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ABSTRACT Rapid evolution of fungal pathogens poses a serious threat to medicine and agriculture. The mutation rate determines the pace of evolution of a fungal pathogen. Hypermutator fungal strains have an elevated mutation rate owing to certain defects such as those in the DNA mismatch repair system. Studies in Saccharomyces cerevisiae show that hypermutators expedite evolution by generating beneficial alleles at a faster pace than the wild-type strains. However, an accumulation of deleterious alleles in a hypermutator may reduce its fitness. The balance between fitness cost and mutation benefit determines the prevalence of hypermutators in a population. This balance is affected by a complex interaction of ploidy, mode of reproduction, population size, and recent population history. Studies in human fungal pathogens like Aspergillus fumigatus, Candida albicans, Candida glabrata, Cryptococcus deuterogattii, and Cryptococcus neoformans have highlighted the importance of hypermutators in host adaptation and development of antifungal resistance. However, a critical examination of hypermutator biology, experimental evolution studies, and epidemiological studies suggests that hypermutators may impact evolutionary investigations. This review aims to integrate the knowledge about biology, experimental evolution, and dynamics of fungal hypermutators to critically examine the evolutionary role of hypermutators in fungal pathogen populations and project implications of hypermutators in the evolution of fungal plant pathogen populations. Understanding the factors determining the emergence and evolution of fungal hypermutators can open a novel avenue of managing rapidly evolving fungal pathogens in medicine and agriculture.

The dynamics of morbidity and mortality in colorectal cancer (CRC) has changed little in recent years and consistently remains at a high level. The carcinogenesis of this type of tumors includes a large number of genetic disorders and epigenetic changes, which show a number of features specific for this nosology, providing the basis for the first consensus classification of molecular subtypes for colorectal cancer. One of the main mechanisms chosen as crucial for this classification is the microsatellite instability (MSI) caused by defects in the DNA Mismatch Repair System (MMR).///The clinical significance of this CRC molecular profile parameter is hard to overestimate. Over the past three decades, the MSI and MMR have been actively studied for prognosis evaluation, determination of need and selection of appropriate adjuvant chemotherapy scheme for CRC. Despite the significant accumulation of clinical and experimental study data, currently the prognostic value of this parameter is still not well defined with reference to CRC adjuvant treatment strategies, and the released data remain controversial.///The purpose of this analytic review is to analyze the current status of MSI and MMR in the setting of adjuvant treatment of CRC patients from a perspective of evidence-based medicine. [ABSTRACT FROM AUTHOR]

Frequent mutations of coding nucleotide repeats are thought to contribute significantly to carcinogenesis associated with microsatellite instability (MSI). We have shown that shortening of the poly(T)11 within the polypyrimidine stretch/accessory splicing signal of human MRE11 leads to the reduced expression and functional impairment of the MRE11/NBS1/RAD50 complex. This mutation was selectively found in mismatch repair (MMR) defective cell lines and potentially identifies MRE11 as a novel target for MSI. Here, we examined 70 microsatellite unstable primary human cancers and we report that MRE11 mutations occur in 83.7 and 50% of the colorectal and endometrial cancers, respectively. In the colorectal cancer series, mutated MRE11 is more frequently associated with advanced age at diagnosis and A/B stages. Biallelic mutations were present in 38.8% of the cases and more frequently associated with lower (G1/G2) grade tumors. Impaired MRE11 expression was prevalent in primary colorectal tumors with larger and biallelic shortening of the poly(T)11. Immunohistochemistry confirmed the impaired MRE11 expression and revealed NBS1-defective expression in MRE11 mutated cancers. Together with the observation that perturbation of the MRE11/NBS1/RAD50 complex predisposes to cancer, our work highlights MRE11 as a new common target in the MMR deficient tumorigenesis and suggests its role in colorectal carcinogenesis.Oncogene (2004) 23, 2640-2647. doi:10.1038/sj.onc.1207409 Published online 29 March 2004 [ABSTRACT FROM AUTHOR]