A doutora Tirzah Braz Petta Lajus recebeu Menção Honrosa como Jovem Geneticista com o trabalho “Identification of new germ-line mutations in brazilian high-risk patients for breast cancer”. O prêmio Jovem Geneticista é a principal premiação concedida pela Sociedade Brasileira de Genética e visa à valorização e o estímulo aos jovens talentos da Genética Brasileira. A Dra. Tirzah Braz Petta Lajus é pós-doutoranda do programa PNPD da CAPES, vinculada ao programa de Pós-graduação em Ciências da Saúde (CCS), e desenvolve seu trabalho no LBMG-CB sob supervisão da Dra. Lucymara Fassarella Agnez-Lima. Confira abaixo o resumo do trabalho premiado!
Identification of new germ-line mutations in Brazilianhigh-risk patients for breast cancer.
Timóteo, ARS1; Matias, MO2; Agnez-Lima, LF1; King, MC3; Walsh, T3 and Lajus, TBP1,2
1- Universidade Federal do Rio Grande do Norte/DBG. 2- Liga Contra o Câncer/RN. 3-University of Washington/USA
Key words: BreastCancer, BRCA1/2, molecular diagnosis, germ-linemutations, next-generationsequencing,
Breast cancer (BC) is the most common malignancy affecting women worldwide, with 15% of disease attributed to hereditary factors. Although BRCA1 and BRCA2 (Breast Cancer 1 and 2) account for a high percentage of hereditary cases, our knowledge of the heritability of BC has increased significantly in the last years, and now, more than 30 genes are associated with BC risk. In 2011, the team of Dr. Mary-Claire King, responsible for BRCA1 identification, had validated a massively parallel sequencing approach (Next Generation Sequencing, NGS) highly sensitive for sequencing a panel of 33 tumor suppressor genes, including BRCA1 and BRCA2 and other genes known to cause inherited BC, named BROCA. In the present study, we apply BROCA to analyze genomic DNA from selected high risk individuals stratified according to National Comprehensive Cancer Network (NCCN) guidelines inclusion criteria andInstitutoNacional de Câncer (Inca). Subjects were 76 women and 1 men, which 11 (14%) do not had cancer and was enrolled for age at onset and family history.DNA sequencing results have shown that 15 subjects (19%) harbored germ-line mutations in BRCA1, BRCA2, ATR, ATM e MSH2 genes. All mutations were confirmed by Sanger sequencing. Among these mutations, 3 (20%) are pathogenic missense mutations with demonstrated effect on protein function as found at the Breast Cancer Information Core (BIC): BRCA1_c.2508delGA; BRCA1_c.5382insC; BRCA2_c.3680_3681delTG. One large genomic deletion of BRCA2 exon 14 was found in the male patient. Two intronic variants (IVS) were detected, one have been associated with an increased BC risk at the BIC, BRCA1_IVS17+2T>C, and another not yet described but predicted to disrupt the exon 18 donor site, BRCA1_IVS+2T>A.Interestingly, the other 6 mutations (40%) are germ-line loss-of-function mutations in genes not described previously(BRCA1_c.2336insA; ATR_c.3043C>T; ATM_c.5644C>T; MSH2_c.2785A>T; BRCA2_c.5792A>T; ATM_c.634delT), showing how important is to test other tumor suppressor genes to improve our understanding of inherited BC. In conclusion, despite the high cost of NGS, this technique should be considered in the management of high risk families negative for BRCA1 or BRCA2 germ-line mutation in Brazilian individuals.
Financial support: CNPq, CAPES, FAPERN.
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