RESUMO
INTRODUCTION: Individuals carrying pathogenic mutations in the BRCA1 and BRCA2 genes have a high lifetime risk of breast cancer. BRCA1 and BRCA2 are involved in DNA double-strand break repair, DNA alterations that can be caused by exposure to reactive oxygen species, a main source of which are mitochondria. Mitochondrial genome variations affect electron transport chain efficiency and reactive oxygen species production. Individuals with different mitochondrial haplogroups differ in their metabolism and sensitivity to oxidative stress. Variability in mitochondrial genetic background can alter reactive oxygen species production, leading to cancer risk. In the present study, we tested the hypothesis that mitochondrial haplogroups modify breast cancer risk in BRCA1/2 mutation carriers. METHODS: We genotyped 22,214 (11,421 affected, 10,793 unaffected) mutation carriers belonging to the Consortium of Investigators of Modifiers of BRCA1/2 for 129 mitochondrial polymorphisms using the iCOGS array. Haplogroup inference and association detection were performed using a phylogenetic approach. ALTree was applied to explore the reference mitochondrial evolutionary tree and detect subclades enriched in affected or unaffected individuals. RESULTS: We discovered that subclade T1a1 was depleted in affected BRCA2 mutation carriers compared with the rest of clade T (hazard ratio (HR) = 0.55; 95% confidence interval (CI), 0.34 to 0.88; P = 0.01). Compared with the most frequent haplogroup in the general population (that is, H and T clades), the T1a1 haplogroup has a HR of 0.62 (95% CI, 0.40 to 0.95; P = 0.03). We also identified three potential susceptibility loci, including G13708A/rs28359178, which has demonstrated an inverse association with familial breast cancer risk. CONCLUSIONS: This study illustrates how original approaches such as the phylogeny-based method we used can empower classical molecular epidemiological studies aimed at identifying association or risk modification effects.
Assuntos
Neoplasias da Mama/genética , Genes BRCA2 , Genes Mitocondriais , Heterozigoto , Mutação , Proteína BRCA1/genética , Feminino , Predisposição Genética para Doença , Haplótipos , Humanos , Filogenia , RiscoRESUMO
BACKGROUND: Capecitabine is an orally administered fluoropyrimidine that is converted to 5-fluorouracil by thymidine phosphorylase. In view of the recognized synergism of fluoropyrimidines with interferon-alpha (IFNalpha), a Phase II study to characterize the toxicity and efficacy of the combination of capecitabine and rHuIFNalpha-2a for the treatment of patients with renal cell carcinoma (RCC) was conducted. PATIENTS AND METHODS: Eligible patients had metastatic RCC, measurable disease, and no prior systemic therapy. A total of 32 patients were entered into the study. Histologic subtypes included clear cell (n = 28) and nonclear cell (n = 2). Histology was unknown for 2 patients. The first 14 patients were treated with capecitabine 1,000 mg/m(2) twice daily on days 1-14 and 22-36, combined with IFNalpha-2a 3.0 MU/m(2) subcutaneously 3 times weekly. Because of toxicity requiring dose reductions during the first cycle, the capecitabine dose was reduced to 825 mg/m(2) twice daily on days 1-14 and 22-36 in the subsequent 18 patients. RESULTS: Responses were seen in 4 of 32 patients (12%) (95% confidence interval 4% to 29%), with 1 complete response and 3 partial responses. There were 3 responses that occurred at the higher capecitabine starting dose level. Median response duration was 12 months (range 4.6-15.0). There were 12 patients (38%) who had stable disease for at least 2 cycles (duration 2.9 to 33.6+ months). One-year survival was 63%. Toxicity was moderate to severe and required dose reductions in 88% of patients. There were 23 patients who had grade > or =3 toxicity. CONCLUSION: The combination of capecitabine and IFNalpha-2a has limited activity in metastatic RCC and is associated with moderate-to-severe toxicity.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Carcinoma de Células Renais/tratamento farmacológico , Desoxicitidina/análogos & derivados , Fluoruracila/análogos & derivados , Interferon-alfa/administração & dosagem , Neoplasias Renais/tratamento farmacológico , Adulto , Idoso , Idoso de 80 Anos ou mais , Capecitabina , Carcinoma de Células Renais/mortalidade , Desoxicitidina/administração & dosagem , Desoxicitidina/efeitos adversos , Feminino , Fluoruracila/administração & dosagem , Fluoruracila/efeitos adversos , Humanos , Interferon alfa-2 , Interferon-alfa/efeitos adversos , Neoplasias Renais/mortalidade , Masculino , Pessoa de Meia-Idade , Proteínas RecombinantesRESUMO
Toxic chemotherapeutic agents are slowly being supplemented by a new generation of drugs that recognize specific targets in or on cancer cells. Although these molecular and genetic approaches are in their infancy, they hold the promise of more effective therapies with markedly fewer side effects. Several targeted agents are already approved by the US Food and Drug Administration (FDA) for use in malignancies, and numerous others are in clinical trials.