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1.
Clin Cancer Res ; 24(3): 569-580, 2018 02 01.
Artigo em Inglês | MEDLINE | ID: mdl-29061645

RESUMO

Purpose: Women with epithelial ovarian cancer generally have a poor prognosis; however, a subset of patients has an unexpected dramatic and durable response to treatment. We sought to identify clinical, pathological, and molecular determinants of exceptional survival in women with high-grade serous cancer (HGSC), a disease associated with the majority of ovarian cancer deaths.Experimental Design: We evaluated the histories of 2,283 ovarian cancer patients and, after applying stringent clinical and pathological selection criteria, identified 96 with HGSC that represented significant outliers in terms of treatment response and overall survival. Patient samples were characterized immunohistochemically and by genome sequencing.Results: Different patterns of clinical response were seen: long progression-free survival (Long-PFS), multiple objective responses to chemotherapy (Multiple Responder), and/or greater than 10-year overall survival (Long-Term Survivors). Pathogenic germline and somatic mutations in genes involved in homologous recombination (HR) repair were enriched in all three groups relative to a population-based series. However, 29% of 10-year survivors lacked an identifiable HR pathway alteration, and tumors from these patients had increased Ki-67 staining. CD8+ tumor-infiltrating lymphocytes were more commonly present in Long-Term Survivors. RB1 loss was associated with long progression-free and overall survival. HR deficiency and RB1 loss were correlated, and co-occurrence was significantly associated with prolonged survival.Conclusions: There was diversity in the clinical trajectory of exceptional survivors associated with multiple molecular determinants of exceptional outcome in HGSC patients. Concurrent HR deficiency and RB1 loss were associated with favorable outcomes, suggesting that co-occurrence of specific mutations might mediate durable responses in such patients. Clin Cancer Res; 24(3); 569-80. ©2017 AACRSee related commentary by Peng and Mills, p. 508.


Assuntos
Cistadenocarcinoma Seroso/genética , Cistadenocarcinoma Seroso/mortalidade , Neoplasias Ovarianas/genética , Neoplasias Ovarianas/mortalidade , Reparo de DNA por Recombinação , Proteína do Retinoblastoma/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Biomarcadores Tumorais , Cistadenocarcinoma Seroso/diagnóstico , Feminino , Recombinação Homóloga , Humanos , Pessoa de Meia-Idade , Mutação , Gradação de Tumores , Estadiamento de Neoplasias , Neoplasias Ovarianas/diagnóstico , Neoplasias Ovarianas/metabolismo , Prognóstico , Proteína do Retinoblastoma/metabolismo , Transdução de Sinais , Análise de Sobrevida , Avaliação de Sintomas
2.
Electrophoresis ; 36(15): 1768-74, 2015 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-25959308

RESUMO

Forensic human identification (HID) is currently based on determining repeat length polymorphisms located in short tandem repeat regions in the human genome. Despite the great progress made in the area of multiplex PCR-based approaches, limitations associated with challenging forensic samples such as DNA degradation, cooccurrence of inhabited microbial DNA and PCR inhibitors significantly affect the success rate of human DNA profiling. We have developed a sequence-specific pre-PCR STR enrichment method and evaluated its efficacy using DNA samples doped with various contaminants in view of its application on compromised forensic samples. This strategy has enabled us to generate complete and reproducible DNA profiles from samples doped with fivefold excess of nonhuman DNA and three to fourfold excess of various potent PCR inhibitors than that is claimed to be tolerated by some of the widely used commercial multiplex STR kits, from as little as two nanograms of degraded human DNA. The "hybrid capture"-based STR enrichment strategy described in this study is easily adaptable and offers a sensitive, efficient, and economical approach for successful human DNA profiling from compromised and recalcitrant forensic samples that are usually encountered in mass disaster incidents and missing persons' identifications.


Assuntos
Genética Forense/métodos , Repetições de Microssatélites/genética , Técnicas de Amplificação de Ácido Nucleico/métodos , Humanos , Reprodutibilidade dos Testes
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