Studying inflammatory bowel disease etiology: a life course approach
Principal investigator : Marie-Claude Rousseau
Co-Principal investigator: Prévost Jantchou
Collaborators: Andrea Benedetti, Sylvie Girard, Sreenath Madathil, Belinda Nicolau, Shu Qin Wei
Background and importance. IBD is a group of chronic relapsing inflammatory disorders of the gastrointestinal tract. Only few risk or predictive factors have been strongly established for CD and UC, including family history, cigarette smoking, and appendectomy. Identifying risk factors was recently rated as the top priority in pediatric and adolescent IBD research by Canadian patients, caregivers, and health professionals. It has been hypothesized that exposures during critical time windows may interfere with the gut microbiota and lead to an increased risk of IBD. Yet, there has never been a formal assessment of possible etiological pathways considering the long term effect of early life exposures, the temporal ordering of various exposures, and disentangling the direct effects from those that occur through intermediary factors.
Research aims. This project’s overarching goal is to identify life periods in which medical, lifestyle, and psychosocial factors have the highest impact on the risk of developing CD and UC, respectively, and determine which factors are most promising for prevention programs. Applying a life course approach, we will explicitly assess the importance of duration and timing of exposures, formally study the inter-relations between these factors and disease risk, and estimate the burden of disease attributable to these factors.
Methods and expertise. This project builds on the Quebec Birth Cohort on Immunity and Health. Established through linkage of provincial administrative databases, this cohort includes 400,611 individuals born from 1970 to 1974 in the Province of Quebec. Data on medical services and hospitalizations for IBD were obtained until 2014. A total of 4100 IBD cases was identified by applying a validated definition based on use of health services. Using a nested case-control design, we will recruit 2600 randomly selected participants (1000 controls, 1000 individuals with CD, and 600 with UC). Information will be gathered through a web survey. A life grid technique will be integrated to minimize recall bias and enhance memory. Factors of interest will be documented along the life course. They include birth circumstances, breastfeeding, antibiotic use, oral contraceptive use, appendectomy, smoking, diet, and psychosocial factors (anxiety, depression, stress). Family history of IBD, sociodemographic characteristics and socioeconomic position will also be documented. Statistical analyses will be conducted separately for CD and UC, and will be based on a structured modeling approach using a series of unconditional logistic regressions to test which life course etiological models best fit the data. Mediation and interactions will be assessed. Finally, we will estimate the attributable fraction due to a given exposure over several life periods and to several exposures in a given life period. We have assembled a unique team, combining expertise in epidemiology, biostatistics, life course approach, perinatal exposures, and gastroenterology.
Expected outcomes. Our distinctive contribution will be to formally consider the timing of exposures and the relations between different types of exposures by applying a life course approach. We will estimate the public health impact of these factors to inform policy. In line with the objectives of the Project Grant program, this study will generate new knowledge on the complex etiology of this highly debilitating disease, which represents a crucial step towards prevention.
Workplace exposures and prostate cancer: analysis and reporting on a Canadian population-based study
Principal investigator: Marie-Élise Parent
Collaborators: Paul Demers, Jérôme Lavoué, Marie-Claude Rousseau, Andrea Benedetti, Cheryl Peters
Rationale: Each year, 21,000 Canadian men are diagnosed with prostate cancer (PCa). About 30% of these are aggressive but diagnosis and treatment of non-aggressive ones seriously impact quality of life. Age, ancestry and family history are the only established risk factors while genetics explain only a proportion of familial cases. There is compelling evidence that environmental factors play a role, but modifiable risk factors have yet to be identified so prevention has not been possible. Other than for pesticides, very little research has been conducted on environmental chemicals in PCa etiology. Several chemicals are themselves carcinogens or act as hormone modulators, and could be implicated. The workplace represents a preferential window to study these since many are encountered there at higher levels, facilitating their measurement. Since most workplace chemicals eventually make their way into the general environment, such exposures are not only relevant to workers but also to the entire population. The absence of large occupational studies benefiting from strong exposure assessment has been the major drawback to advancing knowledge in this area. In 2002-2015, Canadian funding agencies funded what is to our knowledge the largest and most comprehensive population-based study of PCa, to assess the etiological role of workplace exposures. The occupational assessment was completed, as planned, in late 2015, coinciding with the end of funding, and it was anticipated that new funding would need to be secured for primary analyses. CIHR funding is sought at this time to leverage this large effort and investment, and carry out primary analyses and report on this unparalleled Canadian resource.
Broad goal: To investigate whether different exposures measured in the workplace increase the risk of developing PCa.
Methods: 1,933 cases, including 538 aggressive cancers, were ascertained from Montreal metropolitan area hospitals. Concomitantly, 1,994 population controls were selected from electoral lists. Face-to-face interviews collected information on socio-demographic, lifestyle and medical factors, including screening. We documented each job held by each subject over his lifetime, eliciting details on specific tasks, equipment used, etc. This wealth of occupational information (15,724 job descriptions) has been coded by a team of chemists/industrial hygienists into lifetime exposure to hundreds of chemicals.
Aims: This protocol outlines 19 analytical subprojects to be undertaken over the course of the grant. It focuses on suspected exposures with hormone-modulating properties and/or previous evidence such as polycyclic aromatic hydrocarbons, petroleum-derived liquids, engine emissions and combustion products, solvents, welding fumes, resins and polymers, metals, painting-related chemicals, and pesticides. Other projects focus on night work and on physical activity/inactivity at work. Exposures will be analysed individually and combined, taking into account co-exposures, confounding and interactions.
Core expertise: We propose here an exciting, innovative and far-reaching data analysis project, benefiting from a solid expertise in occupational epidemiology, exposure assessment and biostatistics, and involving trainees.
Significance/application: This project, representing a major advance in the field, will generate important new knowledge towards the establishment of preventive measures against PCa.
Immunosenescence as a predictor of MS progression
Co-Principal investigators: Catherine Larochelle, Nathalie Arbour
Collaborators: Marie-Claude Rousseau
Funding: Merck KGaA / EMD Serono
Biological aging is associated with alterations of the immune profile called immunosenescence. Repeated antigen encounter accelerates this process and as such recent studies have hinted that accelerated immunosenescence occurs in multiple sclerosis (MS). Age is the strongest predictive factor for onset of progression in MS; we therefore hypothesize that (biological) age-related modifications of the peripheral immune system represent relevant biomarkers for MS progression, and can predict resistance to treatment.
Our goal is to analyze the expression of immunosenescence, age-sensitive immune markers and mediators in the peripheral blood (PB) of MS patients, and to correlate those markers with age, clinical phenotype, progression and treatment response in both cross-sectional and prospective studies.
Our preliminary data shows that the CD4:CD8 ratio as well as tumor necrosis factor (TNF), interleukin-18 (IL-18) and brain-derived neurotrophic factor (BDNF) levels correlate with age, and that age-related variations are more pronounced in MS than in healthy controls. We now propose to use a large cohort of 200 untreated MS patients with MS, 200 treated patients with MS and 150 healthy controls to i) characterize age-sensitive immune markers in PB of patients with MS versus controls in relation with age, ii) determine the value of age-sensitive immune markers as biomarkers for progression in MS and iii) establish the impact of disease-modifying therapies on age-sensitive immune markers in MS in relation to age and to treatment outcome.
With this study we expect to identify peripheral blood age-sensitive immune markers that are correlated to disease progression and treatment response, and could represent biomarkers for progression in MS.
A machine learning algorithm to predict individual risk of head and neck cancers in clinical settings
Principal investigator: Belinda Nicolau
Collaborators: Paul Allison, Mark Coates, Eduardo Franco, Mary Ellen Macdonald, Sreenath Madathil, Nicholas Makhoul, Marie-Claude Rousseau
Background and Importance: Half a million head and neck cancer (HNC) cases, affecting the oral cavity, oropharynx and larynx, occur annually worldwide. In addition to having lower 5-year survival rates (<50%) than more common cancers, patients diagnosed with HNC have the highest morbidity and suicide rates of all cancer patients. Moreover, there has been a sharp increase in HNC incidence related to human papillomaviruses (HPV) (as much as 225%), and these cancers will overcome cervical cancer rates by 2020. Integrating this body of knowledge into a decision support system that can be used by health professionals is needed. However, this is a challenging task that has yet to be accomplished. We propose to use innovative machine learning (ML) techniques to develop HNC predictive models. In addition, we integrate these models into a decision support tool for primary care settings.
Aims: To develop and evaluate a clinical tool that predicts HNC individual risk. Specifically, we aim to:
1. Develop a Bayesian neural network to predict individual risk for HNC by anatomical subsite using ML techniques
2. Validate the Bayesian neural network using external datasets
3. Develop a web application for use in primary care settings for individual risk prediction
4. Test the feasibility of integrating the tool into clinical settings
Methodology: For aim 1, we develop a Bayesian neural network using the HeNCe Life study database, which is a hospital case-control investigating the aetiology of HNC using the life course framework. This relatively large study conducted in 4 main referral hospitals in Montreal (n=918) includes data on a comprehensive array of exposures (e.g., psychosocial, behavioural, viral). We will use Markov chain Monte Carlo simulations to approximate the full posterior distribution of lifetime probabilities of developing HNC by anatomical subsite. For aim 2, we will validate the models using two external databases: the International Association for Research on Cancer case-control study (n=200) conducted in Montreal and an HNC registry (n=222) from the Montreal General Hospital. Bayesian neural network model performance to classify HNC patients correctly will be assessed using the predictiveness curve analysis. Based on the Bayesian neural network models, we will develop a web application to predict individual risk in primary care and dental office settings (aim 3) using a bridging software (Shiny). We will use a sequential explanatory mixed methods approach to pilot the implementation of the web application for HNC risk prediction (aim 4) in the Department of Dentistry and Oral and Maxillofacial Surgery at the McGill University Health Centre. The quantitative and qualitative evaluations will include time required to use the application, ease of use, comprehension, stress and usefulness. Our multidisciplinary team combining expertise in epidemiology, qualitative and mixed methods approaches, oncology, computer science, biostatistics and public health is well positioned to conduct this project. Expected Outcomes: A decision support tool that health professionals can use with patients for individual risk counselling, which may significantly reduce HNC burden and health care costs.
A novel investigation of the presence and role of the beta- and gamma- human papillomavirus genera in cancers of the upper aero-digestive tract
Principal investigator: Belinda Nicolau
Collaborators: Nicolas Schlecht, Marie-Claude Rousseau, Eduardo Franco, François Coutlée, Alexandra De Pokomandy, Paul Allison, Sreenath Madathil
Problématique: Un demi-million de cas de cancer des voies aérodigestives supérieures (CVADS), incluant des cancers de la cavité buccale, de l’oropharynx et du larynx, et 300 000 décès liés aux CVADS se produisent annuellement dans le monde. Environ les trois quarts des CVADS sont associés au tabagisme et à la consommation d’alcool. Les autres facteurs de risque importants incluent l’alimentation et, dans un sous-ensemble de CVADS (les cancers de l’oropharynx), le virus du papillome humain (VPH). Alors que le taux d’incidence des CVADS négatifs au VPH a diminué depuis la fin des années 1980, probablement en raison d’une réduction de la consommation d’alcool et de tabac, le taux de CVADS positifs au VPH aux États-Unis a augmenté (jusqu’à 225%). Au Canada, les données de notre étude montrent que la prévalence du VPH chez les CVADS est de 35,0% dans l’ensemble, et de 59,6% chez les cancers de l’oropharynx spécifiquement.
Les VPH sont un groupe hétérogène de virus circulaires fermés d’ADN double brin. Plus de 140 types ont été identifiés et classés en trois genres : Alpha (α), Beta (β) et Gamma (γ). Les VPH β et γ ont été principalement isolés à partir de lésions de la peau, tandis que les VPH α sont considérés comme des types muqueux ou génitaux. À ce jour, seuls les VPH α ont été étudiés quant au risque de CVADS, parmi lesquels le VPH-16 est le type le plus fréquemment détecté. Cependant, des études récentes ont démontré une prévalence élevée de VPH β et γ dans la cavité buccale, particulièrement chez des populations séropositives et des patients dentaires ayant des lésions de la bouche. De plus, des données récentes de notre groupe indiquent que des types spécifiques de VPH β (1&2) et γ (11&12) détectés dans la cavité buccale sont associés à un risque accru de cancer de la bouche et du larynx, indépendamment du VPH-16 (données non publiées). Toutefois, la prévalence et la distribution des types de VPH β et γ dans les tumeurs des CVADS sont inconnues. Dans le cadre de ce projet, nous étudierons la prévalence et le rôle des VPH β et γ dans les CVADS en utilisant des données du site canadien d’une étude cas-témoin internationale, l’étude Head and Neck Cancer (HeNCe) Life. La prévalence élevée de VPH β et γ dans la cavité buccale suggère que ces génotypes ont un tropisme élevé pour la muqueuse buccale, et pourraient induire une pathogénèse par la promotion de néoplasie épithéliale. La co-infection par différentes espèces de VPH pourrait également augmenter le risque de CVADS en favorisant la persistance du VPH.
Objectifs : En utilisant les données de l’étude canadienne HeNCe Life, nous visons à : (i) évaluer la prévalence et la distribution des types β et γ de VPH dans des échantillons de rince-bouche et de tissus; (ii) examiner dans quelle mesure les types β et γ de VPH sont associés à un risque accru de CVADS; (iii) estimer dans quelle mesure la co-infection aux VPH α, β et γ se produit et augmente le risque de CVADS; et (iv) identifier les facteurs comportementaux et environnementaux (ex. : tabac et alcool) associés à une infection aux VPH β et γ.
Méthodologie : L’étude canadienne HeNCe Life inclut 460 sujets cas avec des cancers épidermoïdes dans les VADS nouvellement diagnostiqués et 460 sujets témoins exempts de cancer recrutés dans quatre hôpitaux de référence montréalais. Les cas et les témoins ont été appariés par fréquence selon leur âge et leur sexe. Des entrevues face-à-face à l’aide d’un questionnaire et d’une grille de vie ont permis de recueillir de l’information rétrospective dans plusieurs domaines d’exposition (ex. : indicateurs socioéconomiques, familiaux, comportementaux) à trois stades de vie (enfance, jeune adulte et adulte). Des spécimens de biopsie buccale par brossage, rince-bouche et biopsie de la tumeur ont été recueillis pour l’analyse du VPH. Les résultats de cette étude, décrits plus hauts, sont en accord avec la littérature scientifique actuelle. De plus, nos résultats confirment une hétérogénéité étiologique pour les sous-sites de CVADS et une absence d’effet du tabac et de l’alcool sur les CVADS reliés au VPH. La présente proposition s’appuie sur ces résultats pour étudier le rôle des VPH β et γ. Nous effectuerons la détection et le génotypage du VPH par séquençage multiplex de prochaine génération avec ACP (PCR) ciblant les régions avec une phase ouverte de lecture L1 et E1 des types de VPH β et γ. L’analyse de données inclura des statistiques descriptives et des régressions logistiques (OR et IC à 95 %).
Retombées attendues : Le CVADS associé au VPH devient un enjeu majeur de santé publique au Canada et dans d’autres pays développés. Ainsi, on estime que le nombre de CVADS positifs au VPH dépassera celui des cancers du col utérin au cours des cinq prochaines années. L’étude HeNCe Life offre une excellente occasion d’approfondir notre compréhension du rôle de différents types de VPH dans l’étiologie du CVADS. Nous avons déjà effectué l’analyse des VPH α et les résultats soutiennent la littérature actuelle. De plus, nous avons un échantillon relativement important et du matériel biologique provenant de cellules normales et tumorales. Enfin, notre groupe possède une longue histoire de collaboration et est reconnu pour son travail sur le VPH et le cancer, ce qui nous place dans une position unique pour apporter une contribution originale et opportune à ce domaine. Nous croyons qu’il est temps d’aller au-delà de la première génération d’études du VPH et des CVADS, limitées en termes de taille et d’envergure, à un examen plus complet du rôle étiologique de ces virus. La recherche proposée est innovante et fermement ancrée dans les résultats les plus récents de notre équipe. Bien que le risque et les coûts soient relativement faibles pour un projet de cette dimension, le potentiel de récompense est élevé. Cette étude novatrice aidera à mieux comprendre le rôle de l’infection buccale au VPH dans le développement du CVADS, et aura vraisemblablement des implications cliniques (ex. : décisions de traitement) et de santé publique (ex. : vaccination).
Bacillus Calmette-Guerin (BCG) vaccination and multiple sclerosis: a population-based study in Quebec
Principal investigator : Marie-Claude Rousseau
Collaborators: Christina Wolfson, Andrea Benedetti, Marie-Élise Parent, Nathalie Arbour, Pierre Duquette
Funding: Multiple Sclerosis Society Of Canada (MSSOC), CIHR
Multiple sclerosis (MS) is an inflammatory and neurodegenerative disease of the central nervous system. MS is the leading cause of non-traumatic disability among young adults, and thus has important individual and societal impacts. The causes of MS are not known, but some environmental factors have been associated with disease risk such as place of birth, sex, smoking, Epstein Barr Virus (EBV) exposure, and vitamin D exposure through sun and diet. It is generally recognized that the immune system is directly involved in the pathophysiology of MS. In this sense, factors having an impact on the immune system are good candidates to investigate in relation to MS etiology, as either beneficial or harmful agents.
In this proposal, we focus on the Bacillus Calmette-Guerin (BCG) vaccine and its potential immunomodulatory role on MS development. Only six epidemiological studies to date have addressed BCG vaccination and the risk of developing MS. A meta-analysis on immunizations and MS, suggested a lack of association between BCG vaccination and MS, but these studies presented limitations such as limited sample size and, most importantly, use of questionnaire data to define BCG status. Considering these important limitations in all previous studies, there is a need for a methodologically rigorous and well-powered study on early life BCG vaccination and risk of MS. Quebec is a uniquely appropriate setting for such a study, since a province-wide BCG vaccination program was held between 1949 and 1974, and vaccination information was compiled in a registry.
The primary objective is to estimate the association between BCG vaccination and the risk of multiple sclerosis. As secondary objectives, we will assess the impact of age at BCG vaccination, with a particular interest in vaccination during the first year of life, and determine if the associations differ by sex.
We will expand an existing population-based cohort, the Quebec Birth Cohort on Immunity and Health (QBCIH), originally designed to assess non-specific effects of BCG vaccination on inflammatory and autoimmune diseases. Established through probabilistic record linkage of provincial birth, death, and BCG vaccination registries, as well as health administrative databases, the QBCIH includes 81,496 persons, representing 90.5% of those born in Quebec in 1974 at or after 32 weeks of gestation. For this project on MS, we will substantially augment the study population size and duration of follow-up. We will assemble a retrospective cohort of over 400,000 individuals born from 1970 to 1974, in which the QBCIH will be included. Data will be gathered from administrative databases until 2014, and will include sociodemographic and perinatal factors, information on death if applicable, BCG vaccination, as well as data on medical services and hospitalizations for MS. A validated definition based on use of health services will be applied to identify MS cases. Cox proportional hazards regression analyses will be carried out to estimate hazard ratios and 95% confidence intervals for the effect of BCG vaccination on MS, while adjusting for potential confounders.
We believe that our study represents the best opportunity yet to determine whether immunomodulation in early life, such as that resulting from BCG vaccination, is related to the development of MS. Given the paucity of modifiable factors identified so far in relation to the development of MS and the strength of our study methodology, we are in a perfect position to contribute new knowledge towards a better understanding of MS etiology.
Impact of Bacillus Calmette-Guerin (BCG) vaccination on the risk of lymphoma
Principal investigator : Marie-Claude Rousseau
Collaborators: Andrea Benedetti, Marie-Élise Parent
Funding: Candian Cancer Society Research Institute (CCSRI)
BCG vaccination was used in Quebec until 1974 to prevent tuberculosis. The goal of Dr. Marie-Claude Rousseau’s research is to understand other effects that BCG vaccination could have on various diseases. In this project, our team will evaluate if having received the BCG vaccine as a child could prevent lymphoma later in life, as it was suggested by a study conducted in Denmark. We have recently created a cohort of 81,496 persons born in Quebec in 1974 by linking several sociodemographic and medical databases. We will obtain information on medical visits and hospitalizations related to lymphoma until 2013. We will then compare the occurrence of lymphoma among persons who received the BCG vaccine and those who did not. Only a few epidemiological studies were conducted to investigate the effect of BCG vaccination on the risk of developing lymphoma. These studies had methodological problems that do not allow concluding on this question. Some were too small, and others had many participants who left the project before the study was over. In most studies, information about BCG vaccination was reported by the participants instead of coming from health records, which is usually more accurate. Age at vaccination was never considered, but it should be. The effect of BCG on lymphoma could be different if the vaccine was given very early or later in life. A recent study, well designed but small, suggested that persons who received the BCG vaccine were 50% less likely to develop lymphoma than those who were not vaccinated. In this context, we hypothesize that the BCG vaccine has a protective effect on lymphoma. We designed a study which will allow us to test this hypothesis. The BCG vaccine stimulates some cells from the immune system which may help prevent lymphoma. Our team wants to assess if BCG vaccination is related to the risk of developing lymphoma. The effect of BCG vaccination will also be studied separately among persons who were vaccinated at 0-1 year old or later. We created a cohort of 81,496 persons born in Quebec in 1974 by linking provincial birth, death, and BCG vaccination registries, and databases from the healthcare system. We will use this cohort, called the Quebec Birth Cohort on Immunity and Health, for our project. Information related to lymphoma will be obtained from health databases until December 31 2013, when the subjects were 39 years old. This will include physician billing data for medical visits or hospitalizations. From the Quebec Tumor Registry, we will extract information on diagnosis of lymphoma and other cancers. We will compare the risk of developing lymphoma among those who were vaccinated and those who were not. In this project, we are studying a new factor in relation to the development of lymphoma. By studying an existing vaccine which could contribute to lymphoma prevention, this project can have a real impact on cancer prevention. Given that there are few known causes of lymphoma that people can control, it is important to explore all avenues. The existing Quebec Birth Cohort on Immunity and Health offers a unique opportunity to conduct our project. It provides a solid foundation on which we can build. The study setting offers nearly perfect conditions for studying this novel hypothesis. This project has the potential to greatly impact our understanding of the causes of lymphoma. It can lead to concrete preventive approaches to fight this cancer.
Oral Epithelial Dysplasia Registry
Principal investigator : Nicholas Makhoul
Collaborators: Belinda Nicolau, Marie-Claude Rousseau, Jordan Gigliotti
Funding: Canadian Association of Oral and Maxillofacial Surgeons
The aim of this project is to set up a registry of pre-malignant oral lesions at the Montreal General Hospital (MGH) with the ultimate goal of developing a central province wide registry of these lesions in Quebec and potentially abroad with our long-term international collaborators. This idea has emerged from one of the PIs (N Makhoul) who developed such infrastructure for oral cancer patients at the Montreal General Hospital as well as at the University of Michigan. The project was further elaborated through discussions collaborators B Nicolau & M-C Rousseau, who are conducting a pilot multicenter longitudinal study investigating the natural history of potentially malignant lesions. Ultimately, a registry of this type can offer the basis for prospective clinical trials that can potentially lead to a better understanding of the natural history of pre-malignant lesions of the oral cavity.
A Joint Workshop: HeNCe Life and MuCOSAL Studies
Principal investigator : Belinda Nicolau
Collaborators: Marie-Claude Rousseau, Paul Allison, François Coutlée, Eduardo Franco, Nicolas Schlecht
Head and neck cancer (cancers of the mouth, throat, and larynx) have a devastating impact on patients’ quality of life, since both the disease and its treatment can have important negative effects on the way people eat, breathe, speak, and look. As a result, patients with this disease experience high levels of depression and suicide.
Several researchers working in different fields related to head and neck cancer joined forces in 2005 to investigate how these cancers develop. They combined their expertise to form an international research consortium and started the first of two important research projects: The Head and Neck Cancer Life course (HeNCe Life) study.
This study investigates the relationships between genetic, biological (e.g., viral infections), social, psychological and behavioural factors along people’s lives and the occurrence of head and neck cancer. We interview people in Canada, Brazil and India who have head and neck cancer and people who do not have this disease to investigate several characteristics of different populations. Once this study was successfully started, we initiated another international project: the Multi-Center Oro-pharyngeal Atypical Lesions (MuCOSAL) study. This project investigates molecular, infectious, and lifestyle factors in Americans, Canadians and Brazilians who have pre-cancerous lesions in their mouths to identify which patients will develop cancer.
We propose to hold a meeting with all the experts involved in these two related projects, including researchers, doctors, nurses, research personnel and advanced students to discuss our first findings and plan for the future. The strong collaborations established over the years have already contributed to the development of research projects that will be highly beneficial to public health and we hope to achieve even more by continuing and strengthening our collaboration.
Development of an instrument for assessing occupational exposures in cancer case-control studies and its application to cancers of the lung, brain, ovary, and colon
Principal investigator : Jack Siemiatycki
Co-Principal investigator: Michael Pollak
Collaborators: Jérôme Lavoué, Anita Koushik, Igor Karp, Yan Kestens, Bruce Case, , Michal Abrahamowicz, Elham Emami, Marie-Claude Rousseau, Martie Van Tongeren, Mark Daniel, Geetanjali Datta, Michel Gérin, Mark Goldberg, France Labrèche
Funding: Cancer Research Society-MDEIE-FRQS, GRePEC Program
Our research team has been active in studying occupational/environmental causes of cancer for over 30 years, having carried out several case-control studies and having developed and implemented a novel approach to assess past occupational exposures of subjects in case-control studies. Our method involved probing interviews followed by review of each work history by a team of industrial hygiene/chemistry experts to estimate the work exposures of each subject, using a checklist of 300 agents. In the course of our previous studies, our team of exposure experts, with over 50 person years of cumulated work devoted to the task, have assessed exposures in over 30,000 different jobs. The present proposal has two principal aims: (i) to make available to the international research community the benefits of a great deal of work we have done to link the jobs people have with the occupational agents they’ve been exposed to, in the form of a job-exposure matrix (JEM) and (ii) to apply the JEM to studies of lung, brain, ovarian and colorectal cancers. In addition, members of our team have assembled a geographic information system (GIS) called MEGAPHONE that includes extensive social and environmental information on Montreal neighbourhoods. MEGAPHONE can be applied to Montreal case-control subjects to estimate various neighbourhood environmental characteristics. CANJEM and MEGAPHONE will be applied to several case-control data sets as follows: 1) SYNERGY, an international consortium of lung cancer case-control studies, including over 29,000 subjects with lifetime occupational histories. The study currently involves estimation of exposures to 4 lung carcinogens by a team of experts. Our proposal is to use CANJEM to assign exposure to the other >200 agents in CANJEM and then analyse those associations. MEGAPHONE would only be applicable to the Montreal component of SYNERGY. b) The INTEROCC study is an international consortium of brain cancer case-control studies, in which job histories were collected on 9000 subjects. That project was designed to use a JEM developed in Finland. But FINJEM has limitations in its breadth of coverage and in its generalisability. Thus, we will implement CANJEM on the international brain cancer study. 3) An ovarian cancer case-control study is currently underway in our team focusing on inflammation and lack of vitamin D as risk factors. This study has also collected both residential and job histories from subjects. We intend to apply CANJEM and MEGAPHONE to this database to assess occupational/environmental risk factors for ovarian cancer. But because the study is currently underfunded to achieve adequate sample sizes for these variables, we will use some of the funding of this GRePEC project for 2.5 additional years of ovarian cancer data collection. 4) We have designed a case-control study to assess risk factors for colorectal cancer. Among the primary factors to be explored are those related to dental health and diet. But there will also be job and residential history acquisition and this will be used in conjunction with CANJEM and MEGAPHONE to assess occupational and environmental risk factors for colon cancer, including physical exertion at work. Collectively, these studies will produce a wealth of new data on occupational and environmental risk factors for four types of cancer.
The life course approach to studying the aetiology of head and neck cancer: HeNCe Life study
Principal investigator : Belinda Nicolau
Co-Principal investigator: Nicolas Schlecht
Collaborators: Paul Allison, Robert Burk, François Coutlée, Eduardo Franco, Gerald Humphris, Gopal Netuveli, Jennifer O’Loughlin, Amanda Sacker, Marie-Claude Rousseau, Denis Soulières
Dr. Nicolau’s team will explore a new idea to understand how people develop cancer in the mouth and throat, often called “head and neck cancer” (H&NC). This cancer can deeply affect how people swallow, eat, drink, talk, and look and only about half of people diagnosed with it are still alive after five years. This cancer is mainly caused by smoking and drinking, but recent discoveries showed that a family of viruses called human papillomaviruses (HPVs) are also involved. HPVs are responsible for a substantial increase in H&NC, mainly those in an area at the back of the mouth called the oropharynx. There are many types of HPVs categorized into three kinds: alpha, beta, and gamma. Until now, only alpha HPVs have been studied to understand their role in the development of H&NC. However, a few recent studies suggest that the other two kinds of HPVs could also increase the risk of this cancer. Our project will examine if beta and gamma HPVs are linked to H&NC. To do so, we have interviewed Quebecers with and without cancer and collected cells from their mouths and tumours. We will test these cells to find out if beta and gamma HPVs are present. Then, we will combine this information with other data to find out if these HPVs are related to H&NC.
Rôle de l’infection au virus du papillome humain (VPH) dans les cancers des voies aéro-digestives supérieures
Principal investigator : Marie-Claude Rousseau
Co-Principal investigator: Belinda Nicolau
Collaborators: Luiz Paulo Kowalski, Paul Allison, François Coutlée, Eduardo Franco, Silvia Rogato, Amanda Sacker, Nicolas Schlecht, Denis Soulières
Les cancers des voies aéro-digestives supérieures constituent le 6e cancer le plus fréquent dans le monde, touchant plus d’un demi million de personnes et causant plus de 300 000 décès par année. Les principaux facteurs de risque des cancers des voies aéro-digestives supérieures sont le tabac et la consommation d’alcool, ainsi que leurs effets combinés. De plus, le virus du papillome humain (VPH), reconnu comme un agent causal important des cancers anogénitaux, a récemment été identifié comme une des causes des cancers des voies aéro-digestives supérieures et plus spécifiquement des cancers oropharyngés. Afin de mieux comprendre le développement des cancers des voies aéro-digestives supérieures, nous avons démarré en 2005 l’étude HeNCe Life, une étude multicentrique internationale (Canada, Brésil, Inde) qui porte sur l’étiologie de ces cancers en considérant l’ensemble des facteurs environnementaux et sociaux pertinents tout au long de la vie. Une entrevue basée sur un questionnaire structuré et une technique novatrice appelée « grille de vie » permettent de récolter l’information pertinente dans différents domaines d’exposition au cours de trois périodes de vie (enfance, vie de jeune adulte et d’adulte). De plus, des cellules exfoliées de la bouche sont récoltées à l’aide d’une brosse et de rince-bouche, puis analysées afin d’identifier les infections au VPH et d’identifier certains polymorphismes génétiques. Bien que les infections au VPH puissent être détectées de façon précise dans les cellules exfoliées, cette méthode ne permet pas de savoir si le VPH est présent précisément sur le site de la tumeur, ni même d’identifier le type spécifique de VPH qui colonise cette tumeur. Nous proposons de contrer les limites des analyses de cellules exfoliées en analysant l’ADN du VPH dans des échantillons de cellules tumorales prélevées par biopsie et en y détectant un grand nombre de types de VPH, ceci pour plusieurs sites de cancers des voies aéro-digestives supérieures. La présente demande a pour but de bâtir sur la plateforme bien établie de l’étude HeNCe Life, en greffant une nouvelle composante pour les sites canadien et brésilien de l’étude. L’objectif général de cette nouvelle composante est de mieux comprendre le rôle du VPH dans l’étiologie, les comorbidités et le taux de survie liés aux cancers des voies aéro-digestives supérieures. Pour ce faire, nous proposons dans un premier temps, de créer une banque de spécimens afin de détecter les infections au VPH dans des échantillons de tumeurs. Dans un deuxième temps, nous étudierons la relation de l’infection au VPH avec l’étiologie, les comorbidités et le taux de survie des sujets touchés par ces cancers, tel que documenté dans les dossiers médicaux.
Quebec Research Program for Prostate Cancer Prevention
Principal investigator : Marie-Élise Parent
Co-Principal investigator: Pierre Karakiewicz
Collaborators: Marie-Hélène Roy-Gagnon, Jack Siemiatycki, Jérôme Lavoué, Eduardo Franco, Armen Aprikian, Michal Abrahamowicz, Fred Saad, Mark Goldberg; Marie-Claude Rousseau, Belinda Nicolau, Anand Chokkalingam , Ann Hsing
Funding: Société de recherche sur le cancer; Enseignment supérieur, Recherche, Science et Technologie de Québec; Fonds de recherche Santé Québec; RRSE; RioTintoAlcan; National Cancer Institute of Canada, Canada Research Society, MDEIE
We initiated back in 2010, the Quebec Research Program for Prostate Cancer Prevention, which calls upon the collaboration of 12 established Quebec researchers covering environmental, occupational, infectious, lifecourse, molecular and genetic epidemiology, biostatistics and urology. This is probably the largest study ever to evaluate in such depth the possible environmental causes of prostate cancer. In brief, the Program has allowed us to build, on an existing research infrastructure, a major research effort including 12 objectives: (1) recruit 1,000 study subjects to bring the overall study sample of the Program to 4,000 subjects, (2) evaluate the presence of 110 chemicals in the subjects’ workplaces, (3) evaluate physical activity levels in workplaces, (4) evaluate dietary intakes, (5) collect information on all residences held by the subjects, (6) evaluate whether genetic factors determine how exposure to the environment relates to prostate cancer, (7) analyze hair and toenail samples as biomarkers of exposure to trace metals, (8) evaluate the determinants of prostate cancer progression, (9) create analytical databases, (10) conduct statistical analyses, (11) train students and research personnel, (12) disseminate findings. There are no doubts that with the wealth of information collected in the context of this Program, this collective effort in elucidating risk factors for prostate cancer will last for decades to come.
Occupational and selected nonoccupational risk factors for lung cancer: analysis of a case-control study in Montreal
Principal investigator : Jack Siemiatycki
Co-Principal investigator: Marie-Élise Parent
Collaborators: Michal Abrahamowicz, Bruce Case, Mark Goldberg, Igor Karp, Anita Koushik, Daniel Krewski, Jérôme Lavoué, Karen Leffondré, Marie-Claude Rousseau
I am leading and participating to projects using data from a case-control study conducted by Jack Siemiatycki and collaborators in Montreal (1996-2002), and aiming to understand the environmental causes of lung cancer. Through student supervision and several collaborations, I am investigating several types of factors, from lifestyle to environmental exposures, in relation to lung cancer risk. For example, some of these projects covered dietary intake of carotenoids and vitamin C, body mass index, socioeconomic status, history of allergic diseases, as well as occupational exposures such as asbestos, formaldehyde, lead compounds, gasoline emissions, and cotton dust.
Non-specific stimulation of the immune function in early age through Bacillus Calmette-Guérin (BCG) vaccination and occurrence of childhood asthma
Principal investigator : Marie-Claude Rousseau
Collaborators: Andrea Benedetti, Mariam El-Zein, Dick Menzies, Marie-Élise Parent
I am currently conducting studies looking into a possible link between non-specific stimulation of the immune function in early age, such as that induced by Bacillus Calmette-Guérin (BCG) vaccination, and beneficial or detrimental effects on the development of inflammatory and autoimmune diseases later in life. For these studies, we are using information from the Quebec BCG vaccination registry and linking it to administrative health databases in order to determine occurrence of the diseases of interest. After completing a validation study, we assembled the Québec Birth Cohort on Immunity and Health (QBCIH, n=81,496) to study the association between BCG vaccination and childhood asthma. We are also studying BCG vaccination in relation to diabetes occurrence. Perinatal information, BCG vaccination and health encounters related to asthma, diabetes, and several allergic diseases were gathered from administrative databases. Additional relevant information, unavailable in these databases, was collected among 1643 participants using a two-stage sampling strategy with a balanced design. Analyses are ongoing for several sub-projects.