Complex Age- and Cancer-Related Changes in Human Blood Transcriptome—Implications for Pan-Cancer Diagnostics
Fei Qi1, Fan Gao1, Ye Cai1, Xueer Han1, Yao Qi1, Jiawen Ni1, Jianfeng Sun2, Shengquan Huang3, Shaohua Chen3, Chunlin Wu3* and Philipp Kapranov1*
1 School of Medicine, Institute of Genomics, Huaqiao University, Xiamen, China
2 Department of Bioinformatics, Technische Universität München, Freising, Germany
3 Department of Pathology, Second Affiliated Hospital of Fujian Medical University, Quanzhou, China
Edited by: Yun Zheng, Kunming University of Science and Technology, China
Reviewed by: Changning Liu; Jin Chen
Received: 25 July 2021 · Accepted: 16 September 2021 · Published: 15 October 2021
Citation: Qi F et al. (2021) Front. Genet. 12:746879. doi: 10.3389/fgene.2021.746879
Early cancer detection is the key to a positive clinical outcome. While a number of early diagnostics methods exist in clinics today, they tend to be invasive and limited to a few cancer types. Thus, a clear need exists for non-invasive diagnostics methods that can be used to detect the presence of cancer of any type. Liquid biopsy based on analysis of molecular components of peripheral blood has shown significant promise in such pan cancer diagnostics; however, existing methods based on this approach require improvements, especially in sensitivity of early-stage cancer detection. The improvement would likely require diagnostics assays based on multiple different types of biomarkers and, thus, calls for identification of novel types of cancer-related biomarkers that can be used in liquid biopsy. Whole-blood transcriptome, especially its non-coding component, represents an obvious yet under-explored biomarker for pan-cancer detection. In this study, we show that whole transcriptome analysis using RNA-seq could indeed serve as a viable biomarker for pan-cancer detection. Furthermore, a class of long non-coding (lnc) RNAs, very long intergenic non-coding (vlinc) RNAs, demonstrated superior performance compared with protein-coding mRNAs. Finally, we show that age and presence of non-blood cancers change transcriptome in similar, yet not identical, directions and explore implications of this observation for pan-cancer diagnostics.
Keywords: pan-cancer, biomarker, transcriptome, lncRNA, vlincRNA, aging, peripheral blood, liquid biopsy
INTRODUCTION
Cancer is a leading cause of death worldwide; however, it is widely known that early detection of primary tumors can significantly reduce mortality and improve outcome in cancer patients (Siegel et al., 2020). Therefore, a number of tumor screening solutions have been developed for several types of cancer, for example, colonoscopy for colon cancer, mammography for breast cancer, and others. However, such tests are limited to few specific types of cancer and are often fairly invasive. Thus, a strong need exists for non-invasive tests that can simultaneously identify multiple cancers and can be used for universal screening for the disease (Ahlquist, 2018).
MATERIALS AND METHODS
RNA-Seq
Peripheral blood samples were collected from 75 Chinese females between 24 and 82 years old (Supplementary Table S1) into Tempus Blood RNA Tubes (Thermo), and total RNA was isolated using Tempus Spin RNA Isolation Kit (Thermo) following the procedure of the manufacturer.
RNA-Seq Data Analysis
Expression levels of genes were estimated based on the RNA-seq data using Salmon software (Patro et al., 2017)...
Training and Evaluation of Machine Learning Models
The 75 samples were randomly split into two datasets...
Co-Expression Analysis
The gene co-expression network analysis was performed using the WGCNA package...
GO Analysis
The enrichment analyses of GO terms were performed using the clusterProfiler package...
Overlap Analysis
Overlaps between sets of genes or GO terms were analyzed using the GeneOverlap package...
RESULTS
Blood Transcriptome Profile can Potentially Serve as Pan-Cancer Biomarker
This work was based on the analysis of peripheral blood transcriptome from 75 females...
Aging and Cancer Have Similar Effects on Blood Transcriptome
Another crucial property of the individuals in our dataset, which has been found to correlate with occurrence of various cancers, is age...
DISCUSSION
This work represents a proof-of-principle study showing that analysis of whole transcriptome of peripheral blood can serve as a basis or at least as a component of a pan-cancer diagnostic test...
ETHICS STATEMENT
The studies involving human participants were reviewed and approved by the ethics review boards...
DATA AVAILABILITY STATEMENT
The data presented in the study are deposited in the GSA-Human repository, accession number HRA001249.
REFERENCES
Ahlquist, D. A. (2018). Universal Cancer Screening...