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. 2021 Feb 25:11:643136.
doi: 10.3389/fonc.2021.643136. eCollection 2021.

Fecal Multidimensional Assay for Non-Invasive Detection of Colorectal Cancer: Fecal Immunochemical Test, Stool DNA Mutation, Methylation, and Intestinal Bacteria Analysis

Shaobo Mo  1   2 , Hui Wang  3 , Lingyu Han  1   2 , Wenqiang Xiang  1   2 , Weixing Dai  1   2 , Pengfei Zhao  3 , Fengchun Pei  3 , Zhixi Su  3 , Chengcheng Ma  3 , Qi Li  4 , Zhimin Wang  5 , Sanjun Cai  1   2   6 , Hao Wang  7 , Rui Liu  3 , Guoxiang Cai  1   2
Affiliations

Fecal Multidimensional Assay for Non-Invasive Detection of Colorectal Cancer: Fecal Immunochemical Test, Stool DNA Mutation, Methylation, and Intestinal Bacteria Analysis

Shaobo Mo et al. Front Oncol. .

Abstract

Background: Fecal immunochemical test (FIT), DNA mutation, DNA methylation, and microbial dysbiosis all showed promising in colorectal cancer (CRC) non-invasive detection. We assessed CRC detection with an assay combining all these strategies and investigated the effect of clinical features on the performance of this comprehensive test.

Methods: We performed a multidimensional analysis study using stool samples collected from 108 patients with CRC, 18 patients with colorectal adenoma, and 36 individuals with no evidence of colorectal disease. The multidimensional analysis of stool samples including FIT, stool DNA (sDNA) tests for three methylated genes (Septin9, NDRG4, BMP3) and three mutated genes (KRAS, BRAF, PI3KCA) using next generation sequencing as well as detection of stool bacteria level of Fusobacterium nucleatum and Parvimonas micra using qPCR method. We used a linear support vector classification model to analyze the data.

Results: The sensitivity of FIT alone was 69.4% for CRC and 11.1% for adenoma. Separately, the sensitivity of the detection of intestinal bacteria, DNA mutation, and DNA methylation for CRC was 58.3, 50.0, and 51.9%, respectively. The combination of FIT and sDNA tests had a sensitivity of 81.5% for CRC (AUC: 0.93, better than FIT alone, P = 0.017) and 27.8% for adenoma with 94.4% specificity. Sensitivity of the multidimensional test to detect CRC with stage II (84.6%) and III (91.9%) CRC was relatively higher (88.2%) than that of patients with stage I (60.0%) and stage IV (75.0%) (P = 0.024). The rate of CRC detection increased with tumor size (P = 0.008) and age (P = 0.04). Interestingly, the rate of CRC detection was higher in smoking persons than non-smokers with marginal significance (P = 0.08).

Conclusions: The multidimensional assay of stool samples combining FIT and stool DNA tests further improved the diagnostic sensitivity for CRC. This could provide new approach for improvement of CRC screening and further demonstrations are warranted.

Keywords: cancer screening; colorectal cancer; fecal biomarker; human gut microbiome; methylation.

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Conflict of interest statement

HuiW, PZ, FP, ZS, CM and RL were employed by company Singlera Genomics (Shanghai). The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Figures

Figure 1
Figure 1
CRC patients accumulated more stool DNA mutation (A) and methylation (B) than adenoma and NED individuals. Quantitative PCR abundance of two bacteria markers of stool DNA showed relative higher level in adenoma and CRC patients’ samples than NED (C).
Figure 2
Figure 2
Separately, performance of stool DNA mutation (A) and FIT (D) to detect CRC were better than DNA methylation (B) and bacteria markers (C), and stool DNA mutation predicted adenoma much precisely than the left three. The relative receiver operating characteristic (ROC) curves were shown.
Figure 3
Figure 3
Neoplasm detection performance by multidimensional assay of stool samples. The sensitivity and specificity of training and validation datasets were consistent. ROC curves of the multidimensional assay in training set (A), test set (B), and combined data (C) were shown.
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