Mutator Suppression and Escape from Replication Error–Induced Extinction in Yeast

Cells rely on a network of conserved pathways to govern DNA replication fidelity. Loss of polymerase proofreading or mismatch repair elevates spontaneous mutation and facilitates cellular adaptation. However, double mutants are inviable, suggesting that extreme mutation rates exceed an error threshold. Here we combine alleles that affect DNA polymerase δ (Pol δ) proofreading and mismatch repair to define the maximal error rate in haploid yeast and to characterize genetic suppressors of mutator phenotypes. We show that populations tolerate mutation rates 1,000-fold above wild-type levels but collapse when the rate exceeds 10−3 inactivating mutations per gene per cell division. Variants that escape this error-induced extinction (eex) rapidly emerge from mutator clones. One-third of the escape mutants result from second-site changes in Pol δ that suppress the proofreading-deficient phenotype, while two-thirds are extragenic. The structural locations of the Pol δ changes suggest multiple antimutator mechanisms. Our studies reveal the transient nature of eukaryotic mutators and show that mutator phenotypes are readily suppressed by genetic adaptation. This has implications for the role of mutator phenotypes in cancer

Fatores clínicos e anatomopatológicos que influenciam a sobrevida de pacientes com câncer de mama e derrame pleural neoplásico Clinical and pathological factors influencing the survival of breast cancer patients with malignant pleural effusion

OBJETIVO: O objetivo deste estudo foi identificar os fatores clínicos e anatomopatológicos que possam influenciar o prognóstico de pacientes com câncer de mama e sintomas clínicos de derrame pleural neoplásico. MÉTODOS: Trata-se de um estudo clínico de coorte, no qual foram analisados os prontuários médicos de pacientes que receberam diagnóstico de derrame pleural neoplásico entre 2006 e 2010. Por meio da análise dos prontuários, identificamos as pacientes com história de câncer de mama. Para essas pacientes, coletamos dados anatomopatológicos relacionados ao tumor primário e dados citopatológicos relacionados à metástase pleural. RESULTADOS: Das 145 pacientes avaliadas, 87 (60%) apresentaram, no exame citológico, resultado positivo para células neoplásicas no líquido pleural; além disso, 119 (82%) apresentaram tipo histológico ductal. O fenótipo triplo-negativo foi observado em 25 pacientes (17%), as quais apresentaram o pior prognóstico, com queda acentuada na curva de sobrevida. Das 25 pacientes, 20 (80%) evoluíram a óbito durante o período de seguimento (até junho de 2011). A sobrevida média após a identificação de derrame pleural neoplásico foi de 6 meses. CONCLUSÕES: Em pacientes com câncer de mama triplo-negativo e exame citológico com resultado positivo para células neoplásicas no líquido pleural, o prognóstico é ruim e a sobrevida é menor.<br>OBJECTIVE: The objective of this study was to identify the clinical and pathological factors that can influence the prognosis of breast cancer patients with clinical symptoms of malignant pleural effusion. METHODS: This was a clinical cohort study, in which we analyzed the medical charts of patients diagnosed with malignant pleural effusion between 2006 and 2010. By examining the charts, we identified the female patients with a history of breast cancer. For those patients, we collected pathology data related to the primary tumor and cytopathology data related to the pleural metastasis. RESULTS: We evaluated 145 patients, 87 (60%) of whom had tested positive for malignant cells in the pleural fluid. Ductal histology was observed in 119 (82%). The triple-negative breast cancer phenotype was seen in 25 cases (17%). Those patients had the worst prognosis (with a sharp decline in the survival curve), and 20 of the 25 (80%) died during the follow-up period (through June of 2011). The mean survival after the identification of malignant pleural effusion was 6 months. CONCLUSIONS: In patients with triple-negative breast cancer who test positive for malignant cells in the pleural fluid, the prognosis is poor and survival is reduced