Biomarcadores de suscetibilidade em carcinomas de vias aerodigestivas superiores / Biomarkers of susceptibility in upper aerodigestive system cancer

RESUMO

O câncer das vias aerodigestivas superiores (VADS) está entre as formas mais comuns de neoplasias malignas, principalmente em países em desenvolvimento. Os hábitos de consumir tabaco e bebidas alcoólicas são os mais conhecidos e estabelecidos fatores de risco para o desenvolvimento dos carcinomas espinocelulares da boca, faringe e laringe. Somente uma pequena minoria dos consumidores de bebidas alcoólicas vem desenvolver uma neoplasia de VADS e outra pequena parte, não exposta aos carcinógenos do álcool e tabaco pode vir a desenvolver a doença, este fato sugere a existência de suscetibilidade genética individual. A carcinogênese pode ocorrer devido a anormalidades no metabolismo de carcinógenos, alterações nos genes de reparo no DNA ou nos genes envolvidos no ciclo celular... O polimorfismo CCND1 G870A no códon 242 do exon 4 aumenta o splicing alternativo tendo um importante papel na formação das neoplasias... O sistema Wave™ System foi usado para analisar o polimorfismo de cada genótipo. Dez % da amostras com perfil homozigoto e heterozigoto foram examinadas por sequenciamento direto... O genótipo AA do polimorfismo do gene do ADH3 mostrou ser um possível fator de risco especialmente para os indivíduos que consomem baixas quantidades de álcool ou tabaco. Os resultados sugerem que a presença do alelo A do polimorfismo da CCND1 confere riscos elevados especialmente para indivíduos sem história de consumo de bebidas alcoólicas...(AU)

ABSTRACT

Cancers of the upper aerodigestive tract (UADT) are among the most common malignant neoplasms, particularly in developing countries. Although several investigations have shown that tobacco and alcohol are risk factors in the development o f squamous cell carcinoma o f the oral cavity, pharynx, or larynx, such cancers develop in only a small proportion of individuais who use tobacco and or alcohol, and some patients who have these cancers have had no apparent exposure to tobacco and alcohol. This suggests that host susceptibility may play an important role in SCC of the head and neck. The malignant process involves several steps, and recent studies have identified some genes associated with genetic susceptibility, metabolism o f carcinogens, DN A repair, lost o f cell cycle control and head and neck tumorigenesis. Polymorphisms in genes involved in these pathways, like cyclin D 1 (CCNDJ) or alcohol dehydrogenases (ADH3) are candidate genes to be investigated for genetic susceptibility. The risks for development o f upper aerodigestive tract (UADT) cancers may be attributable for alcohol consumption and alcohol dehydrogenase enzymes (ADHs), which convert ethanol to acetaldehyde. Otherwise, the involvement o f cyclin D 1 ( CCND 1), located within chromosome 11 q 13, plays a criticai role in phase G1-S in the cell cycle control. The CCNDJ 870A/G polymorphism at codon 242 in exon 4 increases the alternate splicing, playing an important role in the formation of malignancies. To investigate the relationship between CCNDland ADH3 polymorphisms on susceptibility for UADT cancers, 147 cases (116 male and 31 female) and 135 non-cancer cases (91 male and 44 female) were selected. The tumor sites cases were oral cavity, 66 (44.9%); oropharynx, 43 (29.2%); hypopharynx, 7 (4.8%) and larynx, 31 (21.1%). The Wave™ System was used to polymorphisms analysis for each genotype. Ten percent of samples with heterozygous and homozygous profiles were examined by direct sequenc1ng to confirm the presence of the polymorphism. The stratified analysis of this study showed a significant higher odds ratio for CCNDJ polymorphism A allele OR=7.5 in non-drinkers and non-significant OR = 5.4 for smokers, adjusted for sex, age, tobacco use and first-degree family history of cancer. For ADH3 polymorphism, the stratified and adjusted analysis showed significant higher odds ratio to AA genotypes OR=3.8 compared to GG+GA combined genotype for less than 100 kg ethanol lifetime consumers and OR=4.3 for less than 25 packyears tobacco smokers. These results suggest that CCNDJ combined A allele may be a risk factor especially in individuais without a history of drinking and that ADH3 genotype AA may be a risk factor for subjects that are consumers of small quantities of ethanol or of tobacco smoking (AU)