A Novel Method to Detect Early Colorectal Cancer Based on Chromosome Copy Number Variation in Plasma

Abstract

Background/Aims: Colonoscopy screening has been accepted broadly to evaluate the risk and incidence of colorectal cancer (CRC) during health examination in outpatients. However, the intrusiveness, complexity and discomfort of colonoscopy may limit its application and the compliance of patients. Thus, more reliable and convenient diagnostic methods are necessary for CRC screening. Genome instability, especially copy-number variation (CNV), is a hallmark of cancer and has been proved to have potential in clinical application. Methods: We determined the diagnostic potential of chromosomal CNV at the arm level by whole-genome sequencing of CRC plasma samples (n = 32) and healthy controls (n = 38). Arm level CNV was determined and the consistence of arm-level CNV between plasma and tissue was further analyzed. Two methods including regular z score and trained Support Vector Machine (SVM) classifier were applied for detection of colorectal cancer. Results: In plasma samples of CRC patients, the most frequent deletions were detected on chromosomes 6, 8p, 14q and 1p, and the most frequent amplifications occurred on chromosome 19, 5, 2, 9p and 20p. These arm-level alterations detected in plasma were also observed in tumor tissues. We showed that the specificity of regular z score analysis for the detection of colorectal cancer was 86.8% (33/38), whereas its sensitivity was only 56.3% (18/32). Applying a trained SVM classifier (n = 40 in trained group) as the standard to detect colorectal cancer relevance ratio in the test samples (n = 30), a sensitivity of 91.7% (11/12) and a specificity 88.9% (16/18) were finally reached. Furthermore, all five early CRC patients in stages I and II were successfully detected. Conclusion: Trained SVM classifier based on arm-level CNVs can be used as a promising method to screen early-stage CRC.

Genetic Aberration Analysis in Thai Colorectal Adenoma and Early-Stage Adenocarcinoma Patients by Whole-Exome Sequencing

“…Previous studies showed the gain of chromosome 20 in CRC patients and demonstrated its use as a marker to detect early-stage CRC [41,42]. Our results in Thai CRC patients revealed a gain of chromosome 20 in four out of five samples, in agreement with the previous reports (Figure 4).…”

“…CNVs are structural variations due to chromosome alterations, including duplication or deletion of regions in the genome, that lead to carcinogenesis in tumor patients [39,40]. Early-stage CRC can be detected by the gain of chromosomes 8q, 13, and 20q and loss of chromosomes 8p, 17p, and 18q [41]. Other studies have identified CNVs using plasma and CRC tissues.…”

Identification of Prognostic Dosage-Sensitive Genes in Colorectal Cancer Based on Multi-Omics

“…Compared with the gene expression the DNA copy number often occurs in arm-level, i.e. the same segment tends to have the same copy number alteration (Roy et al, 2016;Xu et al, 2018). The results of this study not only support this opinion but also suggest that even in the same fragment the correlation between different samples is not always 1.…”

Cell‐free tumour DNA testing for early detection of cancer – a potential future tool

“…Using a larger 58‐gene panel increased the detection to 50% of stage I CRC and >89% for stages II‐IV . As CNAs are common in adenomas and early CRC, assaying for CNAs might be an alternative, and indeed, two small studies could detect 5/5 stage I and II CRC and 4/5 stage I CRC, respectively, using cell‐free DNA . Another option is to screen for methylation changes in cfDNA, which are considered early events in CRC (see, e.g.…”