Marta Vilensky

Identification of Circulating Tumor DNA for the Early Detection of Small-cell Lung Cancer

Circulating tumor DNA (ctDNA) is emerging as a key potential biomarker for post-diagnosis surveillance but it may also play a crucial role in the detection of pre-clinical cancer. Small-cell lung cancer (SCLC) is an excellent candidate for early detection given there are no successful therapeutic options for late-stage disease, and it displays almost universal inactivation of TP53. We assessed the presence of TP53 mutations in the cell-free DNA (cfDNA) extracted from the plasma of 51 SCLC cases and 123 non-cancer controls. We identified mutations using a pipeline specifically designed to accurately detect variants at very low fractions. We detected TP53 mutations in the cfDNA of 49% SCLC patients and 11.4% of non-cancer controls. When stratifying the 51 initial SCLC cases by stage, TP53 mutations were detected in the cfDNA of 35.7% early-stage and 54.1% late-stage SCLC patients. The results in the controls were further replicated in 10.8% of an independent series of 102 non-cancer controls. The detection of TP53 mutations in 11% of the 225 non-cancer controls suggests that somatic mutations in cfDNA among individuals without any cancer diagnosis is a common occurrence, and poses serious challenges for the development of ctDNA screening tests.

Leather tanning workers: chromosomal aberrations in peripheral lymphocytes and micronuclei in exfoliated cells in urine

A cytogenetic study was performed on workers of a leather tanning industry. Two different approaches for the biological monitoring of the individuals were used: chromosomal aberration analysis in peripheral lymphocytes and the frequency of micronucleated cells exfoliated in urine samples. 26 men working in the sections considered to present a greater risk were included in the study. Controls were 20 men that were not exposed to chemicals. The percentage of abnormal cells was higher in workers than in controls. Smokers showed higher values of chromosome breaks than non-smokers in both groups. These differences were not statistically significant. The percentage of cells with chromatid and chromosome gaps in workers and controls was different (p less than 0.01). A slight but not significant increase in the mean percentage of micronuclei was observed in the exposed group. We conclude that exposure to chemicals during leather tanning did not produce genotoxic effects measured by chromosomal aberrations in peripheral lymphocytes and micronuclei in urine in this group of workers.

Circulating 92-kilodalton matrix metalloproteinase (MMP-9) activity is enhanced in the euglobulin plasma fraction of head and neck squamous cell carcinoma: Plasma 92-Kilodalton MMP Activity in HNSCC Tumors

Cancer lethality is usually the result of local invasion and metastasis of neoplastic cells from the primary tumor. Because of their ability to degrade extracellular matrix components (EMC), matrix metalloproteinases (MMPs) have been implicated in the breakdown of basement membranes and underlying stroma, thereby facilitating tumor growth and invasion.

Occupational Exposures and Lung Cancer in Buenos Aires, Argentina

The main objective of this study was to analyze the risks associated with occupational exposures in an industrializing country where lung cancer is the primary neoplastic cause of death in men. A full occupational history was collected through interviewing 199 men with lung cancer and 393 control subjects. Exposure to arsenic, asbestos, chromium, dust, nickel, and polynuclear aromatic hydrocarbons was assessed by means of a job-exposure matrix. Elevated odds ratios were observed for employment in the alcoholic beverages industry (5.2; 95% confidence interval [CI], 1.1 to 23.1), sawmills and wood mills (4.8; 95% CI, 1.2 to 19.0), water transport (3.3; 95% CI, 1.1 to 12.1), and chemicals/plastics manufacturers (1.9; 95% CI, 1.1 to 3.3). A small, non-significant increased risk was observed after long-term exposure to arsenic and chromium, with a dose-response for chromium. Although some of the present results may result from chance, most are consistent with those of previous investigations in other countries.

Genome-wide association analyses identify new susceptibility loci for oral cavity and pharyngeal cancer

We conducted a genome-wide association study of oral cavity and pharyngeal cancer in 6,034 cases and 6,585 controls from Europe, North America and South America. We detected eight significantly associated loci (P < 5 × 10−8), seven of which are new for these cancer sites. Oral and pharyngeal cancers combined were associated with loci at 6p21.32 (rs3828805, HLA-DQB1), 10q26.13 (rs201982221, LHPP) and 11p15.4 (rs1453414, OR52N2–TRIM5). Oral cancer was associated with two new regions, 2p23.3 (rs6547741, GPN1) and 9q34.12 (rs928674, LAMC3), and with known cancer-related loci—9p21.3 (rs8181047, CDKN2B-AS1) and 5p15.33 (rs10462706, CLPTM1L). Oropharyngeal cancer associations were limited to the human leukocyte antigen (HLA) region, and classical HLA allele imputation showed a protective association with the class II haplotype HLA-DRB1*1301–HLA-DQA1*0103–HLA-DQB1*0603 (odds ratio (OR) = 0.59, P = 2.7 × 10−9). Stratified analyses on a subgroup of oropharyngeal cases with information available on human papillomavirus (HPV) status indicated that this association was considerably stronger in HPV-positive (OR = 0.23, P = 1.6 × 10−6) than in HPV-negative (OR = 0.75, P = 0.16) cancers.

The INHANCE consortium: toward a better understanding of the causes and mechanisms of head and neck cancer

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.

Lung cancer and smoking: A case-control study in Buenos Aires, Argentina

The objective of this study was to examine the risks for lung cancer associated with lifestyle characteristics of smoking in a developing country where lung cancer is the first cause of mortality by cancer in men, tobacco propaganda is freely allowed, and there are no restrictions operating for smoking. The design was a case-control and hospital-based study. Two hundred men with lung cancer and 397 hospital controls were interviewed. Odds ratio (OR) for current smokers was 8.5, whereas former smokers displayed an OR of 5.3. The risk increased with duration of smoking and with the number of cigarettes smoked per day. The attributable risk for smoking was 85%. Smokers of black tobacco and more than 24 cigarettes/day showed a risk of 12.9 regarding non-smokers, and of 15.5 for 40 or more years duration of smoking. The proportion of cases diagnosed as adenocarcinoma was higher than the proportion of squamous cell carcinoma.

Low frequency of cigarette smoking and the risk of head and neck cancer in the INHANCE consortium pooled analysis

BACKGROUND Cigarette smoking is a major risk factor for head and neck cancer (HNC). To our knowledge, low cigarette smoking (<10 cigarettes per day) has not been extensively investigated in fine categories or among never alcohol drinkers. METHODS We conducted a pooled analysis of individual participant data from 23 independent case-control studies including 19 660 HNC cases and 25 566 controls. After exclusion of subjects using other tobacco products including cigars, pipes, snuffed or chewed tobacco and straw cigarettes (tobacco product used in Brazil), as well as subjects smoking more than 10 cigarettes per day, 4093 HNC cases and 13 416 controls were included in the analysis. The lifetime average frequency of cigarette consumption was categorized as follows: never cigarette users, >0-3, >3-5, >5-10 cigarettes per day. RESULTS Smoking >0-3 cigarettes per day was associated with a 50% increased risk of HNC in the study population [odds ratio (OR) = 1.52, 95% confidence interval (CI): (1.21, 1.90). Smoking >3-5 cigarettes per day was associated in each subgroup from OR = 2.01 (95% CI: 1.22, 3.31) among never alcohol drinkers to OR = 2.74 (95% CI: 2.01, 3.74) among women and in each cancer site, particularly laryngeal cancer (OR = 3.48, 95% CI: 2.40, 5.05). However, the observed increased risk of HNC for low smoking frequency was not found among smokers with smoking duration shorter than 20 years. CONCLUSION Our results suggest a public health message that low frequency of cigarette consumption contributes to the development of HNC. However, smoking duration seems to play at least an equal or a stronger role in the development of HNC.

Mouthwash use and cancer of the head and neck: a pooled analysis from the International Head and Neck Cancer Epidemiology Consortium.

Most mouthwashes contain alcohol, a known cause of head and neck cancer (oral cavity, pharynx, larynx), likely through the carcinogenic activity of acetaldehyde, formed in the oral cavity from alcohol. We carried out a pooled analysis of 8981 cases of head and neck cancer and 10 090 controls from 12 case–control studies with comparable information on mouthwash use in the International Head and Neck Cancer Epidemiology Consortium. Logistic regression was used to assess the association of mouthwash use with cancers of the oral cavity, oropharynx, hypopharynx, and larynx, adjusting for study, age, sex, pack-years of tobacco smoking, number of alcoholic drinks/day, and education. Compared with never users of mouthwash, the odds ratio (OR) of all head and neck cancers was 1.01 [95% confidence interval (CI): 0.94–1.08] for ever users, based on 12 studies. The corresponding ORs of cancer of the oral cavity and oropharynx were 1.11 (95% CI: 1.00–1.23) and 1.28 (95% CI: 1.06–1.56), respectively. OR for all head and neck cancer was 1.15 (95% CI: 1.01–1.30) for use for more than 35 years, based on seven studies (P for linear trend=0.01), and OR 1.31 (95% CI: 1.09–1.58) for use more than one per day, based on five studies (P for linear trend <0.001). Although limited by the retrospective nature of the study and the limited ability to assess risks of mouthwash use in nonusers of tobacco and alcohol, this large investigation shows potential risks for head and neck cancer subsites and in long-term and frequent users of mouthwash. This pooled analysis provides the most precise estimate of the association between mouthwash use and head and neck cancer.

Environmental and occupational cancer in Argentina: a case-control lung cancer study

The main objective of this study was to analyze the risks for lung cancer associated with occupational exposures in a developing country where lung cancer is the first cause of mortality from cancer in men. The study involved 200 men with lung cancer and 397 hospital controls. The OR for current smokers was 8.5, whereas former smokers displayed an OR of 5.3. The fraction attributable to smoking was 85%. Statistically significant high ORs were observed for employment in the alcoholic beverages (4.5, 95% CI: 1.02-20.2), sawmills and wood mills (4.6, 95% CI:1.1-18.4), chemicals/plastics (1. 8, 95% CI:1.04-3.2), and pottery, glass, or mineral manufactures (3.4, 95% CI:1.1-10.6). Other high (but not statistically significant) risks were observed for employment in leather shoe industry and repair (2.1, 95% CI:0.8-5.4), rubber industries (3.4, 95% CI:0.9-12.4), metal workers, including welders (1.9, 95% CI:0.8-4.4), motor vehicle mechanics (2.0, 95% CI:0.9-4.2), workers in cleaning services (1.9, 95% CI: 0.8-4.5), and for workers in agriculture (2.4, 95% CI:0.9-6.0). Although some of the present results may be due to chance, most are consistent with those of previous investigations in other countries.