A comprehensive characterization of the cell-free transcriptome reveals tissue- and subtype-specific biomarkers for cancer detection

Abstract

Cell-free RNA (cfRNA) is a promising analyte for cancer detection. However, a comprehensive assessment of cfRNA in individuals with and without cancer has not been conducted. We perform the first transcriptome-wide characterization of cfRNA in cancer (stage III breast [n = 46], lung [n = 30]) and non-cancer (n = 89) participants from the Circulating Cell-free Genome Atlas (NCT02889978). Of 57,820 annotated genes, 39,564 (68%) are not detected in cfRNA from non-cancer individuals. Within these low-noise regions, we identify tissue- and cancer-specific genes, defined as “dark channel biomarker” (DCB) genes, that are recurrently detected in individuals with cancer. DCB levels in plasma correlate with tumor shedding rate and RNA expression in matched tissue, suggesting that DCBs with high expression in tumor tissue could enhance cancer detection in patients with low levels of circulating tumor DNA. Overall, cfRNA provides a unique opportunity to detect cancer, predict the tumor tissue of origin, and determine the cancer subtype.

Liquid Biopsies for Molecular Biology-Based Radiotherapy

“…The use of liquid biopsies to evaluate analytes released from tumors and normal tissues into the peripheral blood may offer a solution to the challenges associated with molecular biology-based radiotherapy. Most efforts to date have focused on characterizing and tracking ctDNA, but emerging data suggest that cell-free RNA may be a complementary analyte [ 82 ]. Notably, there is also substantial interest in monitoring circulating tumor cells (CTCs) as biomarkers and predictors of cancer treatment response [ 83 ], but a detailed discussion of this approach is outside the scope of this review.…”

“…To date, most analysis of circulating nucleic acids has focused on tracking genetic alterations, but novel approaches are under development to detect DNA features such as methylation and fragmentation patterns (i.e., fragmentomics) [ 146 ]. Furthermore, previous reports have suggested that cancer cells [ 147 , 148 ] and normal tissues [ 82 , 149 ] release RNA into circulation. Because these non-genetic signatures are unique to their cells of origin, they could provide a novel marker of tissue-specific pathologies.…”

“…Because these non-genetic signatures are unique to their cells of origin, they could provide a novel marker of tissue-specific pathologies. There is growing interest in using these new approaches as cancer biomarkers that may be complementary to tracking tumor mutations [ 82 , 106 , 150 , 151 , 152 , 153 , 154 , 155 ]. Furthermore, cell-free DNA epigenetic markers have been shown to be associated with normal tissue injury [ 92 , 156 , 157 , 158 ], raising the possibility that cell-free DNA methylation, fragmentomics, and/or cell-free RNA could identify radiation-induced normal tissue toxicity.…”

Liquid Biopsy in Cervical Cancer: Hopes and Pitfalls

“…In this context, there is considerable interest in miRNAs, namely small non-coding RNAs that regulate gene expression at the post-transcriptional level. miRNAs mediate intercellular communication, and alterations in their expression profile are closely correlated with the onset and/or progression of many types of cancers [24].…”

CRISPR-Cas-amplified urine biomarkers for multiplexed and portable cancer diagnostics

“…However, the eld of synthetic biomarkers has not yet bene ted from DNA multiplexing due to the susceptibility of nucleic acids in vivo 10 . Even measurements of endogenous, cell-free nucleic acids are hampered by the degradation of sequences that are not protected by the nucleosome in circulation [11][12][13][14][15] . Chemicallymodi ed nucleic acids which have been primarily developed as therapeutics are less resistant to systemic degradation; however, they have not been incorporated into diagnostic platforms because they cannot be ampli ed with conventional polymerases, nor inexpensively sequenced [16][17][18] .…”