Bnormalities occurring in the tumor itself [13?5]. Similar mutant fields have been

Bnormalities occurring in the tumor itself [13?5]. Similar mutant fields have been identified surrounding a variety of other cancer types including esophageal [16,17], lung [18,19], bladder [20], breast [21] and colon in the setting of chronic 4-Deoxyuridine chemical information ulcerative colitis [22?24], among others. In many cases, molecularly-definable fields exist in the absence of histological changes. These findings are remarkably in line with Slaughter’s original hypothesis and the currently held evolutionary model of cancer development whereby successive waves of mutation, selection and clonal expansion gradually accrue the genetic changes necessary for malignant transformation. By this model a field is simply an ancestral clone possessing a partial complement of the genotypes and phenotypes of a fully formed cancer. Given that the spread of clonal cell populations over large areas of epithelium appears to be an early part of the developmental pathway of some cancer types, many investigators have asked whether the presence of such clones can be used to predict future tumor development. The most common approach taken for identifying fields has been to screen for molecularSemin Cancer Biol. Author manuscript; available in PMC 2011 October 15.Salk and HorwitzPagechanges commonly found in tumors themselves and thought to drive their growth. This has typically entailed focusing on alterations affecting known proto-oncogenes or tumor suppressors including: point mutations, chromosomal rearrangements, deletions, amplifications, loss-of-heterozygosity events and/or epigenetic modifications. Among the best studied systems have been Barrett’s Esophagus, oral leukoplakia and ulcerative colitis, all Cycloheximide dose highly cancer-predisposing conditions with well-established field intermediates and where tissue is relatively accessible and routinely sampled as part of clinical care. While the cancer-predictive value of mutant fields identified by this method has been remarkably good for some diseases [25], for many others, it has remained limited. One possible explanation derives from the fact that a cancer’s evolution is a stochastic process and the genetic changes driving one tumor will not always be the same as those selected in others [3,26]. Such logic has been substantiated by large-scale sequencing studies of breast and colon cancer exome “landscapes” indicating that, while a handful of genes (“mountains”) are commonly mutated across different tumors, a far greater number are mutated only infrequently (“hills”) [27]. The tactic of screening for mutations in common drivers will, by definition, be unable to detect clonal expansions driven by mutations in unpredicted genes or regulators elsewhere in the genome. Given that it is beyond our current abilities to know of all possible rare drivers, an alternative approach must be taken to identify such clones.NIH-PA Author Manuscript NIH-PA Author Manuscript NIH-PA Author Manuscript3. Identifying clonality through genetic passengersAs cells divide throughout life, irrespective of cancer, mutations are continually introduced into their genomes at low frequency [28]. Most of these land outside of genes or regulatory regions and are likely to be functionally silent (neutral) but serve to indelibly mark each cell with a unique genetic fingerprint. The majority of such mutations will normally be undetectable by routine genotyping techniques because they are present in only one or a few cells whose signal is obscured by the vastly larger number of.Bnormalities occurring in the tumor itself [13?5]. Similar mutant fields have been identified surrounding a variety of other cancer types including esophageal [16,17], lung [18,19], bladder [20], breast [21] and colon in the setting of chronic ulcerative colitis [22?24], among others. In many cases, molecularly-definable fields exist in the absence of histological changes. These findings are remarkably in line with Slaughter’s original hypothesis and the currently held evolutionary model of cancer development whereby successive waves of mutation, selection and clonal expansion gradually accrue the genetic changes necessary for malignant transformation. By this model a field is simply an ancestral clone possessing a partial complement of the genotypes and phenotypes of a fully formed cancer. Given that the spread of clonal cell populations over large areas of epithelium appears to be an early part of the developmental pathway of some cancer types, many investigators have asked whether the presence of such clones can be used to predict future tumor development. The most common approach taken for identifying fields has been to screen for molecularSemin Cancer Biol. Author manuscript; available in PMC 2011 October 15.Salk and HorwitzPagechanges commonly found in tumors themselves and thought to drive their growth. This has typically entailed focusing on alterations affecting known proto-oncogenes or tumor suppressors including: point mutations, chromosomal rearrangements, deletions, amplifications, loss-of-heterozygosity events and/or epigenetic modifications. Among the best studied systems have been Barrett’s Esophagus, oral leukoplakia and ulcerative colitis, all highly cancer-predisposing conditions with well-established field intermediates and where tissue is relatively accessible and routinely sampled as part of clinical care. While the cancer-predictive value of mutant fields identified by this method has been remarkably good for some diseases [25], for many others, it has remained limited. One possible explanation derives from the fact that a cancer’s evolution is a stochastic process and the genetic changes driving one tumor will not always be the same as those selected in others [3,26]. Such logic has been substantiated by large-scale sequencing studies of breast and colon cancer exome “landscapes” indicating that, while a handful of genes (“mountains”) are commonly mutated across different tumors, a far greater number are mutated only infrequently (“hills”) [27]. The tactic of screening for mutations in common drivers will, by definition, be unable to detect clonal expansions driven by mutations in unpredicted genes or regulators elsewhere in the genome. Given that it is beyond our current abilities to know of all possible rare drivers, an alternative approach must be taken to identify such clones.NIH-PA Author Manuscript NIH-PA Author Manuscript NIH-PA Author Manuscript3. Identifying clonality through genetic passengersAs cells divide throughout life, irrespective of cancer, mutations are continually introduced into their genomes at low frequency [28]. Most of these land outside of genes or regulatory regions and are likely to be functionally silent (neutral) but serve to indelibly mark each cell with a unique genetic fingerprint. The majority of such mutations will normally be undetectable by routine genotyping techniques because they are present in only one or a few cells whose signal is obscured by the vastly larger number of.