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Breast Cancer Res Treat ; 189(2): 533-539, 2021 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-34196900


PURPOSE: Mutations in hereditary breast cancer genes play an important role in the risk for cancer. METHODS: Cancer susceptibility genes were sequenced in 664 unselected breast cancer cases from Guatemala. Variants were annotated with ClinVar and VarSome. RESULTS: A total of 73 out of 664 subjects (11%) had a pathogenic variant in a high or moderate penetrance gene. The most frequently mutated genes were BRCA1 (37/664, 5.6%) followed by BRCA2 (15/664, 2.3%), PALB2 (5/664, 0.8%), and TP53 (5/664, 0.8%). Pathogenic variants were also detected in the moderate penetrance genes ATM, BARD1, CHEK2, and MSH6. The high ratio of BRCA1/BRCA2 mutations is due to two potential founder mutations: BRCA1 c.212 + 1G > A splice mutation (15 cases) and BRCA1 c.799delT (9 cases). Cases with pathogenic mutations had a significantly earlier age at diagnosis (45 vs 51 years, P < 0.001), are more likely to have had diagnosis before menopause, and a higher percentage had a relative with any cancer (51% vs 37%, P = 0.038) or breast cancer (33% vs 15%, P < 0.001). CONCLUSIONS: Hereditary breast cancer mutations were observed among Guatemalan women, and these women are more likely to have early age at diagnosis and family history of cancer. These data suggest the use of genetic testing in breast cancer patients and those at high risk as part of a strategy to reduce breast cancer mortality in Guatemala.

Neoplasias da Mama , Predisposição Genética para Doença , Mutação em Linhagem Germinativa , Proteína BRCA1/genética , Proteína BRCA2/genética , Neoplasias da Mama/diagnóstico , Neoplasias da Mama/epidemiologia , Neoplasias da Mama/genética , Feminino , Genes BRCA2 , Células Germinativas , Guatemala , Humanos
Cancer Res ; 80(18): 3803-3809, 2020 09 15.
Artigo em Inglês | MEDLINE | ID: mdl-32631904


Human papillomavirus (HPV) 16 displays substantial sequence variation; four HPV16 lineages (A, B, C, and D) have been described as well as multiple sublineages. To identify molecular events associated with HPV16 carcinogenesis, we evaluated viral variation, the integration of HPV16, and somatic mutation in 96 cervical cancer samples from Guatemala. A total of 65% (62/96) of the samples had integrated HPV16 sequences and integration was associated with an earlier age of diagnosis and premenopausal disease. HPV16 integration sites were broadly distributed in the genome, but in one tumor, HPV16 integrated into the promoter of the IFN regulatory factor 4 (IRF4) gene, which plays an important role in the regulation of the IFN response to viral infection. The HPV16 D2 and D3 sublineages were found in 23% and 30% of the tumors, respectively, and were significantly associated with adenocarcinoma. D2-positive tumors had a higher rate of integration, earlier age of diagnosis, and a lower rate of somatic mutation, whereas D3-positive tumors were less likely to integrate, had later age of diagnosis, and exhibited a higher rate of somatic mutation. In conclusion, Guatemalan cervical tumors have a high frequency of very high-risk HPV16 D2 and D3 sublineages harboring distinct histology, which may help guide future therapeutic strategies to target the tumor and reduce recurrence. SIGNIFICANCE: This study details the biological and molecular properties of the most pathogenic forms of HPV16, the cause of the majority of cervical cancers.

Adenocarcinoma/genética , Papillomavirus Humano 16/genética , Fatores Reguladores de Interferon/genética , Infecções por Papillomavirus/genética , Neoplasias do Colo do Útero/genética , Integração Viral/genética , Adenocarcinoma/virologia , Adulto , Fatores Etários , Idoso , Idoso de 80 Anos ou mais , Classe I de Fosfatidilinositol 3-Quinases/genética , DNA Viral/análise , DNA Viral/genética , Feminino , Genoma Viral , Guatemala , Papillomavirus Humano 16/classificação , Humanos , Pessoa de Meia-Idade , Mutação , Infecções por Papillomavirus/complicações , Infecções por Papillomavirus/virologia , Lesões Pré-Cancerosas/complicações , Lesões Pré-Cancerosas/genética , Lesões Pré-Cancerosas/virologia , Neoplasias do Colo do Útero/patologia , Neoplasias do Colo do Útero/virologia