Nucleosome sensitivity distinguishes colon polyps based on their transformation status

Abstract

ABSTRACTOne of the keys to eliminating the personal and financial costs of cancer lies in the early detection of the disease. Consequently, effective cancer interventions increasingly rely on our understanding of the earliest cellular and nuclear events that lead to oncogenic transformation. Colorectal cancer, the third most prevalent cancer in the United States, results from the transformation of polyps. Our group demonstrated that the alteration of chromatin organization is a pivotal event in this oncogenic transformation. Here, we analyze the differences of the nucleosomal sensitivity to mocroccocal nuclease (MNase) between histopathologically matched pre-cancerous polyps taken from patients that did not develop cancer (cancer-free polyps, CFP) and those that did develop cancer (cancer-associated polyps, CAP). We produced high-resolution nucleosome distribution and nucleosome sensitivity maps from each of the five CFP patient samples and three CAP patient samples. We show that nucleosome distribution is largely invariant between CFP and CAP samples. Nucleosome sensitivity, however, is a powerful analysis that can identify genomic locations that distinguish CFP from CAP. We have identified more than 1000 genomic locations with altered nucleosomal sensitivity that discriminate between CAP and CFP. Furthermore, we show that these genomic locations with altered nucleosomal sensitivity between CFP and CAP include genes that play critical roles in oncogenic transformation. We propose that nucleosome sensitivity serves as a robust biomarker indicating the oncogenic potential of precancerous polyps and could be used for the early detection of polyps that will become cancerous.