Abstract
Background:
Colorectal cancer (CRC) is among the most prevalent malignancies, with an increasing incidence in China, posing increasing challenges to current screening strategies. This study aimed to evaluate the feasibility of a screening strategy based on the stool-based methylated Syndecan-2 gene (mSDC2) test for detecting advanced colorectal neoplasia in the Chinese population.
Methods:
In this multicenter randomized study, participants aged 45–80 years and identified through community screening were randomized to take either the mSDC2 test or a fecal immunochemical test (FIT), and those with positive results were referred for colonoscopy between 2020 and 2022. The primary outcome was the detection rate of advanced colorectal neoplasia, including advanced adenoma, advanced serrated polyps, and CRC. The secondary outcome was adherence to colonoscopy. Univariable and multivariable logistic regression analyses were conducted to evaluate colonoscopy adherence among participants with positive stool-based test results.
Results:
A total of 44,475 eligible participants were enrolled from 189 communities (93 in the mSDC2 test group and 96 in the FIT group). In the mSDC2 test group (n = 21,854), the detection rate of advanced neoplasia was 0.53% (n = 115), including 93 (0.43%) advanced adenomas, 8 (0.04%) advanced serrated polyps, and 17 (0.08%) CRC cases. In the FIT group (n = 22,621), the detection rate of advanced neoplasia was 0.47% (n = 106), including 71 (0.31%) advanced adenomas, 9 (0.04%) advanced serrated polyps, and 29 (0.13%) CRC cases. In addition, adherence to colonoscopy was greater in the mSDC2 test group (35.6% vs. 26.4%; odds ratio: 1.59, 95% confidence interval: 1.36–1.87; P <0.001).
Conclusions:
This study revealed the effectiveness of the mSDC2 test and FIT in detecting advanced colorectal neoplasia in a large Chinese population in a real-world setting, and indicated a possible improvement in adherence to colonoscopy for the mSDC2 test. Further studies with improved comparability and longer follow-up are warranted to clarify its clinical utility.
Registration:
Keywords: Colonoscopy, Colorectal neoplasms, Early detection of cancer, Fecal immunochemical test, Patient compliance, Syndecans
Introduction
Colorectal cancer (CRC) is the third most common and the second most lethal malignancy globally, with 1.9 million new cases and 0.9 million deaths in 2022.[1] In China, CRC ranks second in terms of incidence and fourth in terms of mortality, with an increasing trend annually.[2] Unlike the decreasing trend in the United States,[3] the incidence of CRC, especially early cancer, continues to increase in China,[4,5] with very few satisfactory results in terms of detection rate or colonoscopy adherence being met for the general population in fecal immunochemical test (FIT)-based screening program.[6]
Stool DNA (sDNA) testing, which is based on the continuous shedding of colonic epithelial cells, enables the detection of aberrant genetic and epigenetic alterations of the neoplastic cells.[7] This noninvasive, convenience-sampling approach has been implemented in population screening and was recommended as an alternative screening strategy by the U.S. Preventive Services Task Force in 2016.[8] The methylated Syndecan-2 gene (mSDC2) test, which detects hypermethylation in the SDC2 promoter region from stool and serum samples,[9,10] has been shown to be effective in identifying early-stage CRC and advanced adenomas in a recent multicenter trial,[11] positioning it as a promising marker for screening.
Adherence to referral colonoscopy following positive screening results is crucial for reducing CRC incidence and mortality, with nonadherent patients facing a 1.2-fold higher risk of CRC and nearly double the mortality rate of adherent patients.[12,13] In China, adherence rates to colonoscopy after a positive FIT have been reported to range from 14.0% to 39.8%.[14–16] Previous studies have indicated that compared with FIT, sDNA tests are associated with greater adherence to colonoscopy.[17,18]
In this context, we aimed to evaluate screening strategies based on the stool-based mSDC2 test or FIT in terms of their effectiveness in detecting advanced neoplasia and improving adherence to colonoscopy in the Chinese population.
Methods
Study design and participants
The Chinese Colorectal Cancer Screening and Intervention Project (CCRCSIP) study was designed to evaluate the performance of screening strategies based on a stool-based mSDC2 test or a commercially available FIT for detecting advanced neoplasia in a large cohort of Chinese individuals. Eligible participants were enrolled in this prospective community-based randomized study across four locations in China: Guangzhou, Shanghai, Tianjin, and Haining. The study protocol was approved by the Institutional Review Board of the Sixth Affiliated Hospital, Sun Yat-sen University (No. 2019ZSLYEC-220), and registered with ClinicalTrials.gov (NCT04221854). All the participants or their legal representatives provided written informed consent. Eligible participants aged 45–80 years at the time of consent were enrolled in this study. The exclusion criteria included a history of CRC, adenoma or other digestive tract cancers.
Sample size
For sample size calculation, we assumed advanced colorectal neoplasia detection rates of 0.4% for the FIT group and 0.7% for the mSDC2 test group, with a two-sided significance level (α) set at 0.05 and a statistical power of 90%. Using a community-based cluster randomization design, we anticipate 300 participants per community, with an intracluster correlation coefficient of 0.002. The calculations indicate that a total of 41,400 participants will be required across both groups, with each group necessitating 69 communities, amounting to 20,700 participants per group.
Clinical procedure
Participants provided written informed consent and a stool sample. Those with positive results from stool-based tests were offered a colonoscopy within 6 months; however, an extended timeline for colonoscopy was permitted because of the delay caused by the coronavirus disease 2019 global pandemic.[19] Colonoscopy bowel preparation was prescribed according to the standard of care, and the quality of bowel preparation was assessed by the endoscopist for each participant. A completed colonoscopy was defined as the visualization of the appendiceal orifice or ileocecal valve with photographic documentation, unless a large lesion or mass prohibited completion. The location and size of the lesions identified during the colonoscopy were recorded, and the resected lesions were sent for histopathological review. When multiple lesions were referred for review, the most advanced lesion was designated as the primary lesion for final data analysis. Endoscopic and histopathological reports for lesions assessed locally as advanced neoplasia underwent centralized review.
Primary and secondary outcomes
The primary outcome was the detection rate of advanced colorectal neoplasia in participants aged 45–80 years, which was assessed through two stool-based screening strategies. The secondary outcome focused on adherence to colonoscopy in the two groups. Advanced neoplasia was defined as advanced adenomas, advanced serrated polyps, and CRC, based on colonoscopy and histopathology findings. Advanced adenomas were defined as those with a tubular adenoma ≥10 mm in the largest dimension, any size of adenoma with villous features, high-grade dysplasia, or carcinoma in situ. Advanced serrated polyps were defined as serrated polyps (SPs), which included hyperplastic polyps, sessile serrated adenomas/polyps, and traditional serrated adenomas, measuring ≥10 mm or exhibiting dysplasia.
Laboratory procedure
For the FIT group, stool samples (10 mg) from participants were collected in designated tubes and transported to the laboratory (Guangzhou Hehao Medical Technology Co., Ltd., Guangzhou, China) at temperatures between 2°C and 8°C within 7 days for detection and analysis. A hemoglobin concentration greater than 100 ng/mL was classified as “positive,” whereas a concentration of 100 ng/mL or less was classified as “negative.”
For the mSDC2 test group, stool samples (4.5 g) were collected in a stool collection device containing protection buffer and delivered to the laboratory (Creative Biosciences Co., Ltd., Guangzhou, China) within 2 days. The expression of the target gene SDC2 and the control gene β-actin (ACTB) was analyzed as described previously.[11] A cycle threshold (CT) value of mSDC2 ≤38 was classified as “positive,” whereas values >38 were classified as “negative,” under the precondition—the CT value of ACTB ≤36. A CT value of ACTB >36 was considered invalid.
All samples were anonymized regarding clinical findings, and the laboratory personnel remained unaware of the participants’ clinical attributes throughout the study.
Statistical analysis
Intention-to-treat analysis was used in this study. The primary outcomes were the detection rates of colorectal neoplasia, including advanced adenoma, advanced serrated polyps, and CRC, which were calculated as the number of findings divided by the total number of participants who underwent a stool-based test in the mSDC2 test group and FIT group. Subgroup analyses were performed for those without a family history of CRC or symptoms and those who underwent colonoscopy. For the secondary outcome, adherence to colonoscopy was calculated as the number of participants who underwent colonoscopy divided by the number of those with positive stool-based test results in both groups. Continuous variables were tested for normality. Data conforming to a normal distribution are presented as the mean ± standard deviation, whereas nonnormally distributed data are presented as the median (interquartile range). Categorical variables are expressed as counts and percentages (n [%]). Detection rates of colonoscopy findings were compared using the chi-squared test, and differences across age groups were assessed using the Cochran–Armitage trend test. Both univariable and multivariable logistic regression analyses were performed to assess the adherence to colonoscopy among participants with positive stool-based test results, and odds ratios (ORs) were reported. All the statistical analyses were conducted using SPSS software (version 22, SPSS, Inc., Chicago, IL, USA) and R (version 4.4.2, https://cran.r-project.org/bin/windows/base/old/4.4.2/), with a P value of <0.05 considered to indicate statistical significance.
Results
Participants
Between 2020 and 2022, a total of 49,136 participants were enrolled from a total of 189 communities, with 93 in the mSDC2 test group and 96 in the FIT group, across the cities of Guangzhou, Tianjin, Shanghai, and Haining. After excluding 4661 participants for being ineligible or not completing the stool-based test, a total of 44,475 participants met all the inclusion criteria and completed the stool-based test, including 22,621 in the FIT group and 21,854 in the mSDC2 test group. All 3068 participants with positive results were offered a colonoscopy, and 970 participants (31.6%) accepted the examination. Because 32 participants did not complete the colonoscopy and 4 had incomplete reports, 336 participants in the FIT group and 598 in the mSDC2 test group were ultimately included in the analysis of the colonoscopy results [Figure 1].
Figure 1.
The study flowchart to investigate stool-based methylated syndecan-2 test and fecal immunochemical test for advanced colorectal neoplasia screening in Chinese population. FIT: Fecal immunochemical test; mSDC2: Methylated Syndecan-2.
The median age of the participants in the evaluable cohort was 64 years, with 59.3% being women. Among them, 1487 participants (3.3%) had a family history of CRC, 4750 (10.7%) had a history of diabetes, 2422 (5.4%) had a history of appendicitis, and 1784 (4.0%) had a history of cholecystitis. Regarding digestive symptoms, 1730 (3.9%) reported chronic constipation, 840 (1.9%) reported chronic diarrhea, and 1507 (3.4%) experienced changes in stool. All the characteristics of the participants enrolled in this study, as well as those who underwent colonoscopy, are shown in Table 1. Among the participants who completed the colonoscopies (n = 934), the majority had acceptable bowel preparation (excellent or good: 49.6%; fair: 48.7%) and achieved cecal intubation (98.1%) [Table 2].
Table 1.
Demographic characteristics of the participants in the Chinese Colorectal Cancer Screening and Intervention Project (CCRCSIP) study.
| Characteristics | All participants | Participants who underwent colonoscopy | |||
|---|---|---|---|---|---|
| Total (n = 44,475) | FIT group (n = 22,621) | mSDC2 test group (n = 21,854) | FIT group (n = 336) | mSDC2 test group (n = 598) | |
| Age (years) | 64 (12) | 64 (11) | 64 (12) | 65 (11) | 65 (10) |
| Gender | |||||
| Female | 26,382 (59.3) | 13,284 (58.7) | 13,098 (59.9) | 165 (49.1) | 296 (49.5) |
| Male | 18,093 (40.7) | 9337 (41.3) | 8756 (40.1) | 171 (50.9) | 302 (50.5) |
| BMI* | |||||
| <18.5 kg/m2 | 1073 (2.4) | 498 (2.2) | 575 (2.6) | 18 (5.4) | 15 (2.5) |
| [18.5, 25.0) kg/m2 | 23,158 (52.1) | 10,195 (45.1) | 12,963 (59.3) | 156 (46.4) | 358 (59.9) |
| ≥25.0 kg/m2 | 11,037 (24.8) | 5113 (22.6) | 5924 (27.1) | 81 (24.1) | 172 (28.7) |
| Not provided | 9207 (20.7) | 6815 (30.1) | 2392 (10.9) | 81 (24.1) | 53 (8.9) |
| Education* | |||||
| Illiteracy | 1483 (3.3) | 833 (3.7) | 650 (3.0) | 7 (2.1) | 14 (2.3) |
| Primary school | 9494 (21.3) | 5186 (22.9) | 4308 (19.7) | 84 (25.0) | 106 (17.7) |
| High school | 26,651 (59.9) | 13,588 (60.1) | 13,063 (59.8) | 204 (60.7) | 351 (58.7) |
| Undergraduate | 5553 (12.5) | 2796 (12.4) | 2757 (12.6) | 37 (11.0) | 85 (14.2) |
| Postgraduate | 308 (0.7) | 113 (0.5) | 195 (0.9) | 1 (0.3) | 4 (0.7) |
| Not provided | 986 (2.2) | 105 (0.5) | 881 (4.0) | 3 (0.9) | 38 (6.4) |
| History of diabetes* | |||||
| Yes | 4750 (10.7) | 2729 (12.1) | 2021 (9.2) | 26 (7.7) | 61 (10.2) |
| No | 24,138 (54.3) | 12,352 (54.6) | 11,786 (53.9) | 187 (55.7) | 334 (55.9) |
| Not provided | 15,587 (35.0) | 7540 (33.3) | 8047 (36.8) | 123 (36.6) | 203 (33.9) |
| History of appendicitis* | |||||
| Yes | 2422 (5.4) | 1190 (5.3) | 1232 (5.6) | 10 (3.0) | 32 (5.4) |
| No | 24,778 (55.7) | 12,772 (56.5) | 12,006 (54.9) | 191 (56.8) | 340 (56.9) |
| Not provided | 17,275 (38.8) | 8659 (38.3) | 8616 (39.4) | 135 (40.2) | 226 (37.8) |
| History of cholecystitis* | |||||
| Yes | 1784 (4.0) | 1001 (4.4) | 783 (3.6) | 14 (4.1) | 17 (2.9) |
| No | 24,896 (56.0) | 12,837 (56.7) | 12,059 (55.2) | 188 (56.0) | 344 (57.5) |
| Not provided | 17,795 (40.0) | 8783 (38.8) | 9012 (41.2) | 134 (39.9) | 237 (39.6) |
| Psychological trauma within 20 years* | |||||
| Yes | 1087 (2.4) | 548 (2.4) | 539 (2.5) | 7 (2.1) | 17 (2.8) |
| No | 21,820 (49.1) | 11,360 (50.2) | 10,460 (47.9) | 148 (44.0) | 296 (49.5) |
| Not provided | 21,568 (48.5) | 10,713 (47.4) | 10,855 (49.7) | 181 (53.9) | 285 (47.7) |
| Family history of CRC | |||||
| Yes | 1487 (3.3) | 679 (3.0) | 808 (3.7) | 13 (3.9) | 35 (5.9) |
| No | 41,523 (93.4) | 21,632 (95.6) | 19,891 (91.0) | 320 (95.2) | 524 (87.6) |
| Not provided | 1465 (3.3) | 310 (1.4) | 1155 (5.3) | 3 (0.9) | 39 (6.5) |
| Chronic constipation | |||||
| Yes | 1730 (3.9) | 943 (4.2) | 787 (3.6) | 23 (6.8) | 32 (5.4) |
| No | 25,093 (56.4) | 12,966 (57.3) | 12,127 (55.5) | 184 (54.8) | 332 (55.5) |
| Not provided | 17,652 (39.7) | 8712 (38.5) | 8940 (40.9) | 129 (38.4) | 234 (39.1) |
| Chronic diarrhea* | |||||
| Yes | 840 (1.9) | 451 (2.0) | 389 (1.8) | 8 (2.4) | 15 (2.5) |
| No | 25,448 (57.2) | 13,155 (58.2) | 12,293 (56.3) | 190 (56.5) | 341 (57.0) |
| Not provided | 18,187 (40.9) | 9015 (39.9) | 9172 (42.0) | 138 (41.1) | 242 (40.5) |
| Change in bowel habits* | |||||
| Yes | 1507 (3.4) | 716 (3.2) | 791 (3.6) | 40 (11.9) | 34 (5.7) |
| No | 26,487 (59.6) | 13,767 (60.9) | 12,720 (58.2) | 198 (58.9) | 365 (61.0) |
| Not provided | 16,481 (37.1) | 8138 (36.0) | 8343 (38.2) | 98 (29.2) | 199 (33.3) |
Data are presented as median (interquartile range) or n (%). *Percentages may not be total 100% due to rounding. BMI: Body mass index; CRC: Colorectal cancer; FIT: Fecal immunochemical test; mSDC2: Methylated Syndecan-2.
Table 2.
The quality of colonoscopy in participants who underwent completed colonoscopy in FIT group and mSDC2 test groups.
| Characteristics | Participants who underwent colonoscopy (n = 934) | FIT group (n = 336) | mSDC2 test group (n = 598) |
|---|---|---|---|
| Bowel preparation* | |||
| Excellent/good | 463 (49.6) | 150 (44.6) | 313 (52.3) |
| Fair | 455 (48.7) | 181 (53.9) | 274 (45.8) |
| Poor | 6 (0.6) | 1 (0.3) | 5 (0.8) |
| Missing data | 10 (1.1) | 4 (1.2) | 6 (1.0) |
| Cecal intubation* | |||
| Yes | 916 (98.1) | 325 (96.7) | 591 (98.8) |
| No (prohibited by a large lesion or mass) | 8 (0.9) | 7 (2.1) | 1 (0.2) |
| Missing data | 10 (1.1) | 4 (1.2) | 6 (1.0) |
Data are presented as n (%). *Percentages may not be total 100% due to rounding. FIT: Fecal immunochemical test; mSDC2: Methylated Syndecan-2.
Findings of advanced neoplasia
The proportion of advanced colorectal neoplasia increased with age [Figure 2A]. Specifically, higher detection rates were observed for advanced neoplasia, advanced adenoma and CRC (Cochran–Armitage trend test: P <0.001, P = 0.008, and P <0.001, respectively), whereas no age-related increase was detected for advanced serrated polyps (P = 0.858) [Figure 2B]. Sex-stratified analysis further revealed that compared with female participants, male participants had higher detection rates of advanced neoplasia across the aged 50–80 years groups (chi-squared test: (P = 0.009, P <0.001, and P = 0.025 for aged [50, 60), [60, 70), and [70, 80) years, respectively) and advanced adenomas across the aged 50–70 years groups (P = 0.004 and P <0.001) [Figure 2C].
Figure 2.
Detection rate of colorectal neoplasia among participants of different ages. (A) The number of neoplasia (colorectal cancer, advanced polyps, and other neoplasia) in different age groups. (B) The detection rate of advanced neoplasia in different age groups. (C) The sex-stratified detection rate of advanced neoplasia in different age groups.
The positive rates were 8.0% (1740/21,854) and 5.9% (1328/22,621) in the mSDC2 test and FIT groups, respectively. Among the 934 participants who underwent colonoscopies (598 in the mSDC2 test group and 336 in the FIT group), a total of 305 adenomas, 96 serrated polyps, and 46 CRCs were diagnosed. Of these, 164 were advanced adenomas and 17 were advanced serrated polyps [Table 3]. The detection rates of advanced neoplasia, advanced adenomas, advanced serrated polyps, and CRC were 0.53%, 0.43%, 0.04%, and 0.08%, respectively, in the mSDC2 test group, whereas they were 0.47%, 0.31%, 0.04%, and 0.13%, respectively, in the FIT group [Table 3]. The findings, which were restricted to participants without a family history of CRC or symptoms and participants who underwent colonoscopy only, are shown in Supplementary Tables 1 and 2, http://links.lww.com/CM9/C687. The results stratified by study center and clinical characteristics are shown in Supplementary Tables 3 and 4, http://links.lww.com/CM9/C687.
Table 3.
The detection rate of colorectal neoplasia in FIT group and mSDC2 test group.
| Characteristics | All participants (n = 44,475) | FIT group (n = 22,621) | mSDC2 test group (n = 21,854) |
|---|---|---|---|
| Advanced neoplasia | 221 (0.50) | 106 (0.47) | 115 (0.53) |
| Adenomas | |||
| Advanced adenomas | 164 (0.37) | 71 (0.31) | 93 (0.43) |
| Proximal | 48 (0.11) | 20 (0.09) | 28 (0.13) |
| Distal | 97 (0.22) | 44 (0.19) | 53 (0.24) |
| Rectal | 30 (0.07) | 11 (0.05) | 19 (0.09) |
| Size ≥10 mm | 123 (0.28) | 58 (0.26) | 65 (0.30) |
| Villous/tubule-villous | 85 (0.19) | 36 (0.16) | 49 (0.22) |
| High-grade dysplasia | 51 (0.11) | 23 (0.10) | 28 (0.13) |
| Nonadvanced adenomas | 141 (0.32) | 42 (0.19) | 99 (0.45) |
| Serrated polyps | |||
| Advanced serrated polyps | 17 (0.04) | 9 (0.04) | 8 (0.04) |
| Size ≥10 mm | 13 (0.03) | 8 (0.04) | 5 (0.02) |
| Dysplasia | 4 (0.01) | 1 (0.004) | 3 (0.01) |
| Nonadvanced serrated polyps | 79 (0.18) | 35 (0.15) | 44 (0.20) |
| Synchronous advanced adenomas and advanced serrated polyps* | 6 (0.01) | 3 (0.01) | 3 (0.01) |
| Colorectal cancer | 46 (0.10) | 29 (0.13) | 17 (0.08) |
| Early-stage colorectal cancer | 10 (0.02) | 6 (0.03) | 4 (0.02) |
Data are presented as n (%). *: These cases have already been counted in the advanced adenomas and advanced serrated polyps rows, respectively.FIT: Fecal immunochemical test; mSDC2: Methylated Syndecan-2.
Adherence to colonoscopy
Among participants whose stool-based test results were positive, 35.6% of those in the mSDC2 test group (620/1740) and 26.4% of those in the FIT group (350/1328) adhered to colonoscopy. Univariable logistic regression model analysis revealed that age, education, a family history of CRC, changes in bowel habits, and the type of stool-based test were correlated with compliance with colonoscopy in the total population, whereas a history of diabetes and changes in bowel habits were correlated with compliance in the FIT group and a family history of CRC, chronic diarrhea, and changes in bowel habits were correlated with compliance in the mSDC2 test group (P <0.05) [Supplementary Table 5, http://links.lww.com/CM9/C687]. All the variables were included in the multivariable logistic regression model analysis, which indicated that age, changes in bowel habits, and the type of stool-based test were independent factors influencing the acceptance of colonoscopy in the total population [Table 4]. Participants were more likely to undergo colonoscopy when they used mSDC2 tests than when they used FITs (OR: 1.59; 95% confidence interval: 1.36–1.87; P <0.001).
Table 4.
The multivariable logistic regression model of factors influencing the compliance for colonoscopy.
| Factors | Wald | OR (95% CI) | P values |
|---|---|---|---|
| All population (n = 3068) | |||
| Age | |||
| [50, 60) vs. [45, 50) years | 0.50 | 0.86 (0.57–1.30) | 0.481 |
| [60, 70) vs. [45, 50) years | 1.29 | 0.79 (0.53–1.19) | 0.257 |
| [70, 80) vs. [45, 50) years | 5.01 | 0.62 (0.41–0.94) | 0.025 |
| Education | |||
| Primary school vs. illiteracy | 2.68 | 1.51 (0.92–2.47) | 0.102 |
| High school vs. illiteracy | 1.00 | 1.28 (0.79–2.05) | 0.317 |
| Undergraduate vs. illiteracy | 2.04 | 1.46 (0.87–2.45) | 0.154 |
| Postgraduate vs. illiteracy | 1.02 | 1.92 (0.54–6.81) | 0.313 |
| Family history of CRC: yes vs. no | 3.30 | 1.42 (0.97–2.08) | 0.069 |
| Change in bowel habits: yes vs. no | 18.91 | 2.11 (1.51–2.94) | <0.001 |
| Tests: mSDC2 test vs. FIT | 32.10 | 1.59 (1.36–1.87) | <0.001 |
| FIT group (n = 1328) | |||
| History of diabetes: yes vs. no | 3.25 | 0.62 (0.36–1.04) | 0.072 |
| Change in bowel habits: yes vs. no | 5.06 | 2.17 (1.11–4.26) | 0.024 |
| mSDC2 test group (n = 1740) | |||
| Family history of CRC: yes vs. no | 4.07 | 1.63 (1.01–2.61) | 0.044 |
| Chronic diarrhea: yes vs. no | 3.55 | 2.10 (0.97–4.50) | 0.060 |
| Change in bowel habits: yes vs. no | 0.08 | 1.10 (0.56–2.14) | 0.783 |
CI: Confidence interval; CRC: Colorectal cancer; FIT: Fecal immunochemical test; OR: Odds ratio; mSDC2: Methylated Syndecan-2.
Discussion
The CCRCSIP was a large-scale study evaluating participants aged 45–80 years, which is consistent with the United States Preventive Services Task Force (USPSTF) and Chinese guidelines.[20,21] Although there is increasing focus on CRC screening in China, most prior studies have been regional and retrospective. The generalizability of the CCRCSIP was enhanced through its prospective, community-based randomized design, encompassing representative areas in southern, eastern, and northern China. The established cancer screening programs in these areas provided a solid foundation for this study.[13,22–24]
In this study, the mSDC2 test yielded a higher positive rate than the FIT did (8.0% vs. 5.9%), which was higher than that reported in a recent study.[25] However, it remained lower than that of the widely used multitarget sDNA test (16.1%).[26] According to previous studies, the sensitivity of the mSDC2 test was 83.8% for CRC and 42.1% for advanced adenomas, with a specificity of 98.0%,[11] similar to that of the multitarget sDNA test (sensitivity: 92.3% for CRC, 42.4% for advanced precancerous lesions, specificity: 86.6%).[26] Given the similar capability, a lower positive rate might help reduce the number of unnecessary colonoscopies.
The detection rates of advanced neoplasia, advanced adenomas, advanced serrated polyps, and CRC were 0.50%, 0.37%, 0.04%, and 0.10%, respectively, in the total cohort [Table 3]. A higher detection rate of neoplasia, except for advanced serrated polyps, was observed in older and male participants [Figure 2C], which aligns with findings from a U.S. colonoscopy cohort.[27] The detection rate of CRC matched findings from a recent national study, whereas the rates of advanced adenomas, advanced serrated polyps, and advanced neoplasia were lower than those reported in that study.[28] As we observed an increase in the detection rate of advanced neoplasia with age [Figure 2A], the differing age distributions might have contributed to the lower detection rate observed.
Adherence to screening and subsequent colonoscopy is crucial, especially for noninvasive tests.[29] Although colonoscopy serves as the diagnostic reference standard, it is associated with risks such as bleeding and perforation, which may affect adherence. In this study, factors influencing adherence to colonoscopy included the type of screening test, age, and changes in bowel habits in the total population [Table 4]. Participants who underwent the mSDC2 test exhibited significantly higher adherence rates to colonoscopy than those who received a FIT (35.6% vs. 26.4%). These findings align with those of previous studies demonstrating higher adherence rates for sDNA tests than for FITs.[17,18] Furthermore, the adherence rate in the FIT group was consistent with that in prior studies conducted in China (14.0–76.3%).[14–16,30] Importantly, nonadherence to colonoscopy following a positive screening result increases the incidence of CRC and the mortality associated with CRC.[12,13,31] Therefore, the higher adherence to colonoscopy among mSDC2 participants may enhance the effectiveness of the mSDC2 test-based screening strategy.
In the TARGET-C study,[30] although the FIT group exhibited a high adherence rate to colonoscopy (76.3%), compared with both the one-time colonoscopy group and annual risk-adapted screening group, the FIT group demonstrated a lower detection rate. Compared with FIT alone, integrating patient characteristics with stool-based tests or combining multiple stool-based detection methods has shown superior detection performance, as evidenced by a previous study.[25] Future studies may need to explore the personalized and integrated application of different technologies for CRC screening.
Our study has several notable strengths, including its community-based randomized design, coverage of representative regions in China, and comprehensive histopathological characterization of polyp features. However, several limitations should also be acknowledged. First, given the cluster randomization, those who agreed to participate may represent a medium- to high-risk CRC population or individuals who do not undergo routine health checkups. This could introduce potential selection bias and limit the generalizability of our findings to the broader population. Second, lifestyle factors such as smoking and alcohol consumption were not adequately collected, limiting further analysis of their potential impact. Third, it was not designed as a blinded study because of the differences in fecal sampling devices, which might have influenced the adherence of participants. Furthermore, the mSDC2 test is a single-targeted assay and multiple-targeted tests might increase the diagnostic capability; however, this might also increase the cost. As technology advances, the cost of screening strategies based on sDNA tests may decrease, making them more affordable and widely used in the near future.
The CCRCSIP is a prospective, multicenter randomized study to evaluate the effectiveness of screening strategies based on the mSDC2 test or FIT for detecting advanced colorectal neoplasia in a large Chinese population. Our study revealed the effectiveness of the mSDC2 test and FIT in a real-world setting and offered evidence of adherence to colonoscopy in both groups. Further studies with improved comparability and extended follow-up are warranted to better elucidate the clinical value of the mSDC2 test for large-scale CRC screening.
Data availability statement
The data that support the findings of this study are available from the corresponding author (Xiaosheng He) upon reasonable request.
Acknowledgment
The authors thank Professor Mingyang Song from Harvard T.H. Chan School of Public Health for providing advice in statistical analysis.
Funding
The study is supported by National Key R&D Program of China (No. 2023YFC2507400, 2022YFA1304000, and 2017YFC1308800), National Key Clinical Discipline, National Natural Science Foundation of China (No. 82172561), Guangdong Special Young Talent Plan of Scientific and Technological Innovation (No. 2022B1515020022), Science and Technology Program of Guangzhou, China (No. 2024A04J6399), The National Natural Science Foundation of China Key Joint Project (No. U21A20344), and The program of Guangdong Provincial Clinical Research Center for Digestive Diseases (No. 2020B1111170004).
Conflicts of interest
None.
Supplementary Material
Footnotes
Yufeng Chen, Jiaxin Li, Kai Gu, and Kefeng Ding contributed equally to this study.
How to cite this article: Chen YF, Li JX, Gu K, Ding KF, Qin PZ, Pei ZC, Gong YM, Xu D, Liang YR, Yang D, Dou JM, Huang YQ, Hu JC, Wu P, Zhang SY, Wang WR, Shi LS, Liu Q, Li CJ, Li W, Wang XM, Lan P, Liang BH, He XS. Stool-based methylated syndecan-2 test and fecal immunochemical test for advanced colorectal neoplasia screening in the Chinese population: A multicenter randomized noncomparative study. Chin Med J 2026;139:2922–2929. doi: 10.1097/CM9.0000000000003897
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Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Data Availability Statement
The data that support the findings of this study are available from the corresponding author (Xiaosheng He) upon reasonable request.