Multi-faceted attributes of salivary cell-free DNA as liquid biopsy biomarkers for gastric cancer detection

Neeti Swarup; Jordan Cheng; Irene Choi; You Jeong Heo; Misagh Kordi; Mohammad Aziz; Akanksha Arora; Feng Li; David Chia; Fang Wei; David Elashoff; Liying Zhang; Sung Kim; Yong Kim; David T W Wong

doi:10.1186/s40364-023-00524-2

Multi-faceted attributes of salivary cell-free DNA as liquid biopsy biomarkers for gastric cancer detection

Biomark Res. 2023 Oct 10;11(1):90. doi: 10.1186/s40364-023-00524-2.

Authors

Neeti Swarup^#¹, Jordan Cheng^#¹, Irene Choi¹, You Jeong Heo², Misagh Kordi¹, Mohammad Aziz¹, Akanksha Arora^{1

3}, Feng Li¹, David Chia³, Fang Wei¹, David Elashoff⁴, Liying Zhang³, Sung Kim^{5

6}, Yong Kim⁷, David T W Wong⁸

Affiliations

¹ School of Dentistry, University of California, Los Angeles, Los Angeles, CA, 90095, USA.
² The Samsung Advanced Institute for Health Sciences & Technology (SAIHST), Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, 06355, Republic of Korea.
³ Indraprastha Institute of Information Technology (IIIT), Delhi, India.
⁴ Department of Pathology and Laboratory Medicine, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA, 90095, USA.
⁵ Department of Medicine, Biostatistics and Computational Medicine, University of California Los Angeles, Los Angeles, CA, 90095, USA.
⁶ Department of Surgery, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, 06355, South Korea.
⁷ School of Dentistry, University of California, Los Angeles, Los Angeles, CA, 90095, USA. thadyk@g.ucla.edu.
⁸ School of Dentistry, University of California, Los Angeles, Los Angeles, CA, 90095, USA. dtww@ucla.edu.

^# Contributed equally.

Abstract

Background: Recent advances in circulating cell-free DNA (cfDNA) analysis from biofluids have opened new avenues for liquid biopsy (LB). However, current cfDNA LB assays are limited by the availability of existing information on established genotypes associated with tumor tissues. Certain cancers present with a limited list of established mutated cfDNA biomarkers, and thus, nonmutated cfDNA characteristics along with alternative biofluids are needed to broaden the available cfDNA targets for cancer detection. Saliva is an intriguing and accessible biofluid that has yet to be fully explored for its clinical utility for cancer detection.

Methods: In this report, we employed a low-coverage single stranded (ss) library NGS pipeline "Broad-Range cell-free DNA-Seq" (BRcfDNA-Seq) using saliva to comprehensively investigate the characteristics of salivary cfDNA (ScfDNA). The identification of cfDNA features has been made possible by applying novel cfDNA processing techniques that permit the incorporation of ultrashort, ss, and jagged DNA fragments. As a proof of concept using 10 gastric cancer (GC) and 10 noncancer samples, we examined whether ScfDNA characteristics, including fragmentomics, end motif profiles, microbial contribution, and human chromosomal mapping, could differentiate between these two groups.

Results: Individual and integrative analysis of these ScfDNA features demonstrated significant differences between the two cohorts, suggesting that disease state may affect the ScfDNA population by altering nuclear cleavage or the profile of contributory organism cfDNA to total ScfDNA. We report that principal component analysis integration of several aspects of salivary cell-free DNA fragmentomic profiles, genomic element profiles, end-motif sequence patterns, and distinct oral microbiome populations can differentiate the two populations with a p value of < 0.0001 (PC1).

Conclusion: These novel features of ScfDNA characteristics could be clinically useful for improving saliva-based LB detection and the eventual monitoring of local or systemic diseases.

Keywords: Cell-free DNA; Fragmentomics; Liquid Biopsy; Salivary cell-free DNA.

Abstract

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