DNA Adductomics for Colorectal Cancer Investigation

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Brief Title

DNA Adductomics for Colorectal Cancer Investigation

Official Title

Novel DNA Adductomics Methodological Developments for Research in Colon Cancer

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, 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.
    


Study Type

Observational


Primary Outcome

DNA adductome in CRC and other diseases

Secondary Outcome

 Correlation of DNA adducts with microbiota

Condition

Colorectal Cancer

Intervention

resectomy of the colon

Study Arms / Comparison Groups

 CRC
Description:  Patient affected by any sporadic colorectal cancer

Publications

* Includes publications given by the data provider as well as publications identified by National Clinical Trials Identifier (NCT ID) in Medline.

Recruitment Information


Recruitment Status

Other

Estimated Enrollment

60

Start Date

February 15, 2021

Completion Date

December 31, 2021

Primary Completion Date

December 31, 2021

Eligibility Criteria

        Inclusion Criteria:

          -  Patients with either FAP, Lynch syndrome, other HNPCC, sporadic colorectal cancer,
             ulcerative colitis or other conditions who are scheduled for whole or partial
             resection of their colon

        Exclusion Criteria:

          -  Any condition that makes the investigator or hospital personnel doubt that voluntary
             participation isfeasible.

          -  Patients who are not able to understand and sign the informed consent form for any
             reason, including lack of a sufficient period of time to consider their participation.

          -  Patients who are below 18 years of age.

          -  Patients who donated blood to a blood bank within 3 months prior to their operation.
      

Gender

All

Ages

18 Years - N/A

Accepts Healthy Volunteers

Accepts Healthy Volunteers

Contacts

Lars Ove O Dragsted, PhD, +4535332694, [email protected]

Location Countries

Denmark

Location Countries

Denmark

Administrative Informations


NCT ID

NCT04865601

Organization ID

M239


Responsible Party

Principal Investigator

Study Sponsor

University of Copenhagen

Collaborators

 Hvidovre University Hospital

Study Sponsor

Lars Ove O Dragsted, PhD, Principal Investigator, University of Copenhagen


Verification Date

April 2021