Une étude exhaustive des facteurs de risque du cancer de la tête et du cou : perspectives épidémiologiques et génétiques

Head and neck squamous cell carcinoma (HNSCC) and oesophageal squamous cell carcinoma—both malignancies of the upper aerodigestive tract (UADT)—pose a significant global public health burden. These cancers develop through a multifaceted interplay between modifiable environmental exposures and inherent genetic predispositions. Despite substantial research efforts, important knowledge gaps persist regarding the carcinogenic impact of alcohol consumption independent of tobacco use, as well as the identification of novel genetic susceptibility loci and their interactions with environmental risk factors. This thesis seeks to address these gaps through two complementary investigations aimed at elucidating how both lifestyle and genetic determinants contribute to UADT cancer risk. The first component of this research is a large-scale observational study examining the association between alcohol intake and UADT cancer incidence. This analysis drew on pooled data from 28 prospective cohort studies, encompassing nearly 2.4 million individuals with a median follow-up of 15.5 years, during which 6,903 incident UADT cancer cases were identified. The findings demonstrate that even low levels of alcohol consumption—approximately one standard drink per day—significantly increase cancer risk when compared to minimal intake (0.1-<5 grams per day). Crucially, this dose–response relationship remains evident among individuals who have never smoked, providing robust evidence that alcohol independently contributes to UADT cancer risk. The association persisted across various types of alcoholic beverages, although the magnitude of risk varied by sex, geographic region, and body mass index. Building on these epidemiological insights, the second component of this research involved a multi-ancestry genome-wide association study (GWAS) comprising 19,073 HNSCC cases and 38,857 controls. This study identified 29 previously unreported susceptibility loci, including a protective variant (rs78378222) located in the 3′ untranslated region of the TP53 gene. Analyses of gene–environment interactions further revealed that the effects of specific genetic variants are modulated by exposure to established carcinogens. Collectively, these studies provide compelling evidence that alcohol consumption independently elevates UADT cancer risk and that genetic predisposition influences this risk both directly and through interaction with environmental exposures. The identification of novel genetic loci advances understanding of the biological mechanisms underlying UADT carcinogenesis and underscores the importance of integrated prevention strategies that combine lifestyle modification with genetic risk profiling.