Ignite Creation Date:
2024-05-06 @ 4:05 PM
Last Modification Date:
2024-10-26 @ 2:03 PM
Study NCT ID:
NCT04865601
Status:
RECRUITING
Last Update Posted:
2023-11-30
First Post:
2021-04-26
Brief Title:
DNA Adductomics for Colorectal Cancer Investigation
Sponsor:
University of Copenhagen
Organization:
University of Copenhagen
Study Overview
Official Title:
Novel DNA Adductomics Methodological Developments for Research in Colon Cancer
Status:
RECRUITING
Status Verified Date:
2023-11
Last Known Status:
None
Delayed Posting:
No
If Stopped, Why?:
Not Stopped
Has Expanded Access:
False
If Expanded Access, NCT#:
N/A
Has Expanded Access, NCT# Status:
N/A
Acronym:
adductomics
Brief Summary:
This project seeks to identify DNA-adducts in colon tissue from different groups of patients with CRC scheduled for complete or partial colon resections Other patients scheduled for resection of the colon serve as controls In addition surrogate samples such as white blood cells are investigated for the presense of adducts while blood plasma and urine are investigated for the presense of DNA-repair products
Detailed Description:
Colorectal cancer CRC develops as a result of multiple genetic mutations causing normal intestinal epithelium to transform into a colorectal carcinoma Genetic mutations may be caused by many different genetic events including chemical damage to the DNA nucleosides These chemical modifications are due to both exogenous compounds coming from diet environment and gut microbiota or endogenous compounds produced by our own metabolic processes like inflammation and oxidative stress Such genetic alteration is thought to be the starting event leading to development of sporadic CRC However there is little understanding on which DNA nucleoside modifications are associated with increased risk of CRC and their mechanism of action The study of these DNA nucleoside modifications has been addressed in the recent years by a new research field called DNA adductomics DNA adductomics uses the new advanced high resolution mass spectrometry HRMS instrumentations for identifying the complexes that are formed between toxic compounds and DNA namely DNA adducts
Some studies have been previously identified DNA adducts in CRC with older technology However there is not a real evidence on which DNA adducts are related to sporadic CRC hereditary non polyposis colorectal cancer HNPCC and other diseases such as familial adenomatous polyposis FAP which turns into CRC with a 95 risk before the age of 35 The lack of more recent human studies in DNA adductomics is mainly due to the lack of appropriate analytical methods Developing such methods requires sufficient sample material and the amount of sample in a colon biopsy is too low to be used for method development In this study colon epithelial tissue obtained by resection of colon during surgery will be used for developing a more sensitive method possibly allowing DNA adduct analysis from biopsies in future studies In order to ascertain that the developed method can differentiate the level of DNA-adducts between inherited CRC sporadic CRC and non-CRC subjects also materials from other groups coming to the hospital for colon resections will be obtained By analyzing the materials obtained in a case-control manner we might also be able to resolve whether some of the DNA adducts differ between the different CRC cases or in comparison with cancer-free subjects This knowledge should provide a preliminary basis for suggesting prevention and intervention approaches to reduce morbidity and mortality from CRC
However in case-control studies a proper selection of the subjects should be carried out by assuring gender and age balance between the control group and the CRC group This will be difficult in the first part of the current study since 1 there is limited possibility of obtaining resected colon from healthy subjects 2 CRC incidence rates are markedly higher in men than in women and 3 different types of CRC develop at different ages It is also obvious that a method relying on analyses of colon resections would have a limited application in preventive medicine A solution to these issues may be the use of appropriate surrogate samples like blood faeces and urine Indeed since DNA lesions may be removed from the genome by the DNA repair system they are often excreted in urine in faeces or in blood In order to know whether we may substitute tissues with surrogate samples we will explore whether there is a correlation between DNA-repair product level in surrogate samples and DNA adducts in colon tissues Substituting colon tissues with surrogates or developing a sensitive method for DNA analysis from biopsies would allow an easier collection of the samples giving the possibility in the future of performing large and controlled clinical studies as well as less invasive sampling from patients This could allow to confirm a causal relationship between specific DNA-adducts and CRC providing real advances in prevention and intervention approaches
Finally after the identification of the DNA adducts and DNA-repair products possibly associated with CRC it will be important to identify the real cause of DNA adducts formation Our final purpose is therefore identifying which life-style dietary or environmental factors are possibly associated with the DNA adducts and DNA-repair products identified in colon and surrogate samples respectively For this purpose we will perform a metabolic profiling of serum urine and faeces a microbial profiling of faeces and we will correlate it with basic information on patient life styles about smoking alcohol consumption and intake of red meat eg factors suspected to influence risk of colonic diseases
Establishing a causal relationship between specific DNA-adducts and CRC or other colonic diseases and understanding the causes for DNA adducts formation will not only yield much richer insights into the molecular defects but will also result in advances in prevention and intervention approaches
Some studies have been previously identified DNA adducts in CRC with older technology However there is not a real evidence on which DNA adducts are related to sporadic CRC hereditary non polyposis colorectal cancer HNPCC and other diseases such as familial adenomatous polyposis FAP which turns into CRC with a 95 risk before the age of 35 The lack of more recent human studies in DNA adductomics is mainly due to the lack of appropriate analytical methods Developing such methods requires sufficient sample material and the amount of sample in a colon biopsy is too low to be used for method development In this study colon epithelial tissue obtained by resection of colon during surgery will be used for developing a more sensitive method possibly allowing DNA adduct analysis from biopsies in future studies In order to ascertain that the developed method can differentiate the level of DNA-adducts between inherited CRC sporadic CRC and non-CRC subjects also materials from other groups coming to the hospital for colon resections will be obtained By analyzing the materials obtained in a case-control manner we might also be able to resolve whether some of the DNA adducts differ between the different CRC cases or in comparison with cancer-free subjects This knowledge should provide a preliminary basis for suggesting prevention and intervention approaches to reduce morbidity and mortality from CRC
However in case-control studies a proper selection of the subjects should be carried out by assuring gender and age balance between the control group and the CRC group This will be difficult in the first part of the current study since 1 there is limited possibility of obtaining resected colon from healthy subjects 2 CRC incidence rates are markedly higher in men than in women and 3 different types of CRC develop at different ages It is also obvious that a method relying on analyses of colon resections would have a limited application in preventive medicine A solution to these issues may be the use of appropriate surrogate samples like blood faeces and urine Indeed since DNA lesions may be removed from the genome by the DNA repair system they are often excreted in urine in faeces or in blood In order to know whether we may substitute tissues with surrogate samples we will explore whether there is a correlation between DNA-repair product level in surrogate samples and DNA adducts in colon tissues Substituting colon tissues with surrogates or developing a sensitive method for DNA analysis from biopsies would allow an easier collection of the samples giving the possibility in the future of performing large and controlled clinical studies as well as less invasive sampling from patients This could allow to confirm a causal relationship between specific DNA-adducts and CRC providing real advances in prevention and intervention approaches
Finally after the identification of the DNA adducts and DNA-repair products possibly associated with CRC it will be important to identify the real cause of DNA adducts formation Our final purpose is therefore identifying which life-style dietary or environmental factors are possibly associated with the DNA adducts and DNA-repair products identified in colon and surrogate samples respectively For this purpose we will perform a metabolic profiling of serum urine and faeces a microbial profiling of faeces and we will correlate it with basic information on patient life styles about smoking alcohol consumption and intake of red meat eg factors suspected to influence risk of colonic diseases
Establishing a causal relationship between specific DNA-adducts and CRC or other colonic diseases and understanding the causes for DNA adducts formation will not only yield much richer insights into the molecular defects but will also result in advances in prevention and intervention approaches
Study Oversight
Has Oversight DMC:
None
Is a FDA Regulated Drug?:
False
Is a FDA Regulated Device?:
False
Is an Unapproved Device?:
None
Is a PPSD?:
None
Is a US Export?:
None
Is an FDA AA801 Violation?:
None