Nature Sub-Journal: Chinese scholars achieve true early screening of colorectal cancer based on fecal microbial markers

According to the statistics of the World Health Organization (WHO), colorectal cancer (CRC) is the third-ranked cancer type and the second-ranked fatality rate worldwide, which brings great health hazards and economic burdens to patients and society [ 1】.

Colorectal cancer can occur at any age, but most of it only affects the elderly over 50 years old.
The incidence of colorectal cancer in the young population is very low.

However, in the past 30 years, the incidence of colorectal cancer among young people under the age of 50 has been increasing.

Due to the increase in the incidence of colorectal cancer in young people, the average diagnosis age of colorectal cancer has been advanced from 72 to 66.

And just today, the latest guidelines issued by the Journal of the American Medical Association (JAMA) have recommended that the starting age for colorectal cancer screening be reduced to 45 years.

This further highlights the importance of early screening for colorectal cancer.

On May 24, 2021, Zhu Lixin's research group from the Institute of Gastroenterology, the Sixth Affiliated Hospital of Sun Yat-sen University, and others published a research paper titled: Identification of microbial markers across populations in early detection of colorectal cancer in Nature Communications.

This research has achieved true early screening of colorectal cancer (CRC) based on fecal microbial markers, that is, the screening of colon adenoma (CRA) stage.

At present, the clinical treatment of tumors is still very limited, and the therapeutic effect is not ideal.
The core of tumor prevention and treatment is still "early detection, early diagnosis, and early treatment.
"
Studies have shown that effective screening and early intervention of cancer patients in the early stage of onset can significantly improve the survival rate of patients (the 5-year survival rate of early-stage patients can reach 90%), and save medical resources and time [2].

Because colon adenoma (Colorectal Adenoma, CRA) is the precursor of most CRC occurrence [3] (Figure 1), screening for colon adenoma (CRA) stage is crucial for the prevention and treatment of colorectal cancer (CRC) important.

Figure 1.
CRC "adenoma-cancer" development process Colorectal cancer (CRC) screening has been highly valued by the country, but the existing screening methods (such as traditional imaging, endoscopy and tumor marker screening, Figure 2) There are limitations such as radioactive damage, invasiveness, low sensitivity, and low compliance, and there is an urgent need for technological innovation.

With the maturity of liquid biopsy technology (non-invasive), finding suitable (molecular) markers from blood, urine and stool samples has become the main development direction of cancer screening technology.

Among them, because stool is a direct product of digestive tract metabolism, high hopes are placed on the detection of stool samples for digestive tract diseases, especially colorectal cancer (CRC).

Fecal immunochemical test (FIT), fecal occult blood test (FOBT) and existing fecal microbial marker detection are widely used in the diagnosis of colorectal cancer (CRC).

Although these methods and technologies are effective in screening for advanced colorectal cancer (CRC), unfortunately, the sensitivity for early colorectal cancer (CRC), especially colon adenoma (CRA) is still poor (Figure 2) .

Figure 2.
Shortcomings of existing CRC screening methods.
Professor Zhu Lixin's team from the Institute of Gastroenterology, The Sixth Affiliated Hospital of Sun Yat-sen University and his joint research team integrated healthy controls, colonic adenoma (CRA) and colorectal from multiple research centers The fecal microbial sequencing data of a total of 775 samples of cancer (CRC) have been systematically studied for early diagnosis and screening of colorectal cancer (CRC) based on microbial markers.

Taking into account the influence of confounders on the results of the study, the study first eliminated the batch effect by controlling the confounders, and identified bacteria that were significantly different in the development of colorectal cancer (CRC) and changed consistently in the cross-regional cohort .

Subsequently, the iterative feature elimination method (IFE) was used to screen the bacterial species markers with the strongest disease discrimination ability.
At the same time, in order to avoid the over-fitting of the model, this study constructed a 10-fold cross-validation random forest model.

Finally, based on 11 (eg Christensenellaceae R-7 group sp.
, Ruminococcaceae UCG-005 sp.
, Veillonella parvula) and 26 (eg Streptococcus thermophilus TH1435, Bacteroides dorei, [Clostridium] scindens) bacteria-related markers were constructed /CRA (AUC=0.
80) and CRA/CRC (AUC=0.
89) classification diagnosis models.

Among them, the health/CRA model is significantly improved compared to previous studies.
For example, Thomas et al.
showed that the AUC value of the cross-cohort health-adenoma model constructed by a variety of microorganisms is only 0.
54 [4].

In addition, the sensitivity of this model is 0.
82, which is significantly higher than the current domestic only certified early screening IVD product (Nuohui Health Changweiqing FIT-DNA test, the early screening sensitivity of adenoma stage is 63.
5%) [5].

Furthermore, this study also proved that the selected markers have the versatility of cross-regional cohort through study-to-study and leave-one-dataset-out (LODO) analysis between cohorts.

More importantly, the healthy/CRA and CRA/CRC models are also excellent in two independent cohorts (validation cohort 1: 102 CRA patients and 70 healthy controls; validation cohort 2: 57 CRA patients and 52 CRC patients).
The AUC value of independent verification cohort 1 was 0.
78, and the AUC value of independent verification cohort 2 was 0.
84. In addition, the markers selected in this study can significantly distinguish other diseases closely related to the intestinal flora: such as UC (P=0.
045), CD (P=0.
003), IBS (P=0.
009), NAFLD (P=0.
027) ) And T2D (P=0.
020), indicating that the identified colonic adenoma (CRA) intestinal flora markers have high disease specificity.

In general, the cancer bacteria markers obtained in this study have a strong potential for accurate early diagnosis and early screening of colorectal cancer (CRC).

Furthermore, this study predicted the potential functions of microorganisms based on the marker gene sequencing data, and found that compared with the healthy state, the intestinal flora marker Veillonella parvula participates in ADP-L-glycero-beta-D-manno-heptose (ADP-heptose).
) The abundance of the biosynthetic pathway and the expression of the gene encoding the key enzyme hldE in this pathway are significantly increased in colon adenoma (CRA); further, compared to the status of colon adenoma (CRA), the intestinal flora marker Bacteroides dorei participates The abundance of the menaquinol-10 (MK-10) biosynthetic pathway and the expression of the key enzymes menH and menF genes were significantly increased in colon adenoma (CRA) (Figure 3).
This result was verified in a newly collected independent cohort It provides a potential target for the treatment of early colorectal cancer (CRC).

Figure 3.
The potential pathogenesis of CRA involving microbial markers.
This study has achieved true early screening of colorectal cancer (CRC) based on fecal microbial markers, that is, the screening of colon adenoma (CRA) stage.

It needs to be emphasized that, unlike other studies that use multi-category markers to construct models, the diagnostic model constructed by this institute only uses a single type of bacteria markers, which has great advantages in clinical promotion and will further accelerate colorectal cancer ( CRC) Early screening process.

In addition, the changes in intestinal flora-mediated functional pathways associated with colonic adenoma (CRA) identified in this study also provide new targets for intervention and treatment of colorectal cancer (CRC) from the perspective of intestinal flora.

Professor Zhu Lixin of the Sixth Affiliated Hospital of Sun Yat-sen University, Professor Zhu Ruixin of the Department of Bioinformatics, the Tenth People’s Hospital of Tongji University, Dr.
Tian Chuan (former master student of Zhu Ruixin's research group and now senior researcher at Eli Lilly in the United States) and researcher Liu Ningning from the School of Public Health of Shanghai Jiaotong University Corresponding Author.

Dr.
Jiao Na, postdoctoral fellow of Zhu Lixin's research group, and Wu Yuanqi, a master student in Zhu Ruixin's research group of the Tenth People's Hospital of Tongji University, are the co-first authors. Paper link: References: 1.
Wong, SH and J Yu.
Gut microbiota in colorectal cancer: mechanisms of action and clinical applications.
Nat Rev Gastroenterol Hepatol, 2019, 16(11): 690-7042.
Ungerer, V, AJ Bronkhorst and S Holdenrieder.
Preanalytical variables that affect the outcome of cell-free DNA measurements.
Crit Rev Clin Lab Sci, 2020, 57(7): 484 -5073.
Strum, WB.
Colorectal Adenomas.
N Engl J Med, 2016, 374(11): 1065-754.
Thomas, AM, P Manghi, F Asnicar, et al.
Metagenomic analysis of colorectal cancer datasets identifies cross-cohort microbial diagnostic signatures and a link with choline degradation.
Nat Med, 2019, 25(4): 667-6785.
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