Germline mutations in BRCA1, BRCA2, CHEK2 and TP53 in patients at high-risk for HBOC: characterizing a Northeast Brazilian Population.

Considering the importance of BRCA1, BRCA2, CHEK2 and TP53 in the development of hereditary early-onset breast and ovarian cancer and that the genetic susceptibility profile of the Northeast population from Brazil has never been analyzed, this study aimed to verify the frequency of mutations of clinical significance in these genes in high-risk hereditary breast and ovarian cancer (HBOC) syndrome patients from that region. DNA samples from 106 high-risk unrelated patients mostly from Bahia, the biggest state in the Northeast region, were analyzed. These patients underwent full BRCA1 gene sequencing, screening for common founder mutations in the BRCA2, CHEK2 and TP53 genes and genetic ancestry analysis with nine ancestry informative markers. The positive results were confirmed by two sequencing reactions. Three mutations of clinical significance were found: BRCA1 p.R71G (4.71%), 3450del4 (3.77%) and TP53 p.R337H (0.94%). The genetic ancestry analysis showed a high European ancestry contribution (62.2%) as well as considerable African (31.2%) and Amerindian (6.6%) ancestry contributions (r (2)=0.991); this degree of heterogeneity was also significant in the population structure analysis (r=0.604). This population is highly admixed with a different spectrum of genetic susceptibility, with the Galician founder mutation BRCA1 p.R71G accounting for 50% of all identified mutations in high-risk HBOC patients. TP53 p.R337H was also significantly frequent; thus, the combined screening of BRCA1/2 and TP53 should be offered to high-risk HBOC patients from Northeast Brazil.

Ancestralidade Genômica, nível socioeconômico e vulnerabilidade ao HIV/aids na Bahia, Brasil / Genomic Ancestry, socioeconomic status and vulnerability to HIV/AIDS in Bahia, Brazil

O curso clínico da infecção pelo HIV é determinado por complexas interações entre características virais e o hospedeiro. Variações no hospedeiro, a exemplo das mutações CCR5Δ32 e CCR264I, são importantes para a vulnerabilidade e progressão do HIV/aids. Atualmente, observa-se um aumento do número de casos da infecção entre os segmentos da sociedade com menor nível de escolaridade e pior condição socioeconômica. Com o objetivo de estimar a ancestralidade e verificar a sua associação com renda, escolaridade vulnerabilidade e progressão ao HIV/aids foram analisados 517 indivíduos infectados pelo HIV-1, sendo 289 homens e 224 mulheres. Os pacientes foram classificados segundo a ancestralidade genômica avaliada por 10 AIMs e pela vulnerabilidade e progressão ao HIV/aids através das mutações CCR5Δ32 e CCR264I. Os indivíduos infectados pelo HIV-1 apresentaram contribuição africana de 47 por cento. As mutações CCR5Δ32 e CCR264I foram mais frequentes nos indivíduos brancos (3 por cento) e negros (18 por cento) respectivamente, e essas mutações mostraram frequência mais elevada nos tipicamente progressores (TP), quando comparados com os rapidamente progressores (RP) para aids. Não foi encontrada associação entre ancestralidade e vulnerabilidade ao HIV na análise para o grau de instrução. A pauperização da infecção pelo HIV-1 nessa população foi confirmada pela relação inversa entre renda e ancestralidade africana, pois quanto menor a renda maior a ancestralidade africana. Os resultados deste estudo sugerem associação entre as condições socioeconômicas e vulnerabilidade ao HIV/aids da população afrodescendente.

The clinical course of HIV infection is determined by complex/ interactions between viral and host's characteristics./ Host variations, such as CCR5δ32 and CCR264I mutations, are important/ to vulnerability and progression of HIV/AIDS./ Currently, the number of cases among patients with lower educational level and lower social and economic status is/ increasing./ Aiming to/ estimate the ancestry and verify its association with income,/ education, vulnerability and progression of HIV/AIDS, 517 individuals infected with HIV-1 were studied (55.9 percent men and 43.3 percent women). The/ patients were/ classified according to/ genomic ancestry evaluated by 10 AIMs and by vulnerability and/ progression of HIV/AIDS through CCR5δ32 and CCR264I mutations./ The/ individuals infected with HIV-1 showed 47 percent of African contribution./ CCR5δ32 and CCR264I mutations were more frequent in white/ (3 percent) and black (18 percent) individuals, respectively, and these same mutations/ showed higher frequency in the typically progressive HIV-infected individuals (TP), when compared to the rapidly progressive (RP)./ There was no association between ancestry and/ vulnerability to HIV in the analysis of level of education./ The pauperization of the HIV-1 infection in this population was confirmed by/ the inverse relationship between income and African ancestry, because the lower/ the income, the greater the African ancestry./ The results suggest that there is an association between socioeconomic status and vulnerability to HIV/AIDS in the Afro-descendant population.