Schlagwort: Mutation
A global assessment of cancer genomic alterations in epigenetic mechanisms
Muhammad A Shah, Emily L Denton, Cheryl H Arrowsmith, Mathieu Lupien and Matthieu Schapira
Abstract
Background
The notion that epigenetic mechanisms may be central to cancer initiation and progression is supported by recent next-generation sequencing efforts revealing that genes involved in chromatin-mediated signaling are recurrently mutated in cancer patients.
Results
Here, we analyze mutational and transcriptional profiles from TCGA and the ICGC across a collection 441 chromatin factors and histones. Chromatin factors essential for rapid replication are frequently overexpressed, and those that maintain genome stability frequently mutated. We identify novel mutation hotspots such as K36M in histone H3.1, and uncover a general trend in which transcriptional profiles and somatic mutations in tumor samples favor increased transcriptionally repressive histone methylation, and defective chromatin remodeling.
Conclusions
This unbiased approach confirms previously published data, uncovers novel cancer-associated aberrations targeting epigenetic mechanisms, and justifies continued monitoring of chromatin-related alterations as a class, as more cancer types and distinct cancer stages are represented in cancer genomics data repositories.
Continue reading „A global assessment of cancer genomic alterations in epigenetic mechanisms“ →
A Mitochondrial Paradigm of Metabolic and Degenerative Diseases, Aging, and Cancer: A Dawn for Evolutionary Medicine
Progressive increase in mtDNA 3243A>G heteroplasmy causes abrupt transcriptional reprogramming
Wallace hypothesized mitochondrial dysfunction as a central role in a wide range of age-related disorders and various forms of cancer. Steadily rising increases in mitochondrial DNA mutations cause abrupt shifts in diseases. Discrete changes in nuclear gene expression in response to small increases in DNA mutant level are analogous to the phase shifts that is well known in physics: As heat is added, the ice abruptly turns to water or with more heat abruptly to steam. Therefore, a quantitative change that is an increasing proportion of mitochondrial DNA mutation results in a qualitative change which coordinate changes in nuclear gene expression together with discrete changes in clinical symptoms.
Variation in cancer risk among tissues can be explained by the number of stem cell divisions
Tomasetti and Vogelstein show that the lifetime risk of cancers of many different types is strongly correlated with the total number of divisions of the normal self-renewing cells maintaining that tissue’s homeostasis. These results suggest that only a third of the variation in cancer risk among tissues is attributable to environmental factors or inherited predispositions. The majority is due to bad luck, that is, random mutations arising during DNA replication in normal, noncancerous stem cells.