Ole. In a developing cancer, these genetically*Correspondence: [email protected].

Ole. In a developing cancer, these genetically*Correspondence: [email protected]; Phone: (206) 543-0556; Fax (206) 543-3967. Conflict of interest The authors declare that there are no conflicts of interest. Publisher’s Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.Salk and HorwitzPagehardwired antineoplastic defense mechanisms are systematically mutated away until tumor cells gain the ability to proliferate indefinitely.NIH-PA Author Manuscript NIH-PA Author Manuscript NIH-PA Author ManuscriptMutation leading to T0901317MedChemExpress T0901317 selectable genetic diversity is at the heart of the evolutionary process. Just how this diversity arises in cancer remains uncertain, but recent cancer genome sequencing studies have indicated that tumors contain tens of thousands of mutations [6]. Methods by which healthy tissues suppress the accumulation of genetic errors include: maintaining a very low per-cell-division rate of mutation, minimizing the number of cell divisions that occur in long-lived stem cells, purging of mutated cells through programmed cell death and immune surveillance, and use of a hierarchical structure of cell division whereby most cells become terminally differentiated into non-reproducing entities without the ability to propagate further errors [7]. A long-standing controversy has existed over the question of which, if any, of these mechanisms must be disrupted to allow sufficient diversity to accumulate for a cancer to evolve [1,8?1]. Other articles in this issue consider the evidence for and against a mutator phenotype in cancer. In this review we assume a neutral position on this complex issue and instead focus on ways by which the mutations that do arise can be used to identify the HS-173 custom synthesis signature of clonal evolution. We discuss how heritable genetic changes of many varieties can serve as markers of cell lineages to track the emergence of new clones as an empirical metric of dysregulated cell growth for the purpose of early diagnosis of cancer.2. Field cancerization: early clonal evolutionThe term “field cancerization” first appeared in a 1953 publication by Slaughter et al [12] wherein it was observed that a field of subtly abnormal epithelium commonly surrounds oral cancers and that multiple distinct tumors often co-occur within these zones. They noted: “this pattern of distribution is of interest because it suggests a regional carcinogenic activity of some kind, in which a preconditioned epithelium has been activated over an area in which multiple cell groups undergo a process of irreversible change towards cancer” The authors reported that such fields routinely extended beyond the margins of the surgical resections they examined and posited that this fact might explain the high local recurrence rate of oral cancers following surgery. No biochemical explanation was offered to explain the fields, simply thoughtful phenomenological observations. In the decades since, oral cancer-associated fields have been characterized through molecular means and found to frequently possess a subset of the genetic and epigenetic a.Ole. In a developing cancer, these genetically*Correspondence: [email protected]; Phone: (206) 543-0556; Fax (206) 543-3967. Conflict of interest The authors declare that there are no conflicts of interest. Publisher’s Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.Salk and HorwitzPagehardwired antineoplastic defense mechanisms are systematically mutated away until tumor cells gain the ability to proliferate indefinitely.NIH-PA Author Manuscript NIH-PA Author Manuscript NIH-PA Author ManuscriptMutation leading to selectable genetic diversity is at the heart of the evolutionary process. Just how this diversity arises in cancer remains uncertain, but recent cancer genome sequencing studies have indicated that tumors contain tens of thousands of mutations [6]. Methods by which healthy tissues suppress the accumulation of genetic errors include: maintaining a very low per-cell-division rate of mutation, minimizing the number of cell divisions that occur in long-lived stem cells, purging of mutated cells through programmed cell death and immune surveillance, and use of a hierarchical structure of cell division whereby most cells become terminally differentiated into non-reproducing entities without the ability to propagate further errors [7]. A long-standing controversy has existed over the question of which, if any, of these mechanisms must be disrupted to allow sufficient diversity to accumulate for a cancer to evolve [1,8?1]. Other articles in this issue consider the evidence for and against a mutator phenotype in cancer. In this review we assume a neutral position on this complex issue and instead focus on ways by which the mutations that do arise can be used to identify the signature of clonal evolution. We discuss how heritable genetic changes of many varieties can serve as markers of cell lineages to track the emergence of new clones as an empirical metric of dysregulated cell growth for the purpose of early diagnosis of cancer.2. Field cancerization: early clonal evolutionThe term “field cancerization” first appeared in a 1953 publication by Slaughter et al [12] wherein it was observed that a field of subtly abnormal epithelium commonly surrounds oral cancers and that multiple distinct tumors often co-occur within these zones. They noted: “this pattern of distribution is of interest because it suggests a regional carcinogenic activity of some kind, in which a preconditioned epithelium has been activated over an area in which multiple cell groups undergo a process of irreversible change towards cancer” The authors reported that such fields routinely extended beyond the margins of the surgical resections they examined and posited that this fact might explain the high local recurrence rate of oral cancers following surgery. No biochemical explanation was offered to explain the fields, simply thoughtful phenomenological observations. In the decades since, oral cancer-associated fields have been characterized through molecular means and found to frequently possess a subset of the genetic and epigenetic a.