520 research outputs found
MED12 exon 2 mutations are common in uterine leiomyomas from South African patients
Uterine leiomyomas, or fibroids, are extremely common tumors. Regardless of their benign nature, fibroids can cause considerable morbidity. Women with African ancestry have a threefold increased risk of developing uterine leiomyomas with a greater symptom severity when compared to white women. Recently, we demonstrated that exon 2 of the MED12 gene is somatically altered in up to 70 per cent of uterine leiomyomas in a series of Finnish (Caucasian) patients. To validate these results in other populations, we sequenced a set of 28 uterine leiomyomas for MED12 exon 2 mutations from 18 different Black African or Coloured South African patients. We observed 14 mutation positive lesions (50%). When corrected by tumor size, these results are very similar to those derived in the Finnish material. This study confirms a major role of MED12 in the genesis of leiomyomas, regardless of ethnicity
Loss of expression of ATM is associated with worse prognosis in colorectal cancer and loss of Ku70 expression is associated with CIN
Repair of double strand DNA breaks (DSBs) is pivotal in maintaining normal
cell division and disruption of this system has been shown to be a key factor in
carcinogenesis. Loss of expression of the DSB repair proteins have previously been
shown to be associated with poorer survival in colorectal cancer. We wished to
ascertain the relationship of altered expression of the DSB repair proteins γ-H2AX
(gamma-H2AX), ATM and Ku70 with biological and clinico-pathological features
of colorectal cancer. 908 tumours from the VICTOR clinical trial of stage II/III
colorectal cancer were analysed for expression of γ-H2AX, ATM and Ku70 using
immunohistochemistry. Expression levels were correlated with CIN and with diseasefree
survival, correcting for microsatellite instability, BRAF/KRAS mutation status,
Dukes stage, chemo/radiotherapy, age, gender and tumour location. Down-regulated
Ku70 expression was associated with chromosomal instability (p=0.029) in colorectal
cancer. Reduced ATM expression was an independent marker of poor disease-free
survival (HR=1.67, 95% CI 1.11-2.50, p=0.015). For Ku70, further studies are
required to investigate the potential relationship of non-homologous end joining with
chromosomal instability. Loss of ATM expression might serve as a biomarker of poor
prognosis in colorectal cancer
TERC polymorphisms are associated both with susceptibility to colorectal cancer and with longer telomeres.
Shorter telomeres have been associated with increased risk of malignancy, including colorectal cancer (CRC). Telomere length is heritable and may be an intermediate phenotype linked to genetic susceptibility to CRC
Mutations in normal breast tissue and breast tumours
The accumulation of mutations is a feature of all normal cells. The probability of any individual gene in any cell acquiring a mutation is, however, low. Cancer is therefore a rare disease in comparison with the number of susceptible cells. Mutations in normal tissue are stochastic, vary widely among cells and are therefore difficult to detect using standard methods because each change is so rare. If, however, a tissue such as the breast undergoes considerable clonal expansion, particularly if relatively late in life, normal tissue may have accumulated many thousands of detectable mutations. Since breast cancers are clonal and have almost certainly undergone many more cell divisions than normal cells, each tumour may have many millions of mutations, most of which are entirely innocent and some of which have accumulated in the cell of origin prior to tumorigenesis. Despite some claims to the contrary, even at normal mutation rates, clonal expansion within a tumour is quite sufficient to account for the mutations of five or six genes that are generally supposed necessary for carcinogenesis to occur. Hypermutability does, however, contribute to the pathogenesis of many cancers and, although evidence is indirect in breast cancer, may take forms such as karyotypic instability via centrosome amplification
Comprehensive analysis of common mitochondrial DNA variants and colorectal cancer risk.
Several lines of evidence implicate mitochondrial dysfunction in the development of cancer. To test the hypothesis that common mtDNA variation influences the risk of colorectal cancer (CRC), we genotyped 132 tagging mtDNA variants in a sample of 2854 CRC cases and 2822 controls. The variants examined capture approximately 80% of mtDNA common variation (excluding the hypervariable D-loop). We first tested for single marker associations; the strongest association detected was with A5657G (P=0.06). Overall the distribution of association P-values was consistent with a null distribution. Next, we classified individuals into the nine common European haplogroups and compared their distribution in cases and controls. This analysis also provided no evidence of an association between mitochondrial variation and CRC risk. In conclusion, our results provide little evidence that mitochondrial genetic background plays a role in modifying an individual's risk of developing CRC
Flap endonucleases pass 5′-flaps through a flexible arch using a disorder-thread-order mechanism to confer specificity for free 5′-ends
Flap endonucleases (FENs), essential for DNA replication and repair, recognize and remove RNA or DNA 5′-flaps. Related to FEN specificity for substrates with free 5′-ends, but controversial, is the role of the helical arch observed in varying conformations in substrate-free FEN structures. Conflicting models suggest either 5′-flaps thread through the arch, which when structured can only accommodate single-stranded (ss) DNA, or the arch acts as a clamp. Here we show that free 5′-termini are selected using a disorder-thread-order mechanism. Adding short duplexes to 5′-flaps or 3′-streptavidin does not markedly impair the FEN reaction. In contrast, reactions of 5′-streptavidin substrates are drastically slowed. However, when added to premixed FEN and 5′-biotinylated substrate, streptavidin is not inhibitory and complexes persist after challenge with unlabelled competitor substrate, regardless of flap length or the presence of a short duplex. Cross-linked flap duplexes that cannot thread through the structured arch react at modestly reduced rate, ruling out mechanisms involving resolution of secondary structure. Combined results explain how FEN avoids cutting template DNA between Okazaki fragments and link local FEN folding to catalysis and specificity: the arch is disordered when flaps are threaded to confer specificity for free 5′-ends, with subsequent ordering of the arch to catalyze hydrolysis
Evolutionary Games with Affine Fitness Functions: Applications to Cancer
We analyze the dynamics of evolutionary games in which fitness is defined as
an affine function of the expected payoff and a constant contribution. The
resulting inhomogeneous replicator equation has an homogeneous equivalent with
modified payoffs. The affine terms also influence the stochastic dynamics of a
two-strategy Moran model of a finite population. We then apply the affine
fitness function in a model for tumor-normal cell interactions to determine
which are the most successful tumor strategies. In order to analyze the
dynamics of concurrent strategies within a tumor population, we extend the
model to a three-strategy game involving distinct tumor cell types as well as
normal cells. In this model, interaction with normal cells, in combination with
an increased constant fitness, is the most effective way of establishing a
population of tumor cells in normal tissue.Comment: The final publication is available at http://www.springerlink.com,
http://dx.doi.org/10.1007/s13235-011-0029-
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