkyltransferase Gene in Lung Cancer Risk

O6-Alkylguanine DNA alkyltransferase (AGT) plays an important role in the repair of alkylating agent-induced DNA damage and protection from the carcinogenic effects of environmental agents. To examine the importance of the AGT codon 143 and codon 160 polymorphisms in risk for lung cancer and to assess the prevalence of these polymorphisms in different racial groups, we performed genotype analysis of lung cancer patients and matched controls. The prevalence of the AGT143Val allele in controls was 0.07 in Caucasians and 0.03 in African Americans. The AGT143Val allele was not detected in an unmatched Asian control cohort. The prevalence of the AGT160Arg variant allele was 0.01 in Caucasians, 0.02 in African Americans, and 0.03 in Asians. A marginally significant association was observed between the AGT codon 143 (isoleucine/valine) genotype and risk for lung cancer (odds ratio = 2.1; 95% confidence interval = 1.01-4.7). The prevalence of the AGT160Arg variant allele was similar in lung cancer cases versus matched controls. These results suggest that the AGT codon 143 polymorphism may play an important role in risk for lung cancer.