paper reading

We then sought to determine if we could use microdissected normal epithelium to better understand TNBC transcriptional heterogeneity. We performed a transcriptional chaos analysis by comparing each individual TNBC to the set of 20 microdissected normals, demonstrating a wide range in the number of genes that are dysregulated in each individual TNBC. “Chaos” is a proper term for this analysis as any number of 14,156 genes was dysregulated in at least 2 or more TNBCs. Further the term “chaos” is supported by the observation that transcriptional chaos is associated with the number of non-silent DNA mutations, of which the vast majority are not recurrent. This suggests an interesting link between the burden of non-recurrent, non-silent DNA mutations with observed transcriptional heterogeneity. Of interest, transcriptional chaos was not associated with stage, age, or race, but was correlated with the expression of genes involved in proliferation, cell cycle, and DNA damage repair. Recently, studies using various modalities have sought to subtype TNBCs into distinct molecular subtypes with varying degrees of overlap[15,19,17]. To understand how transcriptional chaos plays a role, we compared our chaos results with TNBCtype and PAM50, and demonstrate that transcriptional chaos adds additional information to molecular subtypes. This suggests that while the commonly used subtyping methods do separate samples into various groups, its the individual uniqueness of each TNBC and its difference compared to normal that also dictates heterogeneity.