Clinical Trial Details
— Status: Recruiting
Administrative data
| NCT number |
NCT04865601 |
| Other study ID # |
M239 |
| Secondary ID |
|
| Status |
Recruiting |
| Phase |
|
| First received |
|
| Last updated |
|
| Start date |
February 15, 2021 |
| Est. completion date |
December 31, 2025 |
Study information
| Verified date |
November 2023 |
| Source |
University of Copenhagen |
| Contact |
Lars Ove Drasted, professor |
| Phone |
+4535332694 |
| Email |
ldra[@]nexs.ku.dk |
| Is FDA regulated |
No |
| Health authority |
|
| Study type |
Observational
|
Clinical Trial 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.
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, e.g. 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.
