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A hallmark of cancerous transformation is altered chromosome structure. Inappropriate regulation of chromatin structure inhibits normal cell function, and may represent the origin of transformation. A handful of important studies have indicated that chromatin structure in the human genome is dynamic and regulatory, but the role of chromatin structure in cancer progression has not been addressed. In our initial studies, we have analyzed chromatin structure of patients with different grades and stages of adenocarcinoma as compared to matched normal tissue using microarray-based nucleosome distribution and chromosomal sensitivity assays. We report that low-grade lung adenocarcinoma displays widespread nucleosome alterations compared to matched normal tissue at over half of 886 genes studied, and that these changes are consistent between patients. Additionally, we determined many changes in early colorectal adenocarcinoma, and the alterations are consistent between patients and concordant with the lung adenocarcinoma alterations. Genes with nucleosome distribution changes are enriched for the phosphoinositide 3-kinase (PI3K) cascade, a key oncoregulatory pathway. Together these results suggest an early, shared regulatory mechanism of transformation. We have also measured substantial disruptions in chromosomal sensitivity in a high-grade and high-stage tumor, linking aggressive tumors with high-order nuclear architecture alterations. From this initial study, we have developed a model in which early adenocarcinoma is linked to changes in nucleosome distributions, whereas aggressive tumors are linked to high-order chromosomal changes. This work has laid the foundation for comprehensive studies on the role of chromatin structure in cancer progression. As such, we have developed a new approach to generate ultra high-resolution, genome-wide nucleosome distribution maps at the transcription start site using deep sequencing, which we call mTSS-seq. Building on the published microarray-based nucleosome distribution mapping of select loci in adenocarcinoma patients, we have provided the first measurements of genome-wide nucleosome distribution using mTSS-seq. We have confirmed that nucleosome distribution is an early, widespread transformation event in lung and colon adenocarcinoma. These findings guide a shift in our perspective from chromatin structural alterations as terminal states to transient events of clinical importance. These altered nucleosome architectures are consistent between patients indicating that they may serve as important early adenocarcinoma markers. We present evidence that the nucleosome alterations are driven by and may influence cis and trans acting factors - the underlying DNA sequence and transcription factor binding. Our study reveals at unprecedented breadth and depth that DNA-directed nucleosome redistributions are a widespread feature early in the progression of cancer, which has allowed us to propose a hierarchical model for genome regulation through chromatin structure.