A hallmark of the transformed phenotype is altered chromosomal structure. The development and progression of lung cancer, one of the most common cancers, is driven by the interplay of genetic and epigenetic changes. Although there have been numerous studies on chromosomal aberrations in lung cancer, and cancer in general, broad assessment of chromatin structure information has been understudied, and its role in malignant transformation remains poorly characterized. Cancer progression is classified by tumor grade, which is determined by examining morphological changes that cells undergo as they de-differentiate. Given that chromosomal aberrations are well-documented in nearly all cancers, it is surprising that there is currently no information on the role of chromatin structure in the progression of cancer. We have identified chromatin-based patterns across different lung adenocarcinoma cancer grades.

To address the role of chromatin structure in the progression of cancer, we compared the chromatin structure from primary lung adenocarcinomas of grades one, two and three to their normal adjacent tissue, from multiple individuals, using an innovative microarray strategy. We measured chromatin structure across cancer grades between normal and tumor samples at three levels of resolution: nucleosome distribution, chromatin accessibility and three-dimensional molecular cytology. We used micrococcal nuclease (MNase) as a surrogate for highly diffusible molecules such as transcription factors, mobile elements, replication and repair machinery, and small RNAs. Our work indicates that grade one lung adenocarcinomas have greatly altered nucleosome distributions compared to the adjacent normal tissue, but nearly identical chromatin accessibility. Conversely, the grade three samples show massive disruptions in chromosomal accessibility, but only modest changes in nucleosome distribution when tumor and normal samples are compared. This data has allowed us to develop a model in which we propose that early grade lung adenocarcinomas are linked to changes in nucleosome distributions, while later grade cancers are linked to large-scale chromosomal changes. These results indicate that we should be able to use these chromatin structural changes to identify grade sub-type specific cancer biomarkers.

Citation Information: Cancer Prev Res 2011;4(10 Suppl):A36.