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Recently, the top academic journal Gastroenterology (IF=22.
7) in the field of international gastrointestinal diseases published a joint report by Shanghai Kunyuan Biotechnology Co.
, Ltd.
(hereinafter referred to as “Kunyuan Biotechnology”) in cooperation with Zhongshan Hospital Affiliated to Fudan University, Tumor Hospital Affiliated to Fudan University, Guangzhou City Major scientific research achievements of First People’s Hospital, Southern Medical University Southern Hospital, Sichuan University West China Hospital, Dalian University Affiliated Xinhua Hospital: A multi-locus blood-based assay targeting circulating tumor DNA methylation enables early detection and early relapse prediction of colorectal cancer (blood Multi-gene methylation detection can achieve early colorectal cancer screening and recurrence prediction)
.
For the first time, the domestic team of this research department systematically demonstrated the complete process of the multi-gene methylation detection method (ColonAiQ, Chang Aike) from marker screening, optimization to verification
.
Chang Aike detects colorectal cancer with an average AUC of 0.
93, colorectal cancer and advanced adenomas with an average of AUC of 0.
84, colorectal cancer (stage I-IV) with a comprehensive sensitivity of 86% (149/173), healthy people in the control group The specificity of detection is 92% (125/136)
.
This is the first time that the Chinese team has combined colorectal cancer screening and recurrence prediction technology into one on a global scale
.
Chang Aike is also the world's first product with combined functions of early colorectal cancer screening and postoperative monitoring
.
According to the latest global cancer burden data released by the World Health Organization’s International Agency for Research on Cancer (IARC) in 2020, colorectal cancer has become the third most common cancer worldwide; in 2020, more than 1.
93 million people worldwide will be newly diagnosed with cancer The incidence of colorectal cancer ranks third among all cancer types; more than 930,000 people died of colorectal cancer, and the mortality rate ranks second among all cancer types
.
In 2020, more than 550,000 people will be newly diagnosed with colorectal cancer in China.
The incidence of colorectal cancer has jumped to the second place among all types of cancer in China, and more than 280,000 people will die of colorectal cancer; most patients with colorectal cancer are already diagnosed In the late period
.
Therefore, early screening and early diagnosis are particularly important for the overall prevention and control of colorectal cancer
.
As far as early colorectal cancer screening is concerned, although colonoscopy is considered the gold standard for the diagnosis of colorectal cancer, it is subject to the compliance and accessibility of colonoscopy, and more patients prefer blood-based non-invasive examinations [ 1]; In addition, accurate prediction of tumor recurrence will help optimize adjuvant treatment plans; reasonable arrangements for postoperative monitoring and follow-up, early detection of tumor recurrence and metastasis, timely intervention and treatment may still regain the chance of recurrence and metastasis for patients with recurrence and metastasis.
Extend the life span
.
Therefore, accurate recurrence prediction and dynamic monitoring are still urgent needs in the diagnosis and treatment of colorectal cancer [2]
.
Based on the correlation between abnormal gene methylation and the occurrence of cancer, the research team explored the screening and diagnosis of colorectal cancer and adenoma by ctDNA methylation in blood samples and the performance of predicting tumor recurrence after surgery.
The results showed that polygene methylation It is expected to become a new type of "tumor marker" to solve the problems of early screening and recurrence monitoring of colorectal cancer in clinical practice
.
First of all, the researchers conducted a rigorous screening of Chang Aike markers
.
Based on the screening of 595 cancer-related genomic regions in the previous PanSeer study [3] (Figure 1), the researchers further selected the first 150 differentially methylated regions (DMRs) through the methylation analysis of tissue samples ( Figure 2A)
.
Considering the clinical applicability of simplified multiplex qPCR detection methods, the researchers further narrowed the scope of methylation markers; finally selected 6 markers with higher detection capabilities in tissues and plasma for use in multiple sites The blood was tested and named Chang Aike (Figure 2C and 2D)
.
Figure 1.
The next stage of the Chang Aike marker verification stage of the study design.
The research team blindly verified the locked Chang Aike model in 507 plasma samples and found that the model was able to detect 173 patients with colorectal cancer.
86%, the specificity in the colonoscopy negative control (136 cases) was 92%; and Chang Aike’s sensitivity increased with the progression of the disease stage of colorectal cancer and the increase in tumor size (Figure 2E and 2F)
.
Table 1.
ColonAiQ's performance in validating early detection of colon cancer.
Figure 2.
Screening of methylation markers in the model.
Subsequently, the research team compared Chang AiQ with other non-invasive screening methods; compared to other non-invasive screening methods Sexual screening methods such as fecal occult blood test (FIT), carcinoembryonic antigen (CEA) and Septin9 single-point gene methylation, Chang Aike has significant advantages
.
In 142 subjects who received Chang Aike also underwent the fecal occult blood test (FIT), Chang Aike performed better than FIT in all stages of bowel cancer disease (88.
3% vs 59.
7%), especially in stage I ( 85.
7% vs 28.
6%, Figure 3D)
.
Compared with CEA, Chang Aike is also significantly better than CEA, and the detection rates of the two for early (I/II) bowel cancer cases are 80-92% and 17-47%, respectively (Figure 3E)
.
Compared with Septin9, the combination of six markers can capture more comprehensive tumor epigenetic heterogeneity than a single marker (Figure 2G)
.
The research team also explored the potential of Chang Aike's application in the prognostic monitoring of colorectal cancer
.
Of all colorectal cancer patients, 39 patients provided blood samples 1-2 days before surgical removal of the tumor and 17-34 days after surgery
.
Of the 33 patients who tested positive for Chang Aike before surgery, 7 patients (2 patients with stage II and 5 patients with stage III) had tumor recurrence from 42 to 238 days after surgery (median 117 days)
.
The researchers observed a significant difference in the Chang Aike scores of the postoperative samples between the relapsed group and the non-relapsed group (p=0.
00017) (Figure 3F)
.
The corresponding data show that Chang Aike has a clear recognition ability in predicting the early recurrence of colorectal cancer, and the follow-up multi-center expansion verification is in progress
.
Figure 3.
Model establishment and verification The corresponding author of the study, Professor Zhou Pinghong, Zhongshan Hospital, Fudan University, said: Early screening and early diagnosis of colorectal cancer are the key tasks for the prevention and control of colorectal cancer; although colonoscopy is used for the diagnosis of colorectal cancer "Gold standard", but limited by the overall penetration rate and compliance of colonoscopy in China, the current screening strategy for bowel cancer in China is still relatively "basic"
.
In this multi-center study, we included a relatively large number of samples of early cancer and precancerous lesions, because early cancer and precancerous lesions are the focus and difficulty of screening
.
Judging from the current results, Chang Aike's screening performance for colorectal cancer is excellent and satisfactory; and the relative convenience of blood samples is more conducive to improving the compliance of colorectal cancer clinical screening
.
The study’s first author and co-corresponding author, Professor Cai Guoxiang, Fudan University Cancer Hospital, said: At present, non-invasive screening for colorectal cancer uses fecal occult blood testing or epidemiological surveys.
A city for non-invasive screening for rectal cancer
.
From the results of this study, the detection of polygene methylation in blood samples is expected to be an important supplementary part of the colorectal cancer screening strategy
.
In addition, through this study, we have also seen the potential of ctDNA methylation in blood samples in predicting postoperative recurrence of bowel cancer, which is rarely reported in other studies
.
The current results are exciting.
This will give clinicians an important tool to assess the recurrence of colorectal cancer after surgery.
It also reminds once again that “DNA methylation biomarkers” are used in the early screening, early diagnosis, and diagnosis of colorectal cancer.
Application value in whole-process management such as recurrence monitoring
.
The co-corresponding author of the study, Dr.
Liu Rui, co-founder and chief technology officer of Kunyuan Biotechnology, said: The study first systematically demonstrated the logical process of methylation gene molecular targets from screening, evaluation and verification to clinical transformation
.
We have established a complete set of cancer marker screening, which can be extended to the development of relevant markers for different types of cancer and different clinical problems
.
Among the six loci we finally screened out, some of them intersect with known markers that have a clear correlation with bowel cancer
.
This also proves the correctness and efficiency of our screening system from the side, as well as the ability to discover innovative targets
.
Secondly, the focus of this research is clinical transformation.
Compared with complex and cumbersome molecular detection technologies such as NGS, the corresponding detection is finally achieved through multiple quantitative PCR methodology, which fully considers clinical suitability and domestic medical conditions, and has more commercial transformation value and Facilitate landing in primary medical institutions
.
Finally, the study also fully demonstrated the clinical application malleability of blood testing, which not only covers early detection of cancer, but also effectively evaluates MRD, has a predictive effect on early recurrence, and can effectively monitor prognosis, thereby covering cancer patients.
The whole process management
.
Mr.
Zhang Jiangli, co-founder and CEO of Kunyuan Biotech, said: In Kunyuan’s entire product system, colorectal cancer is a very important sector.
Kunyuan has started colorectal cancer screening and surgery since its establishment.
Research and development of monitoring technology
.
After continuous exploration, we focused on the detection technology of polygene methylation in blood samples
.
First, a blood sample compliance is very good, more in line with China's current main scene cancer screening, such as medical centers, hospitals, government and other livelihood projects
.
Second, the scalability and universality of blood samples are better
.
Our technology platform can support us to screen more potentially valuable methylation markers from different cancers; thus, we can develop more cancer screening products
.
References: 1.
Adler A, et al.
BMC Gastroenterol 2014;14:183.
2.
Rutter MD, et al.
Gut 2020;69:201-223.
3.
Chen X, Gole J, Gore A, et al.
Nat Commun 2020; 11:3475.
Link to the paper: https://doi.
org/10.
1053/j.
gastro.
2021.
08.
054
7) in the field of international gastrointestinal diseases published a joint report by Shanghai Kunyuan Biotechnology Co.
, Ltd.
(hereinafter referred to as “Kunyuan Biotechnology”) in cooperation with Zhongshan Hospital Affiliated to Fudan University, Tumor Hospital Affiliated to Fudan University, Guangzhou City Major scientific research achievements of First People’s Hospital, Southern Medical University Southern Hospital, Sichuan University West China Hospital, Dalian University Affiliated Xinhua Hospital: A multi-locus blood-based assay targeting circulating tumor DNA methylation enables early detection and early relapse prediction of colorectal cancer (blood Multi-gene methylation detection can achieve early colorectal cancer screening and recurrence prediction)
.
For the first time, the domestic team of this research department systematically demonstrated the complete process of the multi-gene methylation detection method (ColonAiQ, Chang Aike) from marker screening, optimization to verification
.
Chang Aike detects colorectal cancer with an average AUC of 0.
93, colorectal cancer and advanced adenomas with an average of AUC of 0.
84, colorectal cancer (stage I-IV) with a comprehensive sensitivity of 86% (149/173), healthy people in the control group The specificity of detection is 92% (125/136)
.
This is the first time that the Chinese team has combined colorectal cancer screening and recurrence prediction technology into one on a global scale
.
Chang Aike is also the world's first product with combined functions of early colorectal cancer screening and postoperative monitoring
.
According to the latest global cancer burden data released by the World Health Organization’s International Agency for Research on Cancer (IARC) in 2020, colorectal cancer has become the third most common cancer worldwide; in 2020, more than 1.
93 million people worldwide will be newly diagnosed with cancer The incidence of colorectal cancer ranks third among all cancer types; more than 930,000 people died of colorectal cancer, and the mortality rate ranks second among all cancer types
.
In 2020, more than 550,000 people will be newly diagnosed with colorectal cancer in China.
The incidence of colorectal cancer has jumped to the second place among all types of cancer in China, and more than 280,000 people will die of colorectal cancer; most patients with colorectal cancer are already diagnosed In the late period
.
Therefore, early screening and early diagnosis are particularly important for the overall prevention and control of colorectal cancer
.
As far as early colorectal cancer screening is concerned, although colonoscopy is considered the gold standard for the diagnosis of colorectal cancer, it is subject to the compliance and accessibility of colonoscopy, and more patients prefer blood-based non-invasive examinations [ 1]; In addition, accurate prediction of tumor recurrence will help optimize adjuvant treatment plans; reasonable arrangements for postoperative monitoring and follow-up, early detection of tumor recurrence and metastasis, timely intervention and treatment may still regain the chance of recurrence and metastasis for patients with recurrence and metastasis.
Extend the life span
.
Therefore, accurate recurrence prediction and dynamic monitoring are still urgent needs in the diagnosis and treatment of colorectal cancer [2]
.
Based on the correlation between abnormal gene methylation and the occurrence of cancer, the research team explored the screening and diagnosis of colorectal cancer and adenoma by ctDNA methylation in blood samples and the performance of predicting tumor recurrence after surgery.
The results showed that polygene methylation It is expected to become a new type of "tumor marker" to solve the problems of early screening and recurrence monitoring of colorectal cancer in clinical practice
.
First of all, the researchers conducted a rigorous screening of Chang Aike markers
.
Based on the screening of 595 cancer-related genomic regions in the previous PanSeer study [3] (Figure 1), the researchers further selected the first 150 differentially methylated regions (DMRs) through the methylation analysis of tissue samples ( Figure 2A)
.
Considering the clinical applicability of simplified multiplex qPCR detection methods, the researchers further narrowed the scope of methylation markers; finally selected 6 markers with higher detection capabilities in tissues and plasma for use in multiple sites The blood was tested and named Chang Aike (Figure 2C and 2D)
.
Figure 1.
The next stage of the Chang Aike marker verification stage of the study design.
The research team blindly verified the locked Chang Aike model in 507 plasma samples and found that the model was able to detect 173 patients with colorectal cancer.
86%, the specificity in the colonoscopy negative control (136 cases) was 92%; and Chang Aike’s sensitivity increased with the progression of the disease stage of colorectal cancer and the increase in tumor size (Figure 2E and 2F)
.
Table 1.
ColonAiQ's performance in validating early detection of colon cancer.
Figure 2.
Screening of methylation markers in the model.
Subsequently, the research team compared Chang AiQ with other non-invasive screening methods; compared to other non-invasive screening methods Sexual screening methods such as fecal occult blood test (FIT), carcinoembryonic antigen (CEA) and Septin9 single-point gene methylation, Chang Aike has significant advantages
.
In 142 subjects who received Chang Aike also underwent the fecal occult blood test (FIT), Chang Aike performed better than FIT in all stages of bowel cancer disease (88.
3% vs 59.
7%), especially in stage I ( 85.
7% vs 28.
6%, Figure 3D)
.
Compared with CEA, Chang Aike is also significantly better than CEA, and the detection rates of the two for early (I/II) bowel cancer cases are 80-92% and 17-47%, respectively (Figure 3E)
.
Compared with Septin9, the combination of six markers can capture more comprehensive tumor epigenetic heterogeneity than a single marker (Figure 2G)
.
The research team also explored the potential of Chang Aike's application in the prognostic monitoring of colorectal cancer
.
Of all colorectal cancer patients, 39 patients provided blood samples 1-2 days before surgical removal of the tumor and 17-34 days after surgery
.
Of the 33 patients who tested positive for Chang Aike before surgery, 7 patients (2 patients with stage II and 5 patients with stage III) had tumor recurrence from 42 to 238 days after surgery (median 117 days)
.
The researchers observed a significant difference in the Chang Aike scores of the postoperative samples between the relapsed group and the non-relapsed group (p=0.
00017) (Figure 3F)
.
The corresponding data show that Chang Aike has a clear recognition ability in predicting the early recurrence of colorectal cancer, and the follow-up multi-center expansion verification is in progress
.
Figure 3.
Model establishment and verification The corresponding author of the study, Professor Zhou Pinghong, Zhongshan Hospital, Fudan University, said: Early screening and early diagnosis of colorectal cancer are the key tasks for the prevention and control of colorectal cancer; although colonoscopy is used for the diagnosis of colorectal cancer "Gold standard", but limited by the overall penetration rate and compliance of colonoscopy in China, the current screening strategy for bowel cancer in China is still relatively "basic"
.
In this multi-center study, we included a relatively large number of samples of early cancer and precancerous lesions, because early cancer and precancerous lesions are the focus and difficulty of screening
.
Judging from the current results, Chang Aike's screening performance for colorectal cancer is excellent and satisfactory; and the relative convenience of blood samples is more conducive to improving the compliance of colorectal cancer clinical screening
.
The study’s first author and co-corresponding author, Professor Cai Guoxiang, Fudan University Cancer Hospital, said: At present, non-invasive screening for colorectal cancer uses fecal occult blood testing or epidemiological surveys.
A city for non-invasive screening for rectal cancer
.
From the results of this study, the detection of polygene methylation in blood samples is expected to be an important supplementary part of the colorectal cancer screening strategy
.
In addition, through this study, we have also seen the potential of ctDNA methylation in blood samples in predicting postoperative recurrence of bowel cancer, which is rarely reported in other studies
.
The current results are exciting.
This will give clinicians an important tool to assess the recurrence of colorectal cancer after surgery.
It also reminds once again that “DNA methylation biomarkers” are used in the early screening, early diagnosis, and diagnosis of colorectal cancer.
Application value in whole-process management such as recurrence monitoring
.
The co-corresponding author of the study, Dr.
Liu Rui, co-founder and chief technology officer of Kunyuan Biotechnology, said: The study first systematically demonstrated the logical process of methylation gene molecular targets from screening, evaluation and verification to clinical transformation
.
We have established a complete set of cancer marker screening, which can be extended to the development of relevant markers for different types of cancer and different clinical problems
.
Among the six loci we finally screened out, some of them intersect with known markers that have a clear correlation with bowel cancer
.
This also proves the correctness and efficiency of our screening system from the side, as well as the ability to discover innovative targets
.
Secondly, the focus of this research is clinical transformation.
Compared with complex and cumbersome molecular detection technologies such as NGS, the corresponding detection is finally achieved through multiple quantitative PCR methodology, which fully considers clinical suitability and domestic medical conditions, and has more commercial transformation value and Facilitate landing in primary medical institutions
.
Finally, the study also fully demonstrated the clinical application malleability of blood testing, which not only covers early detection of cancer, but also effectively evaluates MRD, has a predictive effect on early recurrence, and can effectively monitor prognosis, thereby covering cancer patients.
The whole process management
.
Mr.
Zhang Jiangli, co-founder and CEO of Kunyuan Biotech, said: In Kunyuan’s entire product system, colorectal cancer is a very important sector.
Kunyuan has started colorectal cancer screening and surgery since its establishment.
Research and development of monitoring technology
.
After continuous exploration, we focused on the detection technology of polygene methylation in blood samples
.
First, a blood sample compliance is very good, more in line with China's current main scene cancer screening, such as medical centers, hospitals, government and other livelihood projects
.
Second, the scalability and universality of blood samples are better
.
Our technology platform can support us to screen more potentially valuable methylation markers from different cancers; thus, we can develop more cancer screening products
.
References: 1.
Adler A, et al.
BMC Gastroenterol 2014;14:183.
2.
Rutter MD, et al.
Gut 2020;69:201-223.
3.
Chen X, Gole J, Gore A, et al.
Nat Commun 2020; 11:3475.
Link to the paper: https://doi.
org/10.
1053/j.
gastro.
2021.
08.
054
