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Cancer genome sequencing studies have identified numerous driver genes, but the relative timing of mutations in carcinogenesis remains unclear. The gradual progression from premalignant Barrett's esophagus to esophageal adenocarcinoma (EAC) provides an ideal model to study the ordering of somatic mutations. We identified recurrently mutated genes and assessed clonal structure using whole-genome sequencing and amplicon resequencing of 112 EACs. We next screened a cohort of 109 biopsies from 2 key transition points in the development of malignancy: benign metaplastic never-dysplastic Barrett's esophagus (NDBE; n = 66) and high-grade dysplasia (HGD; n = 43). Unexpectedly, the majority of recurrently mutated genes in EAC were also mutated in NDBE. Only TP53 and SMAD4 mutations occurred in a stage-specific manner, confined to HGD and EAC, respectively. Finally, we applied this knowledge to identify high-risk Barrett's esophagus in a new non-endoscopic test. In conclusion, mutations in EAC driver genes generally occur exceptionally early in disease development with profound implications for diagnostic and therapeutic strategies. [ABSTRACT FROM AUTHOR]

Gericke and Hagberg (G & H, Sci Educ 16:849–881, 2007) recently published in this journal a thoughtful analysis of the historical progression of our understanding of the nature of the gene for use in instruction. This analysis, however, did not include the findings of the Human Genome Project (HGP), which must be included in any introductory genetics in the modern genomic era today. Many of these findings, especially the limited number of genes and the similarity of this number to that of primitive animals such as roundworms, were surprising and led to questions about the definition of the gene, many of which are addressed in this manuscript. The G & H models are also amended to include crucial concepts, including the history of determining that DNA and not protein is the molecule of inheritance, the work of Barbara McClintock and the discovery of transposons, polygenic/multi-factorial inheritance, and reverse transcription. The following discussion further extends the G & H work to include the more recent work of the ENCyclopedia Of DNA Elements (ENCODE) Project. The results of this work have resulted in even more fundamental questions about the gene. For example, large sections of the genome that were previously identified as non-protein-coding ‘junk’ have been shown to be transcribed into RNA that is likely involved in regulation of genome function that might be more crucial than the coding DNA itself in distinguishing simpler from more complex species. Should these transcribed but not translated sequences be recognized as genes? This level of questioning of our basic definition has not occurred since the modern synthesis of genetics based on the work of Watson and Crick and makes this one of the most exciting times for genetics and medicine. [ABSTRACT FROM AUTHOR]