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Pascal Andujar,
Jean-Claude Pairon,
Annie Renier,
Alexis Descatha,
Ilir Hysi,
Issam Abd-Alsamad,
Marie-Annick Billon-Galland,
Hélène Blons,
Bénédicte Clin,
Claire Danel, [......],
Bruno Housset,
Pierre Laurent-Puig,
Françoise Le Pimpec-Barthes,
Marc Letourneux,
Isabelle Monnet,
Jean-François Régnard,
Pierre Validire,
Jessica Zucman-Rossi,
Marie-Claude Jaurand,
Didier Jean
[show abstract]
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ABSTRACT: Given the interest in defining biomarkers of asbestos exposure and to provide insights into asbestos-related and cell-specific mechanisms of neoplasia, the identification of gene alterations in asbestos-related cancers can help to a better understanding of exposure risk. To understand the aetiology of asbestos-induced malignancies and to increase our knowledge of mesothelial carcinogenesis, we compared genetic alterations in relevant cancer genes between lung cancer, induced by asbestos and tobacco smoke, and malignant pleural mesothelioma (MPM), a cancer related to asbestos, but not to tobacco smoke. TP53, KRAS, EGFR and NF2 gene alteration analyses were performed in 100 non-small cell lung cancer (NSCLC) patients, 50 asbestos-exposed and 50 unexposed patients, matched for age, gender, histology and smoking habits. Detailed assessment of asbestos exposure was based on both specific questionnaires and asbestos body quantification in lung tissue. Genetic analyses were also performed in 34 MPM patients. TP53, EGFR and KRAS mutations were found in NSCLC with no link with asbestos exposure. NF2 was only altered in MPM. Significant enhancement of TP53 G:C to T:A transversions was found in NSCLC from asbestos-exposed patients when compared with unexposed patients (P = 0.037). Interestingly, TP53 polymorphisms in intron 7 (rs12947788 and rs12951053) were more frequently identified in asbestos-exposed NSCLC (P = 0.046) and MPM patients than in unexposed patients (P < 0.001 and P = 0.012, respectively). These results emphasise distinct genetic alterations between asbestos-related thoracic tumours, but identify common potential susceptibility factors, i.e. single nucleotide polymorphisms in intron 7 of TP53. While genetic changes in NSCLC are dominated by the effects of tobacco smoke, the increase of transversions in TP53 gene is consistent with a synergistic effect of asbestos. These results may help to define cell-dependent mechanisms of action of asbestos and identify susceptibility factors to asbestos.
Mutagenesis 02/2013; · 3.18 Impact Factor
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Jean-Claude Pairon,
François Laurent,
Mickaël Rinaldo,
Bénédicte Clin,
Pascal Andujar,
Jacques Ameille,
Patrick Brochard,
Soizick Chammings,
Gilbert Ferretti, Françoise Galateau-Sallé,
Antoine Gislard,
Marc Letourneux,
Amandine Luc,
Evelyne Schorlé,
Christophe Paris
[show abstract]
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ABSTRACT: Background
The association between pleural plaques and pleural mesothelioma remains controversial. The present study was designed to examine the association between pleural plaques on computed tomography (CT) scan and the risk of pleural mesothelioma in a follow-up study of asbestos-exposed workers.Methods
Retired or unemployed workers previously occupationally exposed to asbestos were invited to participate in a screening program for asbestos-related diseases, including CT scan, organized between October 2003 and December 2005 in four regions in France. Randomized, independent, double reading of CT scans by a panel of seven chest radiologists focused on benign asbestos-related abnormalities. A 7-year follow-up study was conducted in the 5287 male subjects for whom chest CT scan was available. Annual determination of the number of subjects eligible for free medical care because of pleural mesothelioma was carried out. Diagnosis certification was obtained from the French mesothelioma panel of pathologists. Survival regression based on the Cox model was used to estimate the risk of pleural mesothelioma associated with pleural plaques, with age as the main time variable and time-varying exposure variables, namely duration of exposure, time since first exposure, and cumulative exposure index to asbestos. All statistical tests were two-sided.ResultsA total of 17 incident cases of pleural mesothelioma were diagnosed. A statistically significant association was observed between mesothelioma and pleural plaques (unadjusted hazard ratio (HR) = 8.9, 95% confidence interval [CI] = 3.0 to 26.5; adjusted HR = 6.8, 95% CI = 2.2 to 21.4 after adjustment for time since first exposure and cumulative exposure index to asbestos).Conclusion
The presence of pleural plaques may be an independent risk factor for pleural mesothelioma.
CancerSpectrum Knowledge Environment 01/2013; · 14.07 Impact Factor
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Aude Lacourt,
Patrick Rolland,
Céline Gramond,
Philippe Astoul,
Soizick Chamming’s,
Stéphane Ducamp,
Catherine Frenay, Françoise Galateau-Sallé,
Anabelle Gilg Soit Ilg,
Ellen Imbernon,
Nolwenn Le Stang,
Jean Claude Pairon,
Marcel Goldberg,
Yuriko Iwatsubo,
Louis-Rachid Salmi,
Patrick Brochard
[show abstract]
[hide abstract]
ABSTRACT: Pleural mesothelioma is a primary tumor of the pleura that is mainly due to asbestos exposure. To study the relationship between
mesothelioma and occupational asbestos exposure in France, two case–control studies (A and B) were conducted. A substantial
difference in the attributable risk in the population (ARp) was observed among men: 44.5% (95% CI: [32.6–56.4]) in study A and 83.2% (95% CI: [76.8–89.6]) in study B. As different
exposure assessment expert methods were used, the main objective of this work was to re-estimate the ARp men in two case–control studies according to a common standardized exposure assessment by using a Job Exposure Matrix (JEM)
and to assess the role of subjects’ selection. The initial observed ARp difference was maintained: 36.3% (95% CI: [24.3–50.3]) in study A and 69.7% (95% CI: [51.7–83.2]) in study B. Further investigations
highlighted the potential selection bias introduced in both studies, especially among controls. The ARp could be underestimated in study A and overestimated in study B. After weighting subjects according to distribution of socio-economic
status in the general population for controls and according to distribution of socio-economic status of cases registered by
the French National Mesothelioma Surveillance Program, re-estimated ARp values were 52.4% in study A and 70.2% in study B. These results provide additional information to describe the relationship
between pleural mesothelioma and occupational asbestos exposure, but also confirm the importance of subjects’ recruitment
in case control studies, particularly control selection.
KeywordsAsbestos-Attributable risk-Case–control study-Men-Mesothelioma-Occupational exposure
European Journal of Epidemiology 04/2012; 25(11):799-806. · 4.71 Impact Factor
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ABSTRACT: To identify which morphologic or densitometric parameters are modified in cell nuclei from bronchopulmonary cancer based on 18 parameters involving shape, intensity, chromatin, texture, and DNA content and develop a bronchopulmonary cancer screening method relying on analysis of sputum sample cell nuclei.
A total of 25 sputum samples from controls and 22 bronchial aspiration samples from patients presenting with bronchopulmonary cancer who were professionally exposed to cancer were used. After Feulgen staining, 18 morphologic and DNA content parameters were measured on cell nuclei, via image cytom- etry. A method was developed for analyzing distribution quantiles, compared with simply interpreting mean values, to characterize morphologic modifications in cell nuclei.
Distribution analysis of parameters enabled us to distinguish 13 of 18 parameters that demonstrated significant differences between controls and cancer cases. These parameters, used alone, enabled us to distinguish two population types, with both sensitivity and specificity > 70%. Three parameters offered 100% sensitivity and specificity. When mean values offered high sensitivity and specificity, comparable or higher sensitivity and specificity values were observed for at least one of the corresponding quantiles.
Analysis of modification in morphologic parameters via distribution analysis proved promising for screening bronchopulmonary cancer from sputum.
Analytical and quantitative cytology and histology / the International Academy of Cytology [and] American Society of Cytology 08/2011; 33(4):183-95. · 0.41 Impact Factor
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ABSTRACT: We report a lethal Myceliophthora thermophila infection in an immunocompromised patient. Based upon the clinical and mycological presentation, an initial diagnosis of invasive aspergillosis was made, possibly delaying optimal management in the patient. Melanized fungi are emerging pathogens that require early identification to improve their unfavorable prognosis.
Diagnostic microbiology and infectious disease 03/2011; 70(2):267-9. · 2.45 Impact Factor
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Didier Jean,
Emilie Thomas,
Elodie Manié,
Annie Renier,
Aurélien de Reynies,
Céline Lecomte,
Pascal Andujar,
Jocelyne Fleury-Feith, Françoise Galateau-Sallé,
Marco Giovannini,
Jessica Zucman-Rossi,
Marc-Henri Stern,
Marie-Claude Jaurand
[show abstract]
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ABSTRACT: Malignant mesothelioma (MM) is an aggressive tumor with a poor prognosis mainly linked to past asbestos exposure. Murine models of MM based on fiber exposure have been developed to elucidate the mechanism of mesothelioma formation. Genomic alterations in murine MM have now been partially characterized. To gain insight into the pathophysiology of mesothelioma, 16 murine and 35 human mesotheliomas were characterized by array-comparative genomic hybridization and were screened for common genomic alterations. Alteration of the 9p21 human region, often by biallelic deletion, was the most frequent alteration in both species, in agreement with the CDKN2A/CDKN2B locus deletion in human disease and murine models. Other shared aberrations were losses of 1p36.3-p35 and 13q14-q33 and gains of 5p15.3-p13 regions. However, some differences were noted, such as absence of recurrent alterations in mouse regions corresponding to human chromosome 22. Comparison between altered recurrent regions in asbestos-exposed and non-asbestos-exposed patients showed a significant difference in the 14q11.2-q21 region, which was also lost in fiber-induced murine mesothelioma. A correlation was also demonstrated between genomic instability and tumorigenicity of human mesothelioma xenografts in nude mice. Overall, these data show similarities between murine and human disease, and contribute to the understanding of the influence of fibers in the pathogenesis of mesothelioma and validation of the murine model for preclinical testing.
American Journal Of Pathology 02/2011; 178(2):881-94. · 4.89 Impact Factor
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Pascal Andujar,
Jinhui Wang,
Alexis Descatha, Françoise Galateau-Sallé,
Issam Abd-Alsamad,
Marie-Annick Billon-Galland,
Hélène Blons,
Bénédicte Clin,
Claire Danel,
Bruno Housset,
Pierre Laurent-Puig,
Françoise Le Pimpec-Barthes,
Marc Letourneux,
Isabelle Monnet,
Jean-François Régnard,
Annie Renier,
Jessica Zucman-Rossi,
Jean-Claude Pairon,
Marie-Claude Jaurand
[show abstract]
[hide abstract]
ABSTRACT: Epidemiological studies have shown that asbestos fibers constitute the major occupational risk factor and that asbestos acts synergistically with tobacco smoking to induce lung cancer. Although some somatic gene alterations in lung cancer have been linked to tobacco smoke, few data are available on the role of asbestos fibers. P16/CDKN2A is an important tumor suppressor gene that is frequently altered in lung cancer via promoter 5'-CpG island hypermethylation and homozygous deletion, and rarely via point mutation. Many studies suggest that tobacco smoking produces P16/CDKN2A promoter hypermethylation in lung cancer, but the status of this gene in relation to asbestos exposure has yet to be determined. The purpose of this study was to investigate the mechanism of P16/CDKN2A alterations in lung cancer in asbestos-exposed patients. P16/CDKN2A gene status was studied in 75 human non-small-cell lung cancer (NSCLC) cases with well-defined smoking habits, and detailed assessment of asbestos exposure, based on occupational questionnaire and determination of asbestos bodies in lung tissue. The results of this study confirm published data on the effect of tobacco smoke on P16/CDKN2A gene alterations, characterized by significantly higher P16/CDKN2A promoter hypermethylation in heavy smokers (more than 40 pack-years (P-Y)) than in smokers of less than 40 P-Y. These results also demonstrate a higher incidence of loss of heterozygosity and homozygous deletion in asbestos-exposed cases, after adjustment for age and cumulative tobacco consumption, than in unexposed cases (P=0.0062). This study suggests that P16/CDKN2A gene inactivation in asbestos-exposed NSCLC cases mainly occurs via deletion, a feature also found in malignant mesothelioma, a tumor independent of tobacco smoking but associated with asbestos exposure, suggesting a possible relationship with an effect of asbestos fibers.
Lung cancer (Amsterdam, Netherlands) 05/2009; 67(1):23-30. · 3.14 Impact Factor
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ABSTRACT: Malignant mesothelioma (MM) is an aggressive neoplasm caused by exposure to asbestos fibers in 80% of cases.1,2 Although asbestos has been banned in most developed countries, the incidence of mesothelioma is still rising because of the
long latency period from the time of exposure to development of the disease (20–40 years). Asbestos fibers interact with the
mesothelial cells from which these tumors arise in several different ways and generate reactive oxygen species (see Chapter
44), cytokines, and growth factors secondary to inflammatory responses from the host, resulting in DNA damage. Protooncogenes
may be activated, leading to cell proliferation and susceptibility to mutations. Over time, structural alterations and numerical
losses and gains to chromosomes occur, producing genomic instability and alteration of the role of tumor suppressor genes.
These complex cytogenetic and molecular events in MM development attest to the multistep process from a benign proliferation
to a malignant neoplasm.
12/2007: pages 347-357;
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The Journal of otolaryngology 07/2006; 35(3):202-4. · 0.50 Impact Factor
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ABSTRACT: Well-differentiated papillary mesothelioma (WDPM) of the pleura represents a distinct mesothelial tumor presenting with unilateral pleural effusion and superficial spreading of stout papillary formations with myxoid cores, lined by bland, flattened, or epithelioid cells, without or with limited invasion of the submesothelial layer. The majority of cases have been reported in the peritoneum in women of reproductive age with no history of asbestos exposure and also in the tunica vaginalis of men. We report 24 cases of pleural WDPM and compared their histologic, epidemiologic, and clinical features with those of classic mesothelioma. Men and women were equally affected, with a mean age of 60 years. Half of the patients had a history of occupational asbestos exposure. In 11 patients with a minimal follow-up period of 24 months, the survival ranged from 36 to 180 months with an average of 74 months as compared with 9.89 months for 1248 paired patients with diffuse malignant mesothelioma. Ten-year survival was 30.8%. We conclude that WDPM is a rare and unusual mesothelial tumor, characterized by a lack of deep invasion and associated with an indolent clinical course and long survival. For these reasons, WDPM is best considered as a specific clinico-pathologic entity distinct from conventional diffuse malignant mesothelioma.
American Journal of Surgical Pathology 05/2004; 28(4):534-40. · 4.35 Impact Factor
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Emmanuelle Berthe,
Michel Henry-Amar,
Jean-Jacques Michels,
Jean-Pierre Rame,
Pascaline Berthet,
Emmanuel Babin,
Philippe Icard,
Guy Samama, Françoise Galateau-Sallé,
Jacques Mahoudeau,
Stéphane Bardet
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[hide abstract]
ABSTRACT: Concerns remain over the risk of cancer following differentiated thyroid carcinoma and its causes. Iodine-131 ((131)I) and external irradiation are known to have potential carcinogenic effects. Thyroid carcinoma is a polygenic disease which may be associated with other malignancies. We investigated the incidence of second cancer and its aetiology in a cohort of 875 patients (146 men, 729 women) with differentiated thyroid carcinoma originating from Basse-Normandie, France. Cancer incidence was compared with that of the general population of the Département du Calvados matched for age, gender and period. The cumulative proportion of second cancer was estimated using the life-table method. Factors that correlated with the risk of second cancer were studied using the Cox model. After a median follow-up of 8 years, 58 second cancers had been observed. Compared with general population incidence rates, there was an overall increased risk of second cancer in women [standardised incidence ratio (SIR)=1.52; P<0.01], but not in men (SIR=1.27; P>0.20). Increased risk related to cancers of the genitourinary tract (SIR=3.31; P<0.001), and particularly to cancer of the kidney (SIR=7.02; P<0.01). Multivariate analysis showed that age above 40 years (P<0.01) and a history of previous primary cancer (P<0.001) correlated with risk. In contrast, neither cervical irradiation nor cumulative activity of (131)I was related to the risk. These data confirm that women with differentiated thyroid carcinoma are at risk of developing a second cancer of the genitourinary tract and kidney. Only age and medical history of primary cancer before thyroid carcinoma are risk factors for second cancer. Common environmental or genetic factors as well as long-term carcinogenic effects of primary cancer therapy should be considered.
European journal of nuclear medicine and molecular imaging 05/2004; 31(5):685-91. · 4.99 Impact Factor
