Estudo de muta????es pontuais de BRCA1, BRCA2, CHEK2 e TP53 em pacientes com alto risco para c??ncer de mama e ov??rio heredit??rio

INTRODU????O: BRCA1, BRCA2, CHEK2 e TP53 s??o os principais genes supressores tumorais associados ??s s??ndromes de c??ncer de mama e ov??rio heredit??rio (HBOC) e Li-Fraumeni (LFS/LFL). Em c??nceres heredit??rios, a frequ??ncia de muta????es em genes de baixa penetr??ncia, como CHEK2, est?? entre 1-10%, entretanto nos genes de alta penetr??ncia, como BRCA1/2 e TP53, a frequ??ncia ?? <1%. At?? o momento, estudos feitos no Brasil apenas descreveram apenas o perfil de susceptibilidade gen??tica de popula????es das regi??es sul/sudeste. OBJETIVO: Analisar a ancestralidade e oito muta????es dos genes BRCA1, BRCA2, CHEK2 e TP53 em 102 pacientes com alto risco para HBOC do Nordeste do Brasil. M??TODO: O DNA gen??mico foi extra??do de sangue perif??rico. Todas as pacientes foram testadas para as seguintes muta????es: BRCA1 (c.211A>G, c.66_67delAG e c.5266dupC), BRCA2 (c.5946_5946delT), CHEK2 (c.1100delC, c.444+1G>A e c.470T>C) e TP53 (c.1010G>A) por AS-PCR, PCR/RFLP ou sequenciamento. Um painel de nove AIMs (APO, AT3-I/D, CKMM, FY-NULL, GC*1S, GC*1F, LPL, PV92 e SB19.3) tamb??m foi utilizado para verificar a ancestralidade gen??tica das pacientes. Todas pacientes assinaram o termo de consentimento. Os dados cl??nicos e epidemiol??gicos foram obtidos durante o aconselhamento gen??tico ou nos prontu??rios m??dicos. RESULTADO: A idade m??dia ao diagn??stico foi 43,08 anos (??10,85). A neoplasia mais frequente foi o c??ncer de mama (91,2%), seguido do c??ncer de ov??rio (4,9%) e de ambos os c??nceres (3,9%). Entre os casos de c??ncer de mama o tipo histol??gico mais frequente foi o carcinoma ductal infiltrante (70,1%), contudo entre os casos de c??ncer de ov??rio foi o carcinoma seroso (77,8%). Observou-se elevada contribui????o europeia (62,2%), provavelmente devido ao fato da maioria ser natural do interior da Bahia (52%). A maioria das pacientes apresentava hist??ria familiar de c??ncer (83,3%). Duas muta????es foram encontradas: BRCA1*c.211A>G (2,94%) e TP53*c.1010G>A (0,98%). Todas as pacientes com muta????o tiveram tumores agressivos e hist??ria familiar sugestiva de HBOC. N??o houve diferen??a entre as pacientes com e sem muta????o para uso de anticoncepcional, paridade, idade da menarca e idade ao diagn??stico. CONCLUS??ES: As muta????es BRCA1*c.211A>G e TP53*c.1010G>A devem ser inclu??das nos pain??is de triagem mutacional usados em pacientes de alto risco para HBOC da Bahia.INTRODUCTION: BRCA1, BRCA2, CHEK2 and TP53 are the mainly tumor suppressor genes associated with Hereditary Breast and Ovarian Cancer (HBOC) and Li-Fraumeni (LFS/LFL) syndromes. In hereditary cancers the frequency of mutations in susceptibility genes of low penetrance like CHEK2 is 1-10%, while in genes of high penetrance as BRCA1/2 and TP53 is <1%. Until now, the studies done in Brazil only described the susceptibility profile of populations from the south/southeast regions. OBJECTIVE: To analyze the ancestry and eight mutations of BRCA1, BRCA2, CHEK2 and TP53 genes in 102 patients at high-risk for HBOC from the Northeast of Brazil. METHOD: The genomic DNA was extracted from the peripheral blood. All patients were tested for the next mutations: BRCA1 (c.211A>G, c.66_67delAG and c.5266dupC), BRCA2 (c.5946_5946delT), CHEK2 (c.1100delC, c.444+1G>A and c.470T>C) and TP53 (c.1010G>A) by AS-PCR, PCR/RFLP or sequencing. A panel of nine AIMs (APO, AT3-I/D, CKMM, FY-NULL, GC*1S, GC*1F, LPL, PV92 and SB19.3) was also used to verify the genetic ancestry. All subjects signed the informed consent. The clinical and epidemiologic data were obtained during the genetic counseling or in the medical records. RESULTS: The mean age at diagnostic was 43.08 yrs (??10.85). The most frequent neoplasia was breast cancer (91.2%), followed by ovarian cancer (4.9%) and both cancers (3.9%). Among the breast cancer cases the most common histological type was the invasive ductal carcinoma (70.1%), while among the ovarian cancer cases was the serous carcinoma (77.8%). The study population showed a higher European ancestry contribution (62.2%), probably because most subjects were from the countryside of Bahia (52%). Most of the patients had familial history of cancer (83.3%). Two mutations were found: BRCA1*c.211A>G (2.94%) and TP53*c.1010G>A (0.98%). All patients with mutations had aggressive tumors and family history suggestive of HBOC. No differences were observed between patients with and without mutation for the use of oral contraceptive, parity, and age of menarche and diagnostic. CONCLUSION: The BRCA1*c.211A>G and TP53*c.1010G>A mutations should be included in mutational screening panel used in high-risk patients for HBOC from Bahia