Frequência de câncer e análise genotípica dos polimorfismos mTOR rs1010447 e IRE1 rs196929 em famílias de pacientes com fissura labial e/ou palatina

Abstract

Cleft lip and / or palate is the most common craniofacial birth defect in humans. The origin of these clefts has been associated with genetic and environmental factors, such as smoking during pregnancy, use of medications, socioeconomic factors, as well as infectious diseases. There is evidence that individuals born with orofacial clefts have a higher prevalence of cancer than the general population, hence, identifying genetic factors that are related to the risk of cancer and the presence of oral clefts may allow the development of strategies for identification of risk groups. The present study aimed to determine the frequency of cancer in families with individuals born with cleft lip and/or palate and to associate them with mTOR rs1010447 and IRE1 rs196929, which are associated with cancer. Eight hundred and thirty-six individuals were evaluated (303 born with cleft lip and/or palate, 256 parents, mostly the mothers of individuals born with cleft lip and/or palate and 277 unaffected individuals). The parents or guardians of the children answered a questionnaire with basic demographic information about their children and family history of cleft lip and palate and cancer. DNA was obtained from whole saliva and the single nucleotide polymorphisms mTOR rs1010447 and IRE1 rs196929 were genotyped using the TaqMan method. Differences in mean age between the groups were determined by the Student’s t test. Relatives of individuals born with cleft lip and palate had a lower frequency of cancer compared to unrelated unaffected individuals. There was an excess of rare homozygotes of IRE1 rs196929 among relatives of individuals born with cleft lip and palate when they had a positive family history of cancer compared to individuals born with cleft lip and palate or with unrelated unaffected individuals (p=0.0006 and p=0.00000001, respectively). This pattern was similar when families reported one type of cancer or multiple cancers, or when the cancer affected women (breast or reproductive tract) or gastrointestinal tract structures. We did not find evidence for significant genotypic variations in mTOR rs1010447 when comparing it to demographic data, such as the history of cancer and smoking. The results provide support for a role of the IRE1-XPB1 stress pathway in the higher frequency of cancer in families of individuals born with cleft lip and palate.