Avec plus de 600 000 nouveaux cas par an, les cancers des voies aéro-digestives supérieures (VADS) se classent au sixième rang mondial. Ces cancers, traditionnellement causés par la consommation chronique de tabac et d’alcool, connaissent depuis une trentaine d’années de profonds changements épidémiologiques. Alors que l’incidence des cancers développés dans la cavité orale, le larynx et l’hypopharynx tend à se stabiliser voire à régresser en raison de la diminution du tabagisme, ceux développés dans l’oropharynx sont en nette augmentation. Cette augmentation est attribuée aux papillomavirus oncogènes et notamment au génotype 16 (HPV16). Les cancers de l’oropharynx (COP) HPV-induits représentent une pathologie distincte des autres cancers des VADS tant au niveau épidémiologique, clinique, histologique que biologique. Ils affectent des sujets plus jeunes, sont extrêmement lymphophiles et leur pronostic est significativement meilleur. L’émergence de ces cancers impose dès aujourd’hui de réfléchir à des stratégies diagnostiques, thérapeutiques et de surveillance spécifiques. Néanmoins, ces objectifs ne pourront être pleinement atteints qu’à condition de mieux comprendre leur histoire naturelle ainsi que leurs mécanismes oncogéniques propres. L’objectif de ce travail est de contribuer à une meilleure compréhension des mécanismes biologiques distinguant les COP HPV-induits de leurs homologues HPV-négatifs sur la base de l’analyse de leur profil d’expression génomique. A partir d’une cohorte de 38 COP, sélectionnés sur des critères stricts, nous avons identifié un set d’ARNm et de miRNA dont l’expression est exclusivement corrélée au statut HPV. L’analyse fonctionnelle de ces sets confirme que les bases biologiques des COP varient en fonction de leur statut HPV et confortent au niveau moléculaire des données cliniques et pathologiques déjà connues ou fortement suspectées (différenciation tumorale, infiltration lymphocytaire…). Cette étude souligne également le rôle potentiel de plusieurs voies de signalisation dont les dérégulations contribueraient au développement de ces tumeurs. L’exploration plus approfondie de ces voies pourrait à terme permettre de mieux comprendre ces tumeurs et avoir d’éventuelles retombées thérapeutiques. / Head and neck squamous cell carcinomas (HNSCCs) represent the sixth most common form of cancer with an annual incidence of approximately 600,000 new cases worldwide. Tobacco and alcohol abuse are the traditional risk factors. Whilst the incidence of oral cavity, larynx and hypopharynx cancers is stabilizing or falling, because of a drop in tobacco consumption, those arising in the oropharynx are on the increase. This epidemiologic change has been attributed to high-risk human papillomavirus and particularly to type 16 (HPV16), which is now recognized as a causative agent in a growing subset of oropharyngeal squamous cell carcinomas (OPSCCs).HPV-induced OPSCCs represent a distinct subgroup, separate from other HNSCCs, with unique epidemiologic, clinical, pathological and molecular characteristics. They affect young patients, are highly lymphophilic and have markedly improved survival outcomes compared to those with HPV-negative HNSCC. The emergence of these cancers demands special attention, as in the coming years diagnosis, treatment and follow up in HNSCC may vary according to HPV status. However, these objectives will not be fully achieved without a better understanding of their natural history and specific oncogenic mechanisms. The goal of this work is to contribute to a better understanding of the biological basis that differentiates HPV-induced OPSCCs from their HPV-negative counterparts. To this end, we have investigated global changes in gene expression in a cohort of 38 strictly selected OPSCCs. We have identified a set of mRNA and miRNA that discriminated between OPSCCs solely according to HPV16 status. The functional analysis of these 2 sets confirms that the biological basis of OPSCCs varies according to their HPV status and consolidates at the molecular level known or suspected clinical and pathological data (e.g tumoral differentiation, lymphoid infiltrations…). This study highlights the potential role of several pathways that, once deregulated, could contribute to the development of HPV-induced OPSCC. Further investigation is required for a more comprehensive understanding of the biological properties of HPV related OPSCCs. These properties may be exploited to develop novel therapeutic agents.

Coordenação de Aperfeiçoamento de Pessoal de Nível Superior / O objetivo desse trabalho foi determinar a prevalência, extensão e severidade da periodontite crônica em pacientes com câncer de boca e/ou orofaringe e verificar se essa forma de doença periodontal é indicadora de risco para essas neoplasias. Trinta e cinco pacientes com câncer de boca e/ou orofaringe, atendidos no Instituto Nacional de Câncer (INCA) e 40 pacientes e/ou acompanhantes do ambulatório do Instituto Nacional de Traumatologia e Ortopedia (INTO), não portadores de neoplasias de boca e/ou orofaringe, foram avaliados por meio de anamnese, exame periodontal e índice de dentes cariados perdidos e obturados (CPOD). A população estudada foi formada predominante por indivíduos do sexo masculino, da raça branca, casados, que cursaram até o ensino fundamental e possuíam renda familiar de até 6 salários mínimos. Não houve diferença estatística significante para esses parâmetros entre os grupos. No grupo caso havia significativamente mais pacientes fumantes e que ingeriam mais bebidas alcoólicas. Pacientes do grupo controle praticavam mais exercícios físicos e tinham o índice de massa corporal (IMC) significantemente mais elevado. O consumo de frutas, legumes e vegetais foi maior para o grupo controle (p>0,05), enquanto o consumo de carne vermelha foi maior no grupo caso (p>0,05). O histórico de casos de câncer na família era baixo em ambos os grupos. O grupo caso apresentou mais sítios com placa e sangramento a sondagem e menos sítios com sangramento gengival. Somente o índice de placa teve diferença estatisticamente significante. O número de dentes presentes era significantemente menor no grupo caso embora não houvesse diferença estatística significante entre os grupos para o índice CPOD. As médias de profundidade de bolsa a sondagem (PBS) e nível de inserção clínica (NIC) foram significantemente maiores para o grupo caso. A prevalência da periodontite crônica generalizada foi de 100% nos pacientes com câncer de boca e ou orofaringe. Oitenta e nove por cento dos pacientes do grupo caso apresentaram periodontite crônica severa. A extensão ou a severidade da periodontite crônica permaneceram indicadores de risco para o câncer de boca e/ou orofaringe independentes mesmo após os ajustes para fatores de confusão, álcool e fumo. / The aim of this study was to determine the prevalence, extension and severity of chronic periodontitis in patients with oral cavity and/or oropharynx cancer, as well as to verify whether this form of periodontal disease is a risk indicator for these neoplasms. Thirty five patients with oral cavity and/or oropharynx cancer from the National Cancer Institute (INCA) Hospital as well as 40 outpatients and/or their companions from the National Institute of Traumatology (INTO) were evaluated by means of anamnesis, periodontal examination and decayed, extracted and filled teeth index (DMFT). The predominant individual of the population in study was male, white, married, had completed grammar school and had a family income of up to 6 times the Brazilian minimum wage. There were no significant statistical differences for these parameters between the case and control groups. The case group had significantly more patients who smoked regularly and their individuals ingested more alcoholic beverages. Patients of the control group practiced more physical activities and had a significantly higher body mass index (BMI). The consumption of fruits and vegetables was higher in the control group (p>0,05) while red meat intake was higher in the case group (p>0,05). The family history for cancer was low in both groups. The case group presented more sites with plaque and bleeding on probing but less sites with gingival bleeding. Only the difference in the plaque index was statistically significant. The number of teeth present in the mouth was significantly lower in the case group although there was no statistically significant difference in the DMTF index between the groups. The mean probing pocket depth and clinical attachment level were significantly higher for the case group. The prevalence of chronic generalized periodontitis was 100% in patients with oral cavity and/or oropharynx cancer. Eighty nine percent of the patients in the case group presented chronic severe periodontitis. The extension and severity of chronic periodontitis remained as a risk indicator for oral cavity and/or oropharynx cancer even after the adjustments for confusion factors, i.e. smoke and alcohol.

Coordenação de Aperfeiçoamento de Pessoal de Nível Superior / O objetivo desse trabalho foi determinar a prevalência, extensão e severidade da periodontite crônica em pacientes com câncer de boca e/ou orofaringe e verificar se essa forma de doença periodontal é indicadora de risco para essas neoplasias. Trinta e cinco pacientes com câncer de boca e/ou orofaringe, atendidos no Instituto Nacional de Câncer (INCA) e 40 pacientes e/ou acompanhantes do ambulatório do Instituto Nacional de Traumatologia e Ortopedia (INTO), não portadores de neoplasias de boca e/ou orofaringe, foram avaliados por meio de anamnese, exame periodontal e índice de dentes cariados perdidos e obturados (CPOD). A população estudada foi formada predominante por indivíduos do sexo masculino, da raça branca, casados, que cursaram até o ensino fundamental e possuíam renda familiar de até 6 salários mínimos. Não houve diferença estatística significante para esses parâmetros entre os grupos. No grupo caso havia significativamente mais pacientes fumantes e que ingeriam mais bebidas alcoólicas. Pacientes do grupo controle praticavam mais exercícios físicos e tinham o índice de massa corporal (IMC) significantemente mais elevado. O consumo de frutas, legumes e vegetais foi maior para o grupo controle (p>0,05), enquanto o consumo de carne vermelha foi maior no grupo caso (p>0,05). O histórico de casos de câncer na família era baixo em ambos os grupos. O grupo caso apresentou mais sítios com placa e sangramento a sondagem e menos sítios com sangramento gengival. Somente o índice de placa teve diferença estatisticamente significante. O número de dentes presentes era significantemente menor no grupo caso embora não houvesse diferença estatística significante entre os grupos para o índice CPOD. As médias de profundidade de bolsa a sondagem (PBS) e nível de inserção clínica (NIC) foram significantemente maiores para o grupo caso. A prevalência da periodontite crônica generalizada foi de 100% nos pacientes com câncer de boca e ou orofaringe. Oitenta e nove por cento dos pacientes do grupo caso apresentaram periodontite crônica severa. A extensão ou a severidade da periodontite crônica permaneceram indicadores de risco para o câncer de boca e/ou orofaringe independentes mesmo após os ajustes para fatores de confusão, álcool e fumo. / The aim of this study was to determine the prevalence, extension and severity of chronic periodontitis in patients with oral cavity and/or oropharynx cancer, as well as to verify whether this form of periodontal disease is a risk indicator for these neoplasms. Thirty five patients with oral cavity and/or oropharynx cancer from the National Cancer Institute (INCA) Hospital as well as 40 outpatients and/or their companions from the National Institute of Traumatology (INTO) were evaluated by means of anamnesis, periodontal examination and decayed, extracted and filled teeth index (DMFT). The predominant individual of the population in study was male, white, married, had completed grammar school and had a family income of up to 6 times the Brazilian minimum wage. There were no significant statistical differences for these parameters between the case and control groups. The case group had significantly more patients who smoked regularly and their individuals ingested more alcoholic beverages. Patients of the control group practiced more physical activities and had a significantly higher body mass index (BMI). The consumption of fruits and vegetables was higher in the control group (p>0,05) while red meat intake was higher in the case group (p>0,05). The family history for cancer was low in both groups. The case group presented more sites with plaque and bleeding on probing but less sites with gingival bleeding. Only the difference in the plaque index was statistically significant. The number of teeth present in the mouth was significantly lower in the case group although there was no statistically significant difference in the DMTF index between the groups. The mean probing pocket depth and clinical attachment level were significantly higher for the case group. The prevalence of chronic generalized periodontitis was 100% in patients with oral cavity and/or oropharynx cancer. Eighty nine percent of the patients in the case group presented chronic severe periodontitis. The extension and severity of chronic periodontitis remained as a risk indicator for oral cavity and/or oropharynx cancer even after the adjustments for confusion factors, i.e. smoke and alcohol.