Titre de la thèse : Perturbation du rythme circadien et risque de cancer de la prostate : rôle du travail de nuit, des gènes circadiens et de leurs interactions

par Meyomo Wendeu-Foyet

Projet de thèse en Santé publique - épidémiologie

Sous la direction de Florence Menegaux.

Thèses en préparation à Paris Saclay , dans le cadre de Santé Publique , en partenariat avec CESP - Centre de recherche en Epidemiologie et Santé des Populations (laboratoire) , Cancer et environnement (Epidémiologie des Cancers, Gènes et Environnement) (equipe de recherche) et de Université Paris-Sud (établissement de préparation de la thèse) depuis le 21-09-2015 .


  • Résumé

    Le cancer de la prostate est le cancer le plus fréquent chez l'homme avec plus de 60 000 nouveaux cas par an en France. Excepté l'âge, l'origine ethnique et les antécédents familiaux de cancer de la prostate, son étiologie reste largement inconnue. Néanmoins, ces dix dernières années, plusieurs études ont suggéré un lien entre un dysfonctionnement du rythme circadien et le risque de cancer. L'objectif de la thèse est d'étudier le rôle de la perturbation du rythme circadien dans sa globalité sur le risque de cancer de la prostate. Plus spécifiquement, nous étudierons (1) l'association entre des indicateurs de perturbation circadienne et le risque de cancer de la prostate, (2) les polymorphismes des gènes de l'horloge et le risque de cancer de la prostate, (3) l'association entre le travail de nuit/posté et le risque de cancer de la prostate en tenant compte du chronotype des sujets et du génotype vis-à-vis des gènes de l'horloge. Le projet de thèse s'appuiera sur les données de l'étude EPICAP, étude cas-témoins réalisée en population générale dans le département de l'Hérault incluant 820 cas et 880 témoins de population. Ce projet permettra d'identifier de nouveaux facteurs de risque modifiables pour le cancer de la prostate pouvant être accessibles à la prévention. La prévalence croissante du travail de nuit et l'incidence élevée de cancer de la prostate en France font de ce projet un enjeu majeur pour la santé publique.

  • Titre traduit

    Disruption of circadian rhythm and risk of prostate cancer: the role of night work, circadian genes and their interactions


  • Résumé

    Context Prostate cancer is a clinically heterogeneous disease with >900 000 cases diagnosed worldwide, including >60 000 new cases each year in France. Except age, ethnic origin and prostate cancer family history, its etiology remains largely unknown. These last ten years, increasing evidence has linked dysfunction of circadian rhythm with the pathogenesis of cancer. Several mechanistic hypotheses for how circadian disruption may be related to cancer have been reviewed including: disruption of the circadian rhythm regulated by several clock genes controlling cell proliferation and apoptosis; repeated phase shifting leading to internal desynchronization and defects in the regulation of the circadian cell cycle and physiological processes; and sleep deprivation that alters immune function. In 2010, the International Agency for Research on Cancer (IARC) classified “shift work leading to a disruption of circadian rhythm” as probably carcinogenic to humans. This classification was based on sufficient evidence from experimental animal models but limited evidence from epidemiological studies in humans. Indeed, the limited evidence in humans was based on: few epidemiological studies mainly focusing on breast cancer and on specific occupation groups (nurses, flight attendance, radio and telegraph operators), too few population-based studies, different definitions of night shift work, and a lack of standardization in exposure assessment. The lack of evidence is even more striking for prostate cancer, the most common cancer in men. To go further in the understanding of “Does disruption of circadian rhythm matter in cancer?”, key domains should be investigated in future epidemiological studies to better capture circadian disruption in its entirety: better characterization of night shift system and need to collect new data such as sleep habits, chronotype (morning/evening type), biomarkers and clock genes polymorphisms. Overall, the literature shows an incomplete and fragmented vision of the role of circadian disruption in cancer, particularly for prostate cancer, warranting urgently further investigations taking into account circadian disruption in its entirety. Research objectives The general aim of this PhD project is to investigate the role of circadian disruption, in its entirety, in prostate cancer risk. As specific objectives, we will specifically investigate: (1) the association between different indicators of the circadian rhythm disruption (night work / shift, chronotypes, sleep habits) and prostate cancer risk, (2) clock genes polymorphisms and prostate cancer risk, (3) the association between night/shift work taking into account individual chronotype and individual clock genes susceptibility. Methodology The PhD project is based on data from the EPICAP study, a population-based case-control study conducted in the departement of Hérault in France. Eligible cases are all cases of prostate cancers newly diagnosed in 2012-2013 in men less than 75 years old and residing in Hérault at the time of diagnosis. Controls are men of the same age as the cases and living in Hérault, recruited in the general population. The study, which data collection is currently ongoing until December 2014, will include a total of 850 incident prostate cancer cases and 850 population-based controls. Cases and controls are face-to-face interviewed by trained clinical research nurses using a comprehensive standardized questionnaire: sociodemographic characteristics, personal and familial medical history, anthropometry, lifestyle including chronotype and sleep duration, occupational history for each job held for more than 6 consecutive months with specific questionnaires on work schedules. Biological samples are also collected for both cases and controls which allow the constitution of a bio-bank (serum + DNA). Expected results This project will allow the identification of new modifiable risk factors for prostate cancer that may be accessible for prevention. The increasing prevalence of night shift work in the general population and the high incidence of prostate cancer in France make this project a key issue for public health.