Abstract 829: Global tumor transcriptional activity reveals aggressiveness across multiple cancers
Authors: Cao Shaolong , Wang Jennifer R. , Demeulemeester Jonas , Chen Jingxiao , Yu Kaixian , Yang Peng , Lim Bora , Urbanucci Alfonso , Campbell Peter , Zhu Hongtu , Van loo Peter , Wang Wenyi 
Published: September 2020

Background: At present, conventional clinical and histopathological evaluations are not sufficient to distinguish biologically indolent cancers from those that will exhibit aggressive behavior. We hypothesize that global transcriptomic activity of tumor cells reflects the end cumulative result of somatic, germline, and epigenetic alterations, as well as additional transcriptional regulatory events. Therefore, it may be more directly associated with clinical outcomes. However, the total number of mRNA molecules is not directly measurable, either in bulk or single-cell RNA sequencing data. To this end, we develop a novel metric: the transcriptional activity score (TAS), to measure the relative global tumor-cell specific transcriptional activity in heterogeneous tumor samples.

Materials and Methods: We propose TAS as the ratio of average total transcript proportion over the count proportion of tumor cells versus surrounding non-tumor cells. The transcript proportions are estimated using RNAseq deconvolution method DeMixT and the count proportions are estimated using DNAseq deconvolution methods such as ASCAT and ABSOLUTE. Using matching bulk RNA and DNA sequencing data from the Cancer Genome Atlas (TCGA) and the International Cancer Genome Consortium (ICGC), we calculated TAS for a total of 5,031 patient samples across 15 cancer types. For validation, we obtained TAS for two genomic studies: 1) from patients with early-onset prostate cancer (n=99) as part of the ICGC, and 2) from patients with localized prostate cancer as part of the Canadian Prostate Cancer Genome Network (CPC-GENE, n=144).

Results: We found that higher TAS corresponds to a more aggressive state of cancer, as characterized by MYC dysregulation, genome instability, known marker genes, and molecular subtypes. By examining the association between TAS and survival outcomes across cancer types, we also found that TAS refines the prognostic ability of pathologic stage, identifying aggressive early-stage tumors associated with poor survival as well as late-stage tumors with favorable outcomes. In prostate cancer, TAS is linearly associated with progression-free probabilities, useful to rank patients within the median risk group (Gleason score = 7). This added prediction power is consistent in TCGA and two independent validation data (ICGC and CPC-GENE).

Conclusion: We have developed a new summary metric using matched DNA and RNA sequencing data from tumor samples, to compute, in vivo and using deconvolution, the relative global gene expression level of tumor cells. The TAS metric evaluates global transcriptional activity, an intrinsic behavior of cells that is well-known, but now for the first time is shown through TAS to be associated with prognosis. TAS may serve as a tractable phenotype to help elucidate the biology that underlies metastasis, prognosis and response to treatment in cancer patients.

Citation Format: Shaolong Cao, Jennifer R. Wang, Jonas Demeulemeester, Jingxiao Chen, Kaixian Yu, Peng Yang, Bora Lim, Alfonso Urbanucci, Peter Campbell, Hongtu Zhu, Peter Van loo, Wenyi Wang. Global tumor transcriptional activity reveals aggressiveness across multiple cancers [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 829.