Cette recherche vise à éclairer les processus en oeuvre lors des procédures de reconnaissance en MP de patients atteints de cancers qui relèvent d’une expertise du comité régional de reconnaissance en maladie professionnelle (CRRMP). Elle s’attache tout d’abord à explorer les fondements historiques du dispositif de reconnaissance en maladie professionnelle (MP) et à comprendre les dynamiques générales de la réparation des cancers liés au travail.Puis, elle s’intéresse aux pratiques du système complémentaire en analysant les procédures en MP de 65 patients atteints de cancer. Dans une démarche qualitative, elle examine les étapes successives en oeuvre : l’expertise d’un dispositif de santé publique de surveillance des cancers professionnels en Seine-Saint-Denis, le GISCOP93, qui a incité à la déclaration en MP de ces cas, l’instruction médico-administrative de la Caisse Primaire d’Assurance Maladie qui décide de la saisine du Comité, puis l’expertise médicale du Comité. L’analyse se poursuit par l’étude d’actions contentieuses auprès du Tribunal des Affaires de Sécurité sociale.Le cadre d’analyse met en lumière les trajectoires de ces demandes dans la procédure de reconnaissance en MP et les logiques des acteurs qui président aux décisions de rejet et de reconnaissance. Il met en évidence une forte variabilité des résultats selon les expertises ainsi qu’un impact important de l’état de santé des patients. Les éléments de variabilité concernent tant l’attribution professionnelle donnée aux cancers par les différents acteurs, que leurs interprétations différentes du cadre de la reconnaissance en MP et des cancérogènes qualifiés dans les parcours professionnels. / This research aims at shedding light on the processes at work in the compensation procedures of occupational disease (OD) in the case of cancer patients falling in the expertise of the Regional Committees for the Recognition of Occupational Diseases (CRRMP), also called complementary system.It first seeks to explore the historical foundations of the French system for OD compensation and to understand the dynamics of compensation for work-related cancers.Then it looks at practices of the complementary system by analyzing the procedures which have been carried out for 65 patients suffering from cancer. In a qualitative approach, it examines three successive steps implemented: first, the expertise of a public health system of surveillance of occupational cancers in Seine-Saint-Denis, the GISCOP93, which led to the reporting of these OD cases; then, the medical and administrative investigation by the French Health Insurance Institution which decides the referral to the Committee; and at last, the medical expertise of the Committee. The analysis continues with the study of contentious actions before the Court of social security affairs.The framework highlights the logics of the different actors underlying decision of rejection and recognition. It shows a high variability of results according to the expertises as well as a significant impact of the health status of patients. The elements of variability concern both professional compensation given to the patients, different interpretations of the scope of compensation system, but also the type of carcinogens qualified in careers by the different actors of the procedure.

La carcinogénèse est une conséquence de la continuelle activation de la prolifération cellulaire. Dans les cellules normales, les signaux mitogéniques sont traités par un réseau complexe d’interactions protéiques et de réactions enzymatiques, appelées voies de signalisation. Dans certains cas, le signal peut induire l’activation de nouveaux gènes et ainsi déclencher la mitose. Lors du développement ou de la cicatrisation, cette régulation du phénotype cellulaire contrôle étroitement le nombre et le comportement des cellules contribuant ainsi au maintien d’un tissu fonctionnel sain. A partir de profils génomiques, transcriptomiques et protéomiques de tumeurs de la vessie ainsi que des transcriptomes de cellules urothéliales normales dans différents états de prolifération et de différenciation, j’ai mis au point de nouvelles méthodologies pour caractériser les voies de signalisation et de régulation responsables des cancers de la vessie. Dans un premier temps, j’ai développé des outils pour l’identification et la visualisation des programmes transcriptionnels spécifiques à une tumeur ou à un sous-type tumoral et ce, par l’inférence d’un réseau de co-régulation et la prédiction de l’activité des facteurs de transcription. Ces méthodes sont disponibles dans un package Bioconductor, CoRegNet (bioconductor.org). La mesure de l’activité transcriptionnelle est basée sur l’influence d’un facteur de transcription sur l’expression de ses gènes cibles. Cette mesure a été utilisée pour identifier les régulateurs les plus actifs de chaque sous-type de cancer de la vessie. L’intégration de profils génomiques a mis en avant deux facteurs de transcription génétiquement altérés et ayant des rôles oncogènes dans les tumeurs luminales et basales. L’un d’entre eux a été validé expérimentalement dans ce travail.L’utilisation de CoRegNet a mis en évidence une large utilisation dans les tumeurs,des réseaux normaux de la différenciation et de la prolifération des cellules normales. Un régulateur de la prolifération normale est identifié comme étant activé de fa¸con constitutive par des altérations génétiques dans les tumeurs. Son impact sur la prolifération des cellules tumorales de la vessie a été expérimentalement validé. Par ailleurs, il a été constaté que l’un des régulateurs de la différenciation urothéliale présentant une baisse d’activité dans la quasi-totalité des tumeurs, est fréquemment muté. De plus amples analyses ont mis en avant son rôle majeur dans les tumeurs différenciées. Dans le but de caractériser les voies de signalisation à partir de données protéomiques d’expériences d’immunoprécipitations, j’ai développé un nouvel algorithme visant à construire un réseau dense à partir d’une liste de protéines d’intérêt et d’un ensemble d’interactions protéiques connues. L’algorithme est proposé sous la forme d’une application Cytoscape et s’intitule Pepper: Protein Complex Expansion using Protein-Proteininteraction networks (apps.cytoscape.org) Enfin, en utilisant à la fois le profil protéomique d’une expérience d’immunoprécipitation de FGFR3 ainsi que le profil transcriptomique des gènes qu’il régule en aval, j’ai appliqué Pepper pour caractériser la voie de signalisation de FGFR3 depuis ses partenaires protéiques jusqu’aux facteurs de transcription en aval. Enfin, ce travail a plus particulièrement permis d’identifier un lien de régulation entre FGFR3 et le gène suppresseur de tumeurs TP53. / Carcinogenesis is a consequence of the unceasing activation of cell proliferation. In normal cells, mito-genic stimuli are processed by a complex network of protein interactions and enzymatic reactions, often referred to as pathways, which can eventually trigger the activation of new genes to engage the cell into mitosis. During developmental or wound healing processes, this complex regulation of cellular phenotypes results in a tight control of the number and behavior of cells and therefore contributes to the maintenance of a functional and healthy tissue architecture. Based on genomic, transcriptomic and proteomic profiles of bladder tumors and transcriptomes of nor-mal urothelial cells at various states of proliferation and differentiation, I devised novel methodologies to characterize the pathways driving bladder cancer. I first developed a set of tools to identify and visualize sample and subtype-specific transcriptional pro-grams through the inference of a co-regulatory network and the prediction of transcription factor activity. These methods were embedded in a Bioconductor package entitled CoRegNet (bioconductor.org). The measure of transcriptional activity is based on the influence of a transcription factor on the expression of its target genes and was used to characterize the most active regulators of each bladder cancer subtypes. The integration of genomic profiles highlighted two altered transcription factors with driver roles in lumi-nal-like and basal-like bladder cancer, one of which was experimentally validated. The use of CoRegNet to model the contribution of regulatory programs of normal proliferation and diffe-rentiation in bladder cancers underlined a strong preservation of normal networks during tumorigenesis. Furthermore, a regulator of normal proliferation was found to be constitutively activated by genetic al-terations and its influence on bladder cancer cell proliferation was experimentally validated. In addition, a master regulator of urothelial differentiation was found to have a loss of activity in nearly all tumors. This was then associated to the discovery of frequent inactivating mutations and further analysis unco-vered a major role in differentiated tumors. In order to characterize signaling pathways from proteomic pull-down assays, I then designed a novel algorithm to grow a densely connected network from a set of proteins and a repository of protein interac-tions. The proposed algorithm was made available as a Cytoscape application named Pepper for Protein Complex Expansion using Protein- Protein interaction networks (apps.cytoscape.org). Finally, using both a proteomic pull-down assay of the bladder cancer oncogene FGFR3 and a transcrip-tomic profiling of its downstream regulated genes, I applied Pepper to characterize the full FGFR3 signa-ling pathway from its protein partners to the downstream transcriptional regulators. In particular, this uncovered a regulatory link between FGFR3 and the tumor suppressor TP53.

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Thesis (Ph. D.)--Ohio State University, 2005. / Document formatted into pages; contains 375 p. Includes bibliographical references. Abstract available online via OhioLINK's ETD Center; full text release delayed at author's request until 2006 March 9.

Introduction: There is considerable epidemiologic evidence that drinking alcoholic beverages is associated with an increased risk for certain cancers (i.e. cancers of the upper-aero digestive tract) though the evidence of an increased risk for colorectal and breast cancer is controversial. For other cancers (e.g. kidney, bladder, lung, ovarian) the evidence remains inconclusive. Considering the high prevalence of many of these cancers in Scotland, even a small increase in cancer risk is of great importance, therefore from a public health perspective it is important that the evidence linking alcohol to an increased risk of cancer is continuously evaluated. Questions still remain, however, concerning the robustness and consistency of the alcohol information collected across studies. Furthermore, the heterogeneity of drinking levels, drinking patterns, and definitions of standard drinks internationally make it problematic to generalise the findings of these studies. Aim: To further clarify the role of alcohol in the occurrence of cancer in a country marked by high levels of alcohol consumption and rising incidence of many of the cancers linked with alcohol consumption. The aim of this study, therefore, is to (1) investigate the association between alcohol consumption and the risk of fourteen cancers using routine Scottish data sources and (2) to test the hypothesis that alcohol consumption increases the risk of these cancers in a sample of the Scottish population. Methods: A systematic review of the published literature between 1999, the date of the last major review, and 2009 on alcohol related cancers to determine the strength of evidence on the association between alcohol and cancer, and if it varies by amount drunk, by drinking pattern and drink type. Two cohort studies were formed; in the first a population based cohort study, based on a linkage between a representative general population sample and hospital, cancer registry and death records in Scotland, describes risk of cancer by amount of alcohol consumed per week and by drinking frequency and in a second study, based on a linkage between hospital and cancer and death records, the risk of cancer in a population that has been admitted to hospital (between 1981 and 2007) with an alcohol related diagnosis was investigated. Results: The present study provides weak evidence of a relationship, in a sample of the Scottish general population, between alcohol drinking frequency and amount consumed and cancers of the upper aero digestive tract. An increased risk (though non-significant) of colorectal cancer for daily drinkers was observed but no relationship was detected for amount consumed for this cancer. There was no association observed between drinking frequency or amount consumed and risk of breast, lung and prostate cancer. People with an alcohol-related hospital admission, however, are at substantially higher relative risk of head and neck and upper gastrointestinal cancers compared to the general population, and relative risks increase with increasing levels of deprivation. It is likely that tobacco smoking also contributes to this excess risk. Conclusions: The generalisability of findings from the international literature to Scotland is problematic due to different measures of alcohol consumption. Although the present study provides evidence that people in Scotland who require in-hospital care for an alcohol related condition are at substantial subsequent relative risk of head and neck and upper gastrointestinal cancers and that the relative risk increases with increasing levels of deprivation, further prospective studies with longer-follow-up are required to assess the risk between alcohol consumption and cancer in the Scottish general population.

ABSTRACT INTRODUCTION: Cancer is one of the most common diseases in the developed world and both genetic and environmental factors play a role in the development of cancer. About 5-10% of all cancers are due to predisposing genes. Some of the more common inherited cancer syndromes are hereditary breast and ovarian cancer (HBOC) and two colorectal cancer syndromes, familial adenomatous polyposis (FAP) and hereditary nonpolyposis colorectal cancer (HNPCC). Recognition of cancer susceptibility can allow “at risk” individuals and families to participate in cancer risk assessment, genetic testing, and various cancer prevention strategies. As the public is becoming more aware of inherited cancers, it is expected that there will be an increasing demand for genetic services and testing. For this reason more GP involvement is required to assess patients and families at risk and refer them appropriately. Since the Clinical and Counselling Section, Division of Human Genetics, National Health Laboratory Service and University of the Witwatersrand, Johannesburg is establishing a cancer genetics service it woud be of great value to assess the GPs’ practice, knowledge and attitudes with regards to cancer genetics and this was therefore the aim of this study. METHODOLOGY: A quantitative, exploratory research design was chosen and GPs in the Johannesburg area were selected as subjects. After the completion of a pilot study a research package was mailed to 196 GPs. This package was sent out twice and both times the GPs were asked to respond within 3-4 weeks. The final sample consisted of 61 GPs and the data were analysed using descriptive statistics. RESULTS: Of the 61 participants more male GPs (42, 69%) than female GPs (19, 31%) responded and there were about an equal number of GPs practicing alone (29, 48) and in a multiple practice (32, 52%). Twenty two (33%) of the GPs had never had personal experience of cancer. Practices: The GPs made use of several cancer screening procedures but obtained limited information on cancer history from their patients particularly from second degree relatives and about age of onset. Very few subjects (15, 25%) reported that they assess patients’ risk for inherited cancer susceptibility and only 22 (36%) reported that they refer patients to other facilities for risk assessment and genetic testing. Knowledge: Only 32 (52%) of the GPs were aware of genetic testing facilities and 54 (86%) reported never having received advertising material to promote genetic testing for cancer susceptibility services. They also are not aware of genetic counselling facilities but do feel patients should have genetic counselling by a genetic counselor, clinical geneticist or oncologist before genetic testing. Even though genetic testing for inherited cancer susceptibility is only available at some academic institutions, mostly on a research basis, the GPs seem to be unaware of the availability of genetic testing in South Africa for colorectal cancer genes (8, 13% and 9, 15%) but 28 (46%) knew about breast cancer genes. They were not aware of the autosomal dominant inheritance of hereditary breast cancer and the percentage of individuals with breast cancer who carry the BRCA1/2 gene nor did they know the penetrance of HNPCC genes. Attitudes: The subjects’ attitudes to genetic testing for inherited cancer susceptibility were positive although they reported that they were unaware of several general factors regarding cancer genetic testing. The GPs had limited knowledge about inherited cancers and do not take an active part in cancer genetic management. However, 53 (87%) of the GPs reported interest in learning about these services and expected to play a role in cancer genetics in the future. CONCLUSION: The findings of this study suggest that there is a need to educate GPs about the basic cancer genetic concepts so that they can identify patients at risk for an inherited cancer syndrome. They need to be informed about the genetic tests currently available for the inherited cancer syndromes, and about genetic counselling and testing facilities.

Contexte : L’incidence des cancers différenciés de la thyroïde (CDT) est caractérisée par de fortes variations géographiques et ethniques. L’un des plus forts taux d’incidence a été rapporté en Nouvelle-Calédonie et particulièrement dans la population mélanésienne. En dehors de l’exposition aux radiations ionisantes dans l’enfance et l’obésité, les facteurs de risque de CDT restent très mal connus. Bien qu’il ait été rapporté que ce cancer constitue une des localisations cancéreuses ayant la composante héréditaire la plus élevée, le rôle des facteurs génétiques a été jusqu’à présent peu étudié. Des études de cas familiaux et des études gène-candidat ont identifié des polymorphismes dans plusieurs gènes mais très peu de ces associations ont été répliquées. Des études d’association génomes entier (GWAS) ont également mis en évidence des régions de susceptibilité génétiques de CDT, les associations les plus robustes ont été rapportés sur les loci 9q22 et 14q13. Au final, l’ensemble des variants identifiés jusqu’à présent ne permettent d’expliquer qu’une faible part de l’héritabilité génétique dans l’étiologie des CDT, suggérant que d’autres facteurs de risque génétiques restent à découvrir.Objectifs : L’objectif général de ce travail était d’étudier les facteurs de risque génétique et leurs interactions avec les facteurs environnementaux. Plus spécifiquement, il s’agissait 1) d’étudier le rôle de gènes candidats ou de loci identifiés dans des études GWAS dans deux études cas-témoins menées en Nouvelle-Calédonie et en France métropolitaine 2) d’explorer plus en détail dans ces populations, les loci GWAS 9q22 et 14q13 pour l’identification des variants causaux ou d’autres variants candidats ; 3) d’identifier de nouveaux facteurs de risque génétiques dans les CDT chez les femmes en utilisant une approche dite par « pathway candidat » en combinant les données de deux études françaises et américaines.Matériels et méthodes : Les analyses portant sur les gènes candidats et les loci GWAS reposent sur deux populations d’études : une population européenne de 508 cas et 621 témoins issus des études cas-témoins conduites en France métropolitaine (étude CATHY) et en Nouvelle-Calédonie (NC) et une population mélanésienne de 156 cas et 114 témoins de l’étude de NC. Les approches pathway candidat ont porté dans un premier temps sur les femmes d’origine européenne de l’étude CATHY (365 cas/376 témoins) et d’une partie de l’étude cas-témoins Young-Thyr (83 cas/93 témoins) conduites en France métropolitaine. Dans un second temps, nous avons combiné ces sujets avec les femmes de l’étude cas-témoins USRT/UTMDACC (332 cas/443 témoins) conduite aux Etats-Unis.Résultats : Nous n’avons pas observé d’association entre les CDT et les polymorphismes des gènes identifiés précédemment par les études gène-candidat dans les populations européennes et mélanésiennes étudiées. Toutefois, nous avons montré que la délétion des gènes GSTM1 et GSTT1 pouvait moduler les associations rapportées entre l’obésité ou la consommation d’alcool et le risque de CDT. Nous avons répliqué chez les européens et chez les mélanésiens les associations avec des variants des loci GWAS 9q22, 14q13 et 2q35. Nous avons également mis en évidence, dans les régions GWAS 9q22 et 14q13 de nouveaux variants candidats à risque de CDT et rapporté des interactions entre ces variants et la parité ou la consommation de tabac. Les analyses par pathway portant sur une population de femmes d’origine européenne suggèrent des interactions entre la consommation d’alcool ou la consommation de tabac et les gènes impliqués dans le métabolisme de ces substances et des interactions entre l’âge aux premières règles, la prise de contraceptifs oraux et les gènes impliqués dans la biosynthèse et le métabolisme des hormones stéroïdiennes. / Context : Differentiated thyroid cancer (DTC) incidence is characterized by considerable geographic and ethnic variations. Particularly high incidence rates were observed in Melanesian women of New Caledonia. Except for the exposure to ionizing radiation in childhood and obesity, the role of other DTC risk factors is not clearly established. Genetic factors have been suggested to play an important role in DTC risk since epidemiological studies have shown that DTC has a higher familial relative risk than any other cancers. Linkage studies in multiple-case DTC families and candidate gene studies have identified polymorphisms in several genes but very few have been replicated so far. Genome-wide association studies (GWAS) also identified several DTC susceptibility loci with the most robust associations reported on the loci 9q22 and 14q13. Only few susceptibility loci were highlighted by GWAS and the identified variants were shown to account less than 10% of the DTC familial risk, emphasizing that much remains to be discoveredObjectives: The main objective of this work was to study the role of genetic risk factors and their interaction with environmental factors in DTC risk. More specifically, we aimed to: 1) replicate the association between DTC risk and polymorphisms reported in candidate gene and GWAS studies in 2 case-control studies conducted in Metropolitan France and New Caledonia; 2) identify potential causal variants of DTC risk in GWAS loci 9q22 and 14q13 using fine-mapping approach; 3) identify new genetic risk factors for DTC in women using pathway approach by pooling data from 2 case-control studies conducted in France and USA..Materials and methods: The analysis of the candidate genes and of the GWAS loci were based on a European population of 508 cases and 621 controls from 2 case-control studies conducted in metropolitan France (CATHY study) and in New Caledonia (NC study) and, a Melanesian population of 156 cases and 114 controls from the NC study. The pathway analysis was conducted in a first step on European women from the CATHY study (365 cases/376 controls) and from the Young-Thyr study (83 cases /93 controls) both conducted in metropolitan France. In a second step, we pooled the data from CATHY/Young-Thyr study and USRT/UTMDACC study (332 cases/443 controls) conducted in the United States.Results: In Europeans and Melanesians, we found no association with polymorphisms reported previously by candidate genes studies. However, we observed that among these genes, GSTM1 and GSTT1 may modulate the associations between DTC risk and obesity or alcohol consumption. Some polymorphisms identified in GWAS studies at loci 9q22, 14q13 and 2q35 were replicated in Europeans and in Melanesians. In the GWAS loci 9q22 and 14q13, we identify new variants that can be functionally related to DTC pathogenesis in Europeans and Melanesians. We also reported interactions between some of these variants and parity or tobacco smoking. The analysis of candidate pathways in European women showed interactions between alcohol consumption or tobacco smoking and genes involved in the metabolism of these compounds and, between age at first menarche or oral contraception and genes involved in biosynthesis and metabolism of sex steroid hormones.

Les cancers épithéliaux de l’ovaire sont la première cause de décès par cancer gynécologique. Dans ce travail, nous nous sommes intéressés aux cancers ovariens séreux de haut grade (HGSOC) et de stade avancé, pour lesquels les options thérapeutiques demeurent limitées. Plusieurs laboratoires, dont le nôtre, ont identifié des groupes moléculaires distincts au sein de ces HGSOC sur la base de données transcriptomiques.Dans toutes ces études, un sous-groupe moléculaire, nommé « fibrose » ou« mésenchymateux », est systématiquement observé et invariablement associé à un pronostic sombre pour les patientes. La signature transcriptomique qui identifie ce groupe de patientes inclue de nombreux gènes impliqués dans le remodelage de la matrice extracellulaire et la composition stromale, suggérant un rôle possible du stroma dans l’agressivité de ce sous-groupe moléculaire particulier d’HGSOC.Par une étude combinant de façon originale l’analyse concomitante de 6 marqueurs de fibroblastes associés au cancer (CAF), nous mettons en évidence pour la première fois l’existence de 4 sous-populations de CAF. De façon intéressante, l’une de ces 4 populations(dite CAF-S1) s’accumule significativement dans le sous-type moléculaire« fibrose/mésenchymateux » des HGSOC. Or, cette population particulière de CAF-S1 présente une activité immunosuppressive, en favorisant non seulement la survie ou l’attraction des lymphocytes T régulateurs, mais également en stimulant leur activation par l’expression du facteur de transcription FOXP3 (Forkhead Box P3). Enfin, nous identifions l’isoforme β de CXCL12 (chimiokine à motif C-X-C ligand 12) comme un acteur majeur de l’identité et de la fonctionnalité de ces CAF-S1 immunosuppresseurs. En effet, CXCL12βs’accumule spécifiquement dans les CAF-S1 et joue un rôle clé dans la fonction immunosuppressive de ces CAF au sein du stroma des HGSOC mésenchymateux.Nos résultats mettent ainsi en évidence un mécanisme expliquant, au moins en partie, le pronostic sombre des patientes atteintes d’HGSOC mésenchymateux. La caractérisation approfondie du stroma de ces tumeurs agressives permet d’envisager de nouvelles stratégies thérapeutiques ciblant à la fois les CAF et les cellules immunitaires dans le but d’améliorer la survie des patientes mésenchymateuses. / Epithelial ovarian cancers are the first cause of death from gynecologic cancer. We focusedour work on high-grade serous ovarian cancer (HGSOC) patients, for who only very fewtherapeutic options exist. In the past, several laboratories, including ours, have identified -based on transcriptomic data- distinct molecular subgroups amongst HGSOC. Interestingly,among these different molecular subgroups, one of them, referred to as “Fibrosis” or“Mesenchymal” is systematically identified and consistently associated with poor patientprognosis in all studies. Transcriptomic signature that defines this specific molecularsubgroup of HGSOC contains mainly genes involved in extracellular matrix remodeling andstromal composition, suggesting a potential role of stroma and Carcinoma-AssociatedFibroblasts (CAF) in this particular “Fibrosis/Mesenchymal” HGSOC subgroup.By combining various technics studying concomitantly 6 different CAF markers, we identifiedfor the first time 4 different subpopulations of CAF in HGSOC. Interestingly, one of thesesub-populations, referred to as CAF-S1, significantly accumulates in the“Mesenchymal/Fibrosis” subgroup of HGSOC. Importantly, we demonstrated that the CAFS1cellular subpopulation exhibits immunosuppressive activities. Indeed, CAF-S1 fibroblastsnot only by attract regulatory T lymphocytes but also promote their survival and activation(assessed by expression of FOXP3). Finally, we uncovered the specific role of the CXCL12βisoform as an important player of CAF-S1 identity and immunosuppressive functions inmesenchymal HGSOC.All together, these results identify a stromal heterogeneity in HGSOC, which has beenbroadly underestimated until now. Moreover, our work demonstrates the accumulation of aCAF subpopulation with immunosuppressive functions in HGSOC mesenchymal patients thatcould account, at least in part, for their poor survival rate. Deep characterization of thestroma may enable us to define new therapeutic options combining CAF-targeting therapiesand immunotherapies, in order to improve survival of HGSOC mesenchymal patients.