Biomarkers for screening of lung cancer and pre-neoplastic lesions in a high risk Chilean population.

BACKGROUND: The mortality of lung cancer (LC), increases each year in the world, in spite of any advances, in development of new drugs to advance stages of LC. The high incidence of LC has been associated with smoking habit, genetic diversity and environmental pollution. Antofagasta region has been reported to have the highest LC mortality rate in Chile and its inhabitants were exposed to arsenic in their drinking water in concentrations as high as 870 µg/L. Non-invasive techniques such as biomarkers (Automatic Quantitative Cytometry: AQC and DR70) and Auto Fluorescence Bronchoscopy (AFB) might be potentially useful as a supplementary diagnostic approach and early detection. Early detection is one of the most important factors to intervene and prevent cancer progression in LC. This is a work of an ongoing prospective bimodality cancer surveillance study in high risk LC volunteers. Enrolment was done in subjects from Antofagasta and Metropolitan regions. In addition, we enrolled subjects who were suspected of having lung cancer. AQC, DR70 and AFB were used as tools in the detection of pre-neoplastic (PNL) and neoplastic lesions (NL). RESULTS: Half of the samples, classified as suspicious by AFB, were confirmed as metaplasia or dysplasia by histopathology. For LC, DR70 showed a higher sensitivity (95.8%) and specificity (91.9%) than AQC. However, for PNL AQC showed a higher sensitivity (91.9%) than DR70 (27.3%), although both with low PPV values. As a pre screener, both biomarkers might be employed as complementary tools to detect LC, especially as serially combined tests, with a sensitivity of 60% and a PPV of 65.2%. Additionally, the use of parallel combined tests might support the detection of PNL (sensitivity 91.2%; PPV 49.1%). CONCLUSION: This work adds information on cellular and molecular biomarkers to complement imaging techniques for early detection of LC in Latin America that might contribute to formulate policies concerning screening of LC. Supported by INNOVA-CORFO, Chile.

Biomarkers for screening of lung cancer and pre-neoplastic lesions in a high risk Chilean population

BACKGROUND: The mortality of lung cancer (LC), increases each year in the world, in spite of any advances, in development of new drugs to advance stages of LC. The high incidence of LC has been associated with smoking habit, genetic diversity and environmental pollution. Antofagasta region has been reported to have the highest LC mortality rate in Chile and its inhabitants were exposed to arsenic in their drinking water in concentrations as high as 870 µg/L. Non-invasive techniques such as biomarkers (Automatic Quantitative Cytometry: AQC and DR70) and Auto Fluorescence Bronchoscopy (AFB) might be potentially useful as a supplementary diagnostic approach and early detection. Early detection is one of the most important factors to intervene and prevent cancer progression in LC. This is a work of an ongoing prospective bimodality cancer surveillance study in high risk LC volunteers. Enrolment was done in subjects from Antofagasta and Metropolitan regions. In addition, we enrolled subjects who were suspected of having lung cancer. AQC, DR70 and AFB were used as tools in the detection of pre-neoplastic (PNL) and neoplastic lesions (NL). RESULTS: Half of the samples, classified as suspicious by AFB, were confirmed as metaplasia or dysplasia by histopathology. For LC, DR70 showed a higher sensitivity (95.8%) and specificity (91.9%) than AQC. However, for PNL AQC showed a higher sensitivity (91.9%) than DR70 (27.3%), although both with low PPV values. As a pre screener, both biomarkers might be employed as complementary tools to detect LC, especially as serially combined tests, with a sensitivity of 60% and a PPV of 65.2%. Additionally, the use of parallel combined tests might support the detection of PNL (sensitivity 91.2%; PPV 49.1%). CONCLUSION: This work adds information on cellular and molecular biomarkers to complement imaging techniques for early detection of LC in Latin America that might contribute to formulate policies concerning screening of LC. Supported by INNOVA-CORFO, Chile.

Whole-genome sequencing analysis identifies a distinctive mutational spectrum in an arsenic-related lung tumor.

INTRODUCTION: Arsenic exposure is a significant cause of lung cancer in North America and worldwide. Arsenic-related tumors are structurally indistinguishable from those induced by other carcinogens. Because carcinogens, like tobacco, induce distinctive mutational signatures, we sought to characterize the mutational signature of an arsenic-related lung tumor from a never smoker with the use of whole-genome sequencing. METHODS: Tumor and lung tissues were obtained from a never smoker with lung squamous cell carcinoma (LUSC), without familiar history of lung cancer and chronically exposed to high levels of arsenic-contaminated drinking water. The Illumina HiSeq-2000 platform was used to sequence each genome at approximately 30-fold haploid coverage. The mutational signature was compared with those observed in previously characterized lung tumors. RESULTS: The arsenic-related tumor exhibited alterations common in LUSC, such as the increased number of copies at 3q26 (SOX2 locus). However, the arsenic-related genome not only harbored a lower number of point mutations, but also had a remarkably high fraction of T>G/A>C mutations and low fraction of C>A/G>T transversions, which is uncharacteristic of LUSCs. Furthermore, at the gene level, we identified a rare G>C mutation in TP53, which is uncommon in lung tumors in general (<0.2%) but has been observed in other arsenic-related malignancies. CONCLUSIONS: We generated the first whole-genome sequence of an LUSC from a never-smoker patient chronically exposed to arsenic, and identified a distinct mutational spectrum associated with arsenic exposure, providing novel evidence supporting the hypothesis that arsenic-induced lung tumors arise through molecular mechanisms that differ from those of the common lung cancer.

Arsenic biotransformation as a cancer promoting factor by inducing DNA damage and disruption of repair mechanisms.

Chronic exposure to arsenic in drinking water poses a major global health concern. Populations exposed to high concentrations of arsenic-contaminated drinking water suffer serious health consequences, including alarming cancer incidence and death rates. Arsenic is biotransformed through sequential addition of methyl groups, acquired from s-adenosylmethionine (SAM). Metabolism of arsenic generates a variety of genotoxic and cytotoxic species, damaging DNA directly and indirectly, through the generation of reactive oxidative species and induction of DNA adducts, strand breaks and cross links, and inhibition of the DNA repair process itself. Since SAM is the methyl group donor used by DNA methyltransferases to maintain normal epigenetic patterns in all human cells, arsenic is also postulated to affect maintenance of normal DNA methylation patterns, chromatin structure, and genomic stability. The biological processes underlying the cancer promoting factors of arsenic metabolism, related to DNA damage and repair, will be discussed here.

Strategic approaches to informing the public about biotechnology in Latin America

The benefits of today's biotechnology products are not evident to consumers. The public will accept biotechnology only when individuals decide for themselves that biotec products will contribute to their personal well-being. To make such a decision, people will need greater awareness and understanding of how biotechnology will affect the environment, human health, local and national economies, and the well-being of society. A low level of awareness and understanding about biotechnology is characteristic of Latin America and the Caribbean countries, as elsewhere, efforts to remedy poor public perception often seem inadequate and do not reflect a well-designed strategy. In order to improve the understanding of the biotechnology and their human applications, a strategic plan for public communications is required. Specific objectives for this initiative may include: (1) to make evident to decision makers that modern biotechnology can be an effective tool for increasing agricultural productivity, and thereby economic growth, without imposing unacceptable risk to the environment or human and animal health; (2) to enable members of the public to make informed decisions about appropriate uses of biotechnology by providing accurate information about benefits, risks and impacts; or (3) to incorporate modern biotechnology into science curricula for secondary schools, university and college students, and agriculture extension officers. A variety of specialized expertise, including communication specialists, technical writers, graphic artists and illustrators to design information materials and conduct training is needed to implement this. Ideally, members bring expertise in biotechnology and biosafety, public communications and project management. The plan will need to identify scientists and technical experts who can provide expertise in science writing for general audiences...

Occupational and environmental levels of mutagenic PAHs and respirable particulate matter associated with diesel exhaust in Santiago, Chile.

This work studied the mutagenic potential and polycyclic aromatic hydrocarbon (PAH) levels onto PM10 collected in diesel revision plants, in an urban area as well as in a rural area in Santiago, Chile. The PM10 average levels in diesel emission plants during working hours (there is no occupational PM10 Chilean standard) were significantly higher than the atmospheric Chilean PM10 standard and highly mutagenic and with high PAHs levels. Additionally, we evaluated the contribution of CYP1A1 and GSTM1 polymorphisms on 1-OH-pyrene urinary levels. The diesel-exposed workers carrying the CYP1A1*2A allele showed significantly higher 1-OH-P levels than the subjects from the rural area with the same genotype. The higher levels of 1-OH-P were found in individuals carrying the combined CYP1A1*2A and GSTM1 null genotype. This kind of information might be relevant to establish prevention, protection, and mitigation actions to protect public health.

Modulation of the hepatic antioxidant defense system by air polluants from urban areas

This study describes the changes induced by organic extracts from airborne particuiate matter in some enzymes related to the antioxidant defense system as well as in peroxisomal acyl CoA oxidase activity in rat liver. After 48 h of i.p. injection (40 mg/kg b.wt.) the hepatic GSH content decreased by about 30 per cent, which was accompanied by a parallel increase in glutathione-S-transferase activity. In contrast the activity of glutathione peroxidase was significantly decreased (p < 0.05).Peroxisomal acyl CoA-oxidase was enhanced by about 40 per cent with a parallel increase of liver catalase (27 per cent), the peroxisomal H2O2-destroying enzyme. With the only exception hepatic lipid peroxidation, that remains unchanged, all the effects showed a dose-dependent response with respect to the content of polycyclic aromatic hydrocarbons in the organic airborne extracts. However, the content of other chemical pollutants such as plasticizers, pestcides and other organic compounds must be taken into account. These results suggest that organic extracts from Santiago airborne particles might induce a prooxidant state. According to this view the increase in GSTs and catalase activity may be considered as a protective response against the damage induced by airborne pollutants.