Ubiquitous somatic mutations in simple repeated sequences reveal a new mechanism for colonic carcinogenesis

  title={Ubiquitous somatic mutations in simple repeated sequences reveal a new mechanism for colonic carcinogenesis},
  author={Yurij Ionov and Mar{\'i}a Angeles Peinado and Sergei R. Malkhosyan and Darryl Shibata and Manuel Perucho},
SPONTANEOUS errors in DNA replication have been suggested to play a significant role in neoplastic transformation and to explain the chromosomal alterations seen in cancer cells1. A defective replication factor could increase the mutation rate in clonal variants arising during tumour progression, but despite intensive efforts, increases in tumour cell mutation rates have not been unambiguously shown2. Here we use an unbiased genomic fingerprinting technique3 to show that 12 per cent of… 
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In vivo and in vitro results show that the genomic instability persists after transformation and that microsatellite mutations accumulate as consecutive somatic slippage events of a single or a few repeated units.
Genomic Instability and Carcinogenesis: An Update
This review gives an update of the latest data on the relevance of genomic instability to the pathogenesis of colorectal carcinoma particularly its hereditary and familial subsets as well as mathematical modelling.
Elevated frequency of microsatellite mutations in TK6 human lymphoblast clones selected for mutations at the thymidine kinase locus
Evidence is provided that a global trans-acting mutagenic process exists in human cells and the activation of this process could be responsible for causing multiple essential mutations in tumor cells.
Defects in mismatch repair occur after APC mutations in the pathogenesis of sporadic colorectal tumours
It is likely that in sporadic colon tumours, APC mutations, rather than genomic instability, are the initiating events in tumorigenesis, and there is no evidence that sporadic RER+ and RER‐ colon cancers (including cell lines) differ in any of these three ways.
Extensive characterization of genetic alterations in a series of human colorectal cancer cell lines
There are significant correlations between mutational profiles in these colorectal cell lines associated with differences in mismatch repair status and these results may prove to be very useful for understanding the different biological pathways involved in the development of colon cancer, and for groups studying cellular biology and pharmacology on the same cell lines.
Differential rates of frameshift alterations in four repeat sequences of hereditary nonpolyposis colorectal cancer tumors
The methodology can contribute to define tumor characteristics and may, if applied to genes strongly involved in tumorigenesis, improve tumor classification and outcome prediction.
Mutations and epimutations in the origin of cancer.
Human cancers express a mutator phenotype
Measurements of random single-nucleotide substitutions in normal and neoplastic human tissues indicate that accelerated mutagenesis prevails late into tumor progression, and suggest that elevation of random mutation frequency in tumors might serve as a novel prognostic indicator.
Mutations associated with microsatellite unstable colorectal carcinomas exhibit widespread intratumoral heterogeneity
It seems likely that a random accumulation of mutations, as a result of a defect in the mismatch repair pathway, drives tumour progression in this type of colorectal carcinoma.


Isolation and characterization of allelic losses and gains in colorectal tumors by arbitrarily primed polymerase chain reaction.
The ability of the AP-PCR to detect and isolate DNA sequences representing two of the genetic alterations that underlie the aneuploidy of cancer cells: losses of heterozygosity and chromosomal gains provides the basis for an alternative molecular approach to cancer cytogenetics.
Errors in DNA replication as a basis of malignant changes.
A hypothesis is presented that relates mistakes in DNA replication, as promoted by error-prone DNA polymerases, to tumor progression and both of these hypotheses are open to immediate experimental analysis.
The c-K-ras gene and human cancer (review).
Findings support the hypothesis that c-K-ras oncogenes are contributing in a dominant but dose dependent manner to the multistage process of human tumorigenesis.
Telomeres shorten during ageing of human fibroblasts
The amount and length of telomeric DNA in human fibroblasts does in fact decrease as a function of serial passage during ageing in vitro and possibly in vivo.
Mutagenesis by transient misalignment.
DNA polymorphisms amplified by arbitrary primers are useful as genetic markers.
A new DNA polymorphism assay based on the amplification of random DNA segments with single primers of arbitrary nucleotide sequence is described, suggesting that these polymorphisms be called RAPD markers, after Random Amplified Polymorphic DNA.