Detection of cryptogenic malignancies from metagenomic whole genome sequencing of body fluids

Abstract

Background Metagenomic next-generation sequencing (mNGS) of body fluids is an emerging approach to identify occult pathogens in undiagnosed patients. We hypothesized that metagenomic testing can be simultaneously used to detect malignant neoplasms in addition to infectious pathogens. Methods From two independent studies (n = 205), we used human data generated from a metagenomic sequencing pipeline to simultaneously screen for malignancies by copy number variation (CNV) detection. In the first case-control study, we analyzed body fluid samples (n = 124) from patients with a clinical diagnosis of either malignancy (positive cases, n = 65) or infection (negative controls, n = 59). In a second verification cohort, we analyzed a series of consecutive cases (n = 81) sent to cytology for malignancy workup that included malignant positives (n = 32), negatives (n = 18), or cases with an unclear gold standard (n = 31). Results The overall CNV test sensitivity across all studies was 87% (55 of 63) in patients with malignancies confirmed by conventional cytology and/or flow cytometry testing and 68% (23 of 34) in patients who were ultimately diagnosed with cancer but negative by conventional testing. Specificity was 100% (95% CI 95–100%) with no false positives detected in 77 negative controls. In one example, a patient hospitalized with an unknown pulmonary illness had non-diagnostic lung biopsies, while CNVs implicating a malignancy were detectable from bronchoalveolar fluid. Conclusions Metagenomic sequencing of body fluids can be used to identify undetected malignant neoplasms through copy number variation detection. This study illustrates the potential clinical utility of a single metagenomic test to uncover the cause of undiagnosed acute illnesses due to cancer or infection using the same specimen.

Pulmonary infection of Schizophyllum commune diagnosed by metagenomic next- generation sequencing: A case report

“…It is playing an important role in rare and severe infections in clinic. [7] On the 1 hand, conventional microbial culture requires pathogens to be living, corresponding growth conditions, long culture time and demanding, while morphological identification needs to provide special equipment, and laboratory physician need to have the ability to identify rare pathogens, which is obviously difficult to achieve. On the other hand, compared with the polymerase chain reaction, the huge shared gene information database of mNGS can provide rich comparative sources and reduce the difficulty of diagnosis of rare infections.…”

Comparison of the Diagnostic Significance of Cerebrospinal fluid Metagenomic Next-generation Sequencing Copy Number Variation Analysis and Cytology in Leptomeningeal Malignancy

“…Previous studies have demonstrated that gene pro les in CSF can provide valuable insights into CNS tumors [19,25,26]. Recently, researchers have found that mNGS testing of human peripheral blood, bronchoalveolar lavage uid, CSF or other body uids can offer clues for distinguishing between malignancies and infectious/in ammatory diseases [27,28,29,30,31,32]. This approach was mainly based on CNV analysis, which exhibits relatively high speci city.…”

Diagnosis of lung squamous cell carcinoma based on metagenomic Next-Generation Sequencing

“…The large CNVs (> 10 M) encompassing several chromosomes were unlikely to be caused by inherited disorders. Instead, these CNVs were indicative of tumor cells [ 16 ]. Although the detection of these chromosomal aberrations does not render a definitive cancer diagnosis, it prompted clinicians to conduct more focused diagnostic testing for tumors instead of infectious diseases.…”