Faecal Microbiota Characterization in Lynch Syndrome (LS) Patients With or Without Colorectal Neoplasia

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Brief Title

Faecal Microbiota Characterization in Lynch Syndrome (LS) Patients With or Without Colorectal Neoplasia

Official Title

Faecal Microbiota Characterization in Lynch Syndrome (LS) Patients With or Without Colorectal Neoplasia ( AAS-Lynch-Microbiote)

Brief Summary

      Colorectal cancer (CRC) is the second cause of cancer-related death in western countries. CRC
      prevention and screening are major public health issues. Better knowledge of colorectal
      carcinogenesis could lead to better prevention. Gut microbiota (GM) is a complex community of
      bacteria, fungi, protozoa, viruses and bacteriophages which live in a symbiotic and
      epigenetic relationship with the host. GM can promote either digestive health or CRC through
      inflammatory and proliferative effects.

      Lynch syndrome (LS) is the most common familial CRC syndrome with a lifetime CRC risk of 52%
      in women and 69% in men. The risk of CRC depends upon type of altered mismatch-repair gene
      and environmental factors (diet, exercise, obesity, tobacco and alcohol intake, etc.).
      Regular surveillance including annual or biannual colonoscopy is recommended in LS patients.

      Chemoprevention has the potential to represent a cost-effective intervention in these
      high-risk patients and could allow a delay in colonoscopy surveillance. Regular low dose
      aspirin use is associated with a 20 to 30% reduction in the risk of sporadic colonic adenomas
      and CRC. The real benefit of aspirin is still to be consolidated. AAS-Lynch trial is an
      ongoing prospective multicenter (n=37), double-blind, placebo-controlled, randomized clinical
      trial, designed to investigate whether daily aspirin, at a dose of 100 or 300 mg compared
      with placebo, would decrease the occurrence or recurrence of colorectal adenomas in LS
      patients. The primary endpoint is the number of patients with at least one adenoma detected
      by chromo-endoscopy 48 months after initial colon clearance. At randomization and at the end
      of study, stool collection, blood collection, quality of life questionnaire, validated food
      frequency questionnaire (SU-VI-MAX2) and physical activity questionnaire are performed.

      The ongoing AAS-Lynch study allow accessing to a unique fecal collection in very well
      characterized LS patients including a comprehensive dietary evaluation at high risk for
      colorectal neoplasia and planned colonoscopy surveillance during a 48 months follow-up,
      exposed or not exposed to chronic low dose aspirin. The expertise of the scientific
      consortium with state of the art microbiota analysis, the comprehensive collection of data
      and the prospective design of the study will allow the evaluation of the true role of gut
      microbiota in CRC carcinogenesis.
    

Detailed Description

      Background and originality of the project with regards to the state of the art :

      Colorectal cancer (CRC) is the second leading cause of cancer-related death in western
      countries and the third most prevalent cancer worlwide. CRC prevention and screening are
      major public health issues. Better knowledge of colorectal carcinogenesis could lead to
      better prevention and screening. Recent observational data in human and experimental data in
      vitro or in rodents showed that gut microbiota could contribute to CRC pathogenesis.

      The proposal will allow the evaluation of the role of gut microbiota in CRC carcinogenesis in
      a cohort of Lynch syndrome (LS) patients at high risk for colorectal neoplasia and with well
      characterized environmental risk factors particularly dietary factors.

      Microbiota and CRC Gut microbiota is a complex community consisting of bacteria, fungi,
      protozoa, viruses and bacteriophages which live in a symbiotic and epigenetic relationship
      with the host. Gut microbiota can promote either health or tumor progression through its
      inflammatory and proliferative effects likely dependent on the context and genetic factors of
      the host. Specific microorganisms or variability of the microbiome have been associated with
      CRC over the past years. Fusobacterium nucleatum and Porphyromonas gingivalis sequences are
      over represented in CRC versus matched normal control tissue, and a positive association with
      lymph node metastasis has been characterized. In patients with sporadic CRC, Fusobacterium
      nucleatum overexpression is associated with specific CRC carcinogenesis pathways. Studies
      have also identified several other bacteria as Escherichia coli, Bacteroides fragilis, and
      Enterococcus faecalis increase in CRC patients, whereas the Clostridiales, Faecalibacterium,
      Blautia, Bifidobacterium, or Lactobacillus genus were low or absent. In vitro, Fusobacterium
      nucleatum promotes CRC cell proliferation; in mice, the presence of F. nucleatum
      inpatient-derived CRC xenografts (where patient CRC samples are implanted in mice) increases
      tumor growth rates. A possible mechanism to explain these findings is that the F. nucleatum
      adhesin, FadA, binds to E-cadherin on the CRC cell surface and activates oncogenic
      Wnt/β-catenin signaling. F. nucleatum can also alter the function of tumor-infiltrating
      lymphocytes and natural killer (NK) cells by binding to the inhibitory immune receptor TIGIT
      (T cell immunoreceptor with Ig and ITI Mdomains) through another adhesin, Fap2. Fap2 also
      binds a disaccharide sugar motif [galactoseN-acetyl-D-galactosamine (Gal-GalNAc)] which is
      expressed at high levels on the surface of many tumor cell types, as well as other cell
      types, and facilitates F. nucleatum binding to CRC cells. Enterotoxigenic Bacteroides
      fragilis (ETBF) potentiates colorectal carcinogenesis in mice, and ETBF was detected in
      biofilms coating human CRCs and precancerous colonic lesions. Escherichia coli expressing the
      genomic island polyketide synthase (pks+) enhance tumorigenesis in preclinical CRC models and
      are enriched in human CRC tissues. pks+ E. coli produce the genotoxin colibactin, which
      alkylates DNA, resulting in DNA adducts in colonic epithelial cells.

      Bacterial metabolites have also been seen to have an effect. Butyrate which can only be
      produced by specific members of the Firmicutes phylum through the fermentation of dietary
      fiber and resistant starches can modulate inflammation, epithelial proliferation, and
      apoptosis. Hydrogen sulfide is also an important regulatory metabolite.

      The complexity of microbiota and the relationship between microorganisms in the gut does not
      underline yet a particular bacterial signature for tumor progression so far. Then, how gut
      microbiota really contributes to CRC pathogenesis in the host is not fully understood.

      CRC and Lynch syndrome LS is the most common familial CRC syndrome. Cancer family history is
      an important way to identify these at-high risk individuals. Inheritance of a germline
      alteration in one of the DNA mismatch repair (MMR) genes MLH1, MSH2, MSH6, PMS2 or in EPCAM
      genes causes a high risk of CRC and other extra-colonic related cancers. Recent studies have
      suggested a median age of CRC diagnosis of 61 years and a lifetime CRC risk of 52% in women
      and 69% in men. Specific carcinogenesis pathways are characterized in LS neoplasia.

      LS patients presents precancerous lesion as non-advanced or advanced adenomas and serrated
      polyps that should be detected and removed. The risk of CRC depends upon which
      mismatch-repair gene is mutated. MSH6 and PMS2 germline mutations are associated with a lower
      risk with late onset of CRC.

      Environmental factors (dietary factors, exercise, obesity, tobacco and alcohol intake, etc.)
      are also involved in LS carcinogenesis. Regular surveillance including annual or biannual
      colonoscopy is recommended in LS patients.

      Aspirin CRC chemoprevention Chemoprevention has the potential to represent a cost-effective
      intervention in these high-risk patients and could allow a delay in colonoscopy surveillance.
      Several epidemiological studies have shown that regular use of low dose aspirin (75 to 300
      mg/d) is associated with a 20 to 30 % reduction in the risk of sporadic colonic polyps and
      CRC. Five out of seven randomized controlled trials (RCT) showed a significant decrease in
      neoplasia recurrence and a meta-analysis of four of these studies shown a decrease in
      sporadic colorectal polyp recurrence. However, in a recent large randomized study in diabetic
      patients, aspirin was not associated with a lower CRC incidence.

      An observational large study suggests also a preventive aspirin effect in LS. The primary
      analysis of the Colorectal Adenoma/Carcinoma Prevention Program 2 (CAPP2) study in LS
      patients receiving 600-mg daily aspirin (300 mg b.i.d) showed no significant decrease in CCR
      neoplasia. However, a preplanned secondary analysis after extended follow-up (mean 56 months)
      showed a reduced risk of CRC in the aspirin group (HR=0.41; 95% CI, 0.32-0.99). In this
      study, the endoscopic follow-up was not optimal with a low detection rate of colorectal
      neoplasia. Therefore the real effect and clinical benefit of aspirin are still to be
      consolidated in LS patients since aspirin chronic use is associated with possible
      side-effects (bleeding).

      AAS-Lynch Study AAS-Lynch trial is an ongoing prospective multicenter (n=37), double-blind,
      placebo-controlled, randomized clinical trial, designed to investigate whether daily aspirin,
      at a dose of 100 or 300 mg compared with placebo, would decrease the occurrence or recurrence
      of colorectal adenomas in LS patients under 75 years of age. The primary endpoint is the
      number of patients with at least one adenoma detected by chromo-endoscopy 48 months after
      initial colon clearance with complete polyp removal and after treatment onset. The secondary
      end-points are the delay between the appearance of the first adenoma and treatment onset,
      adenomatous polyp burden measured by chromo-endoscopy, the number of patients who presented
      an adenoma during follow-up according to the affected gene (MLH1, MSH2, MSH6, PMS2 or other),
      sessile serrated adenoma burden, colon cancers diagnosed at scheduled surveillance
      colonoscopies, interval colon cancer (diagnosed between two colonoscopies). The number of
      colonoscopies performed during follow-up, the quality of bowel cleansing, the observance
      assessed by remaining tablets in blisters and adverse events are monitored. At randomization
      and at the end of study, stool collection, blood drops collection on blotting paper, quality
      of life using the SF36 questionnaire, validated food frequency questionnaire (SU-VI-MAX2,
      U557 INSERM) and physical activity questionnaire are performed.

      Hypothesis, main objective(s) and endpoint(s) Gut microbiota seems to be a major player in
      CRC carcinogenesis. Better knowledge on microbiota role in CRC carcinogenesis could lead to
      better prevention and surveillance particularly in high risk LS patients but also in standard
      risk patients.

      The main objective of this study is to evaluate the role of the gut microbiota using
      metagenomic analysis in CRC carcinogenesis in LS patients. The AAS-LYNCH study design design
      will allow evaluation of the role of the gut microbiota in adenoma apparition or recurrence
      in patients according to well characterized associated dietary risk factors and other life
      style factors, involved genes and neoplasia involved pathways.

      Primary objective To compare fecal microbiota diversity in LS patients with no previous
      adenoma vs LS patients with an history of adenoma or adenoma at inclusion in AAS-Lynch study.

      Secondary objectives

      To describe differences in the gut microbiota diversity using metagenomic analysis according
      to :

        -  involved LS genes (MLH1, MSH2, MSH6, PMS2 or in EPCAM genes)

        -  adenoma type (advanced or non-advanced adenoma) and presence of serrated polyp

        -  diet, using dietary patterns (a priori and a posteriori patterns)

        -  other life style factors : BMI, physical activity, alcohol, tobacco

      Perspectives (not included in the present application) :

      With an expected 30% adenoma recurrence after colon initial clearance, the 48 months
      follow-up will allow to explore differences in gut microbiota characterized by metagenomic
      analysis according adenoma recurrence. The 48 months follow-up with new fecal collection will
      also allow describing differences in gut microbiota according to aspirin exposition. No
      additional funding will be required for these evaluations.

      A study evaluating the chemopreventive aspirin effect in LS patients coordinated by the
      UK-CAPP group is ongoing with a similar design but without placebo group and different
      endpoints. Final shared analysis was discussed. An evaluation of international variation in
      fecal microbiota in relation with LS will be discussed with this group.

      Primary endpoint (linked to the primary objective) This study will compare fecal microbiota
      richness and composition differences between LS patients with no previous adenoma at
      inclusion in AAS-Lynch study and LS patients with history of adenoma or adenoma at inclusion
      in AAS-Lynch study.

      Secondary endpoints (linked to the secondary objectives)

      Gut microbiota composition(taxonomic, functional and richness assessed by metagenomic
      analysis) will be described according to :

        -  involved LS genes (MLH1, MSH2, MSH6, PMS2 or in EPCAM genes)

        -  adenoma type (advanced or non-advanced adenoma) and presence of serrated polyp

        -  diet, using dietary patterns (a priori and a posteriori patterns)

        -  other life style factors : BMI, physical activity, alcohol, tobacco

      Project plan describing the methodology and work to be performed :

        -  WP 1. Preparation of the project, regulatory issues and fecal handling

        -  WP 2. Verification of socio-demographic, lifestyle and nutritional data quality,
           nutritional data management.

        -  WP 3. Microbiota metagenomic study and data analysis

        -  WP 4. Final meeting and report, submission for publication

      Expected results and scientific and medical potential impact of the translational research:

      Colorectal cancer (CRC) is the second leading cause of cancer-related death in western
      countries. CRC prevention and screening are major public health issues. Better knowledge of
      the role of gut microbiota in CRC carcinogenesis could contribute to a better description of
      CRC risk with at a putative better surveillance.

      Interventional therapies as prebiotic or probiotic therapies using specific microbes or
      genetically modified microbes could also be considered as preventive tools in near future.
    


Study Type

Observational [Patient Registry]


Primary Outcome

This study will compare fecal microbiota richness and composition differences between LS patients with no previous adenoma at inclusion in AAS-Lynch study and LS patients with history of adenoma or adenoma at inclusion in AAS-Lynch study.

Secondary Outcome

 Gut microbiota composition description

Condition

Lynch Syndrome



Publications

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

Recruitment Information



Estimated Enrollment

285

Start Date

April 20, 2021

Completion Date

December 30, 2024

Primary Completion Date

December 30, 2024

Eligibility Criteria

        Inclusion Criteria:

          -  Patients included in the AAS-Lynch study (NCT02813824 on clinicaltrials.gov)

          -  Fecal samples taken for the AAS-Lynch study (NCT02813824 on clinicaltrials.gov)

          -  Food questionnaires collected as part of the AAS-Lynch study (NCT02813824 on
             clinicaltrials.gov)

        Exclusion Criteria:

          -  Patients who did not included in the AAS-Lynch study (NCT02813824 on
             clinicaltrials.gov)

          -  Patients who did not consent for the Fecal samples in AAS-Lynch study (NCT02813824 on
             clinicaltrials.gov)

          -  Patients who did not do the Food questionnairy in AAS-Lynch study (NCT02813824 on
             clinicaltrials.gov)
      

Gender

All

Ages

18 Years - 75 Years

Accepts Healthy Volunteers

No

Contacts

Robert BENAMOUZIG, MD, PhD, 33148957104, [email protected]

Location Countries

France

Location Countries

France

Administrative Informations


NCT ID

NCT04791644

Organization ID

APHP200136


Responsible Party

Sponsor

Study Sponsor

Assistance Publique - Hôpitaux de Paris


Study Sponsor

Robert BENAMOUZIG, MD, PhD, Principal Investigator, Assistance Publique - Hôpitaux de Paris


Verification Date

February 2021