Newborns and do not portend malignancy for the overwhelming number of

Newborns and do not portend malignancy for the overwhelming number of individuals in whom they are present [124]. Correlating the detection of clones under different circumstances with future outcomes is essential for determining clinical relevance.Semin Cancer Biol. Author manuscript; available in PMC 2011 October 15.NIH-PA Author NIK333 chemical information Manuscript NIH-PA Author Manuscript NIH-PA Author ManuscriptSalk and HorwitzPage10. Conclusions and future directionsMost adult cancers appear to develop over a period of years, but exist for the majority of this time as clinically unrecognizable entities [125]. While tumorigenesis is strongly associated with age, environmental exposures and certain predisposing conditions, many unknown factors and randomly occurring replication errors contribute to the unpredictable clinical emergence of the disease. The underlying process of clonal evolution, itself, leaves a molecular signature in the genome of neoplastically transforming cell populations with the potential to be identified prior to the appearance of overt malignancy. In this article we have reviewed different techniques for using neutral passenger mutations as lineage markers of preneoplastic clones and discussed important considerations for, and limitations of, their use. While the presence of certain driver mutations is of unquestionable clinical utility for partially predicting cancer risk in some predisposing conditions, passenger-based analysis has the benefit of identifying anomalous clonal proliferation in a mechanism-independent manner which remains operative in scenarios were growth results from unknown molecular drivers. Clinically, the mutational signature of evolving clones offers a means of precisely defining the margins of a disease process so that affected tissues may best be treated, resected or monitored for recurrence. With sufficient mutational information it should be possible, not only to detect neoclones, but to characterize their specific features such as size [126], spatial arrangement [23,127], diversity among foci [65,116] and lineage age [60,107,128], all of which are important metrics of evolution and evolvability in traditional ecological populations. Powerful new tools for genetic analysis are rapidly making their way into the mainstream and promise to significantly alter the way in which cancer is diagnosed and managed over the next decade. The unprecedented amount of data generated by these technologies will soon afford complete access to the vast amount of somatic evolutionary history encrypted in the genome of early neoplasia, leaving only the daunting task of meaningfully deciphering it. Early detection has historically been among the most effective means of preventing cancer deaths [129] and we hope that the concepts and past Chloroquine (diphosphate) chemical information approaches discussed herein will help stimulate creative thinking about ways in which this wealth of information can be translated to a new generation of clinical diagnostics.NIH-PA Author Manuscript NIH-PA Author Manuscript NIH-PA Author ManuscriptAcknowledgmentsJJS was supported by NIH grant F30AG033485 and the University of Washington Medical Scientist Training Program under NIH grant T32GM007266. MSH was supported by NIH grants R01DK078340 and DP1OD003278.AbbreviationsCGH COX1 FISH G6PD HUMARA LOH mtDNA PCR comparative genomic hybridization cytochrome c oxidase gene fluorescent in situ hybridization glucose-6-phosphate dehydrogenase gene human androgen receptor gene loss-of-heterozygosity mitoc.Newborns and do not portend malignancy for the overwhelming number of individuals in whom they are present [124]. Correlating the detection of clones under different circumstances with future outcomes is essential for determining clinical relevance.Semin Cancer Biol. Author manuscript; available in PMC 2011 October 15.NIH-PA Author Manuscript NIH-PA Author Manuscript NIH-PA Author ManuscriptSalk and HorwitzPage10. Conclusions and future directionsMost adult cancers appear to develop over a period of years, but exist for the majority of this time as clinically unrecognizable entities [125]. While tumorigenesis is strongly associated with age, environmental exposures and certain predisposing conditions, many unknown factors and randomly occurring replication errors contribute to the unpredictable clinical emergence of the disease. The underlying process of clonal evolution, itself, leaves a molecular signature in the genome of neoplastically transforming cell populations with the potential to be identified prior to the appearance of overt malignancy. In this article we have reviewed different techniques for using neutral passenger mutations as lineage markers of preneoplastic clones and discussed important considerations for, and limitations of, their use. While the presence of certain driver mutations is of unquestionable clinical utility for partially predicting cancer risk in some predisposing conditions, passenger-based analysis has the benefit of identifying anomalous clonal proliferation in a mechanism-independent manner which remains operative in scenarios were growth results from unknown molecular drivers. Clinically, the mutational signature of evolving clones offers a means of precisely defining the margins of a disease process so that affected tissues may best be treated, resected or monitored for recurrence. With sufficient mutational information it should be possible, not only to detect neoclones, but to characterize their specific features such as size [126], spatial arrangement [23,127], diversity among foci [65,116] and lineage age [60,107,128], all of which are important metrics of evolution and evolvability in traditional ecological populations. Powerful new tools for genetic analysis are rapidly making their way into the mainstream and promise to significantly alter the way in which cancer is diagnosed and managed over the next decade. The unprecedented amount of data generated by these technologies will soon afford complete access to the vast amount of somatic evolutionary history encrypted in the genome of early neoplasia, leaving only the daunting task of meaningfully deciphering it. Early detection has historically been among the most effective means of preventing cancer deaths [129] and we hope that the concepts and past approaches discussed herein will help stimulate creative thinking about ways in which this wealth of information can be translated to a new generation of clinical diagnostics.NIH-PA Author Manuscript NIH-PA Author Manuscript NIH-PA Author ManuscriptAcknowledgmentsJJS was supported by NIH grant F30AG033485 and the University of Washington Medical Scientist Training Program under NIH grant T32GM007266. MSH was supported by NIH grants R01DK078340 and DP1OD003278.AbbreviationsCGH COX1 FISH G6PD HUMARA LOH mtDNA PCR comparative genomic hybridization cytochrome c oxidase gene fluorescent in situ hybridization glucose-6-phosphate dehydrogenase gene human androgen receptor gene loss-of-heterozygosity mitoc.