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Chromosomal instability (CIN) refers to ongoing chromosome segregation errors throughout consecutive cell divisions. CIN is a hallmark of human cancer, and it is associated with poor prognosis, metastasis, and therapeutic resistance. Analyzing CIN of the DNA extracted from urothelial cells in urine samples seems a promising method for diagnosing, monitoring, and predicting the prognosis of bladder cancer patients. CIN can be assessed using experimental techniques such as bulk DNA sequencing, fluorescence in situ hybridization (FISH), or conventional karyotyping. However, these techniques are either time-consuming or non-specific. We here intend to study whether a new method named Ultrasensitive Chromosomal Aneuploidy Detection (UCAD), which is based on low-coverage whole-genome sequencing, can be used to analyze CIN thus help diagnosing and treating bladder cancer patients.
CIN results from errors in chromosome segregation during mitosis, leading to structural and numerical chromosomal abnormalities. It will generate genomic heterogeneity that acts as a substrate for natural selection. Furthermore, it is proved that tumors with aneuploidies and polyploidy resulting from whole-genome doubling are related with metastasis, treatment resistance, and decreased overall survival. It is estimated that 60%-80% of human tumors exhibit chromosomal abnormalities suggestive of CIN. CIN positively correlates with tumor stage and is enriched in relapsed as well as metastatic tumor specimens. Due to the ubiquity of CIN in cancer cells, it is a potentially non-invasive way to detect CIN in the urothelial cells from the urine sample for diagnosing and monitoring bladder cancer patients. UCAD is a new method to detecting CIN in the DNA sample from patients, including extracting DNA from urine, analyzing DNA by low-coverage whole-genome sequencing, processing the data by bio-information techniques, and finally optimizing the management of bladder cancer patients.
The investigators intended to conduct a prospective study by analyzing urine samples from bladder cancer patients and control groups that without any tumor in the urinary system or other organs to compare the specificity and sensitivity of UCAD test for diagnosing urothelial carcinoma to other modalities, such as urine cytology or fluorescence in situ hybridization (FISH).
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| Urothelial carcinoma group | Pre-surgery patients with urothelial carcinoma will be the experimental group to determine the sensitivity and specificity of UCAD analysis, the result will be compared with cytology and FISH. |
| |
| Non-cancer participants group | Patients being treated for other diseases but without any tumor will provide a negative control to provide data for determining the sensitivity and specificity of UCAD analysis. |
|
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| Low-coverage whole-genome sequencing of urine exfoliated cells | Diagnostic Test | The level of CIN The extracted DNA from morning urine will be analyzed by UCAD to determine the level of CIN. |
| Measure | Description | Time Frame |
|---|---|---|
| Sensitivity of urinalysis by UCAD analysis | Number of patients "declared positive" with the UCAD test among the patients suffered from urothelial carcinoma. | Up to 1 years |
| Specificity of urinalysis by UCAD analysis | Number of patients "declared negative" with the UCAD test among the patients without cancer. | Through study completion, an average of 12 months |
| Measure | Description | Time Frame |
|---|---|---|
| Comparison of the sensitivity of the UCAD analysis versus urine cytology | Number of patients "declared positive" with the UCAD analysis versus patients "declared positive" with the urine cytology. | Up to 1 years |
| Comparison of the specificity of the UCAD analysis versus urine cytology |
| Measure | Description | Time Frame |
|---|---|---|
| Identification of the correlation between the level of CIN and the grade of the tumor sample | Level of CIN in the urine sample compared with the grade of the tumor confirmed by histopathologic examination | Up to 1 years |
| Identification of the correlation between the level of CIN and the stage of the tumor sample |
Inclusion Criteria:
Exclusion Criteria:
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Patients diagnosed with urothelial carcinoma or participants in control group in Changhai Hospital from May 2019 till the end of this study.
| Name | Role | Phone | Extension | |
|---|---|---|---|---|
| Shuxiong zeng, M.D., Ph.D | Contact | +8618930568759 | zengshuxiong@126.com |
| Name | Affiliation | Role |
|---|---|---|
| Chuangliang Xu, M.D., Ph.D | Changhai Hospital | Study Chair |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| Changhai Hospital | Recruiting | Shanghai | Shanghai Municipality | 200433 | China |
| PubMed Identifier | Type | Citation | Retractions |
|---|---|---|---|
| 24346386 | Background | Wadhwa N, Mathew BB, Jatawa SK, Tiwari A. Genetic instability in urinary bladder cancer: An evolving hallmark. J Postgrad Med. 2013 Oct-Dec;59(4):284-8. doi: 10.4103/0022-3859.123156. | |
| 29342134 | Background | Bakhoum SF, Ngo B, Laughney AM, Cavallo JA, Murphy CJ, Ly P, Shah P, Sriram RK, Watkins TBK, Taunk NK, Duran M, Pauli C, Shaw C, Chadalavada K, Rajasekhar VK, Genovese G, Venkatesan S, Birkbak NJ, McGranahan N, Lundquist M, LaPlant Q, Healey JH, Elemento O, Chung CH, Lee NY, Imielenski M, Nanjangud G, Pe'er D, Cleveland DW, Powell SN, Lammerding J, Swanton C, Cantley LC. Chromosomal instability drives metastasis through a cytosolic DNA response. Nature. 2018 Jan 25;553(7689):467-472. doi: 10.1038/nature25432. Epub 2018 Jan 17. |
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We will try to protect the information of the included participants
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| ID | Term |
|---|---|
| D002295 | Carcinoma, Transitional Cell |
| D002869 | Chromosome Aberrations |
| D004194 | Disease |
| ID | Term |
|---|---|
| D002277 | Carcinoma |
| D009375 | Neoplasms, Glandular and Epithelial |
| D009370 | Neoplasms by Histologic Type |
| D009369 | Neoplasms |
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DNA from Urine Exfoliated Cells will be analyzed by Ultrasensitive Chromosomal Aneuploidy Detection
Number of patients "declared negative" with the UCAD analysis versus patients " declared negative " with the urine cytology. |
| Up to 1 years |
Level of CIN in the urine sample compared with the stage of the tumor confirmed by histopathologic examination. |
| Up to 1 years |
| 29907142 | Background | Liu H, He W, Wang B, Xu K, Han J, Zheng J, Ren J, Shao L, Bo S, Lu S, Lin T, Huang J. MALBAC-based chromosomal imbalance analysis: a novel technique enabling effective non-invasive diagnosis and monitoring of bladder cancer. BMC Cancer. 2018 Jun 15;18(1):659. doi: 10.1186/s12885-018-4571-7. |
| 30178746 | Background | Hieronymus H, Murali R, Tin A, Yadav K, Abida W, Moller H, Berney D, Scher H, Carver B, Scardino P, Schultz N, Taylor B, Vickers A, Cuzick J, Sawyers CL. Tumor copy number alteration burden is a pan-cancer prognostic factor associated with recurrence and death. Elife. 2018 Sep 4;7:e37294. doi: 10.7554/eLife.37294. |
| 33037018 | Derived | Zeng S, Ying Y, Xing N, Wang B, Qian Z, Zhou Z, Zhang Z, Xu W, Wang H, Dai L, Gao L, Zhou T, Ji J, Xu C. Noninvasive Detection of Urothelial Carcinoma by Cost-effective Low-coverage Whole-genome Sequencing from Urine-Exfoliated Cell DNA. Clin Cancer Res. 2020 Nov 1;26(21):5646-5654. doi: 10.1158/1078-0432.CCR-20-0401. Epub 2020 Oct 9. |
| D010335 |
| Pathologic Processes |
| D013568 | Pathological Conditions, Signs and Symptoms |