RNA turbulence by tumor type: Overexpression of actionable mRNA signaling pathways by histology.

e23213 Background: Overexpression of mRNA provides an oncogenic mechanism, downstream of DNA level changes detected by sequencing, that can be treated with targeted therapies. It is still unknown why a subset of patients experience substantial responses to targeted therapies, while others experience minimal benefit. We hypothesize that the occurrence of multiple mRNA drivers may segment by cancer type in a similar manner to mutation burden. Methods: We examined results from 2088 patients with the 23 most common histologies that had received molecular testing at Paradigm Diagnostics by a panel of 56 mRNA targets, including 21 from the MAPK pathway, 14 from the P53 pathway, and 18 from the PI3K pathway. We calculated RNA turbulence, defined as the number of mRNA overexpressed in each case, as well as the pathway-specific RNA turbulence for the MAPK, PI3K and TP53 pathways. Results: Significant differences in overall and pathway-specific RNA turbulence across cancer types was observed. Colon and rectal cancers had high turbulence in the MAPK and TP53 pathways, with 87% having multiple putative drivers in the MAPK pathway and 29% having multiple drivers in the PI3K pathway. Small cell lung cancer and kidney cancers had high turbulence in the PI3K pathway, with 33% and 39% having multiple RNA drivers respectively. Overall, pancreatic, kidney and colon cancers had the highest turbulence and GIST, melanoma and cholangiocarcinoma had the lowest. There was a slight inverse relationship in tumor type when ranked by mutation burden vs. RNA turbulence Conclusions: RNA turbulence represents a unique mechanism by which to analyze tumors and correlates with disease type. Multiplex diagnostics assaying DNA, RNA, and protein level tumor changes will likely be needed to guide cancer therapeutics.

Duke Scholars

Author Jeffrey Melson Clarke Medicine, Medical Oncology