Exploratory Study of Rectal Mucus for Diagnosing Disease
Condition: Bowel Cancer; Bowel Disease; Genomic; Epigenetic Disorder
MeSH terms: Intestinal Diseases
Study type: Observational

Summary: 
      The identification of patients with colorectal cancer is challenging as they present with a
      variable symptom profile and require invasive tests (colonoscopy) for diagnosis (through
      histological analysis of biopsies) and complimented by cross-sectional radiology, prior to
      commencement of treatment. The biopsy forms the basis of the diagnosis and management
      planning for a patient with colorectal cancer through the multidisciplinary team.

      The biggest challenge currently faced in the management of colorectal cancer is the accurate
      identification of patients who present with various symptoms none of which are specific for
      bowel cancer. Currently the NICE referral guidelines are used to determine the
      appropriateness of referral pathway, i.e. Fast-Track/Two-Week Wait referral. A recent review
      of over 10000 referrals revealed a colorectal cancer diagnosis in 4.1% of referrals. Previous
      literature reports rates as high as 8%, but in series of cases with only 72-89% adherence to
      the referral guidance leading to at best 40% of all colorectal cases being diagnosed through
      this route. The remainder of colorectal cancers being diagnosed through the bowel cancer
      screening programme (NBCSP), non-two-week wait referrals and other processes such as
      emergency admissions. Inherently the Two-Week Wait pathway refers a large volume of
      "symptomatic patients" and it has become a "cancer exclusion pathway." Once cancer has been
      excluded, patients are often discharged back to General Practice, yet the patients often
      still have symptoms. The current Covid-19 pandemic has had a significant impact on the
      already pressed Two-Week pathway impacting on the reduction of endoscopic and radiological
      appointments available leading to delays in treatment. Each test performed in the diagnostic
      pathway has a significant financial, personal, and institutional resource profile.

      It is our aim to develop a novel diagnostic device based upon the identification of genetic
      mutations and genomic alterations from material trapped in the rectal mucous layer allowing
      focused endoscopic assessment, confirmation/exclusion of cancer diagnosis from
      cross-sectional imaging in those unfit for endoscopic examination and identification of
      high-risk lesions (dysplasia). This would allow a greater triage, and focus colonoscopic
      services onto therapeutic procedures, improving overall care.
    

Detailed description: 
      Colorectal cancer (CRC) is the fourth most common cancer overall worldwide contributing to
      9.7% of global cancer burden. It affects 746,000 men (10% of all cancer cases) and 614,000
      women (9.2% of all cancer cases) with most cases (55%) occurring in developed countries.
      Furthermore, in the UK, 42,300 new colorectal cancer cases are diagnosed each year making it
      the fourth most common cancer overall, and third most common in males and females. In
      addition, the incidence of colorectal cancer increased between 1991 and 2016 and is
      attributed to lifestyle, environmental changes, and aging populations. Although bowel cancer
      incidence has fallen in the UK in the past decade by 4%, the lifestyle risk factors remain.
      Moreover, the burden of CRC is expected to increase with 2.2 million new cases and 1.1
      million deaths expected globally by 2030. In addition, significant challenges remain in
      managing disease burden.

      In England, five-year overall survival for CRC is 58.4% which is lower than the US reported
      60-65%. Further challenges remain due to the ageing demographic and advanced presentation of
      disease. Older patients, above age 75 years, make up 44% of new colorectal cancer diagnoses
      and an estimated 20-25% of CRC is diagnosed at the metastatic stage with an additional 25% of
      patients developing metastasis during their illness. As a result, CRC accounts for 8.5% of
      cancer related deaths worldwide with 16,300 deaths per year in the UK making it the second
      most frequent cause of cancer related deaths at 10%. Although survival is stage dependent
      with 92% survival for stage I, compared to 10% in stage IV, there has been an improvement in
      survival for the 60-69-year age group attributed to screening. Thus, CRC remains a prevalent
      challenge in cancer management emphasizing the need for early diagnosis.

      Declining mortality due to improvements has been shown with early detection through screening
      and effective treatment. The UK CRC screening program relying on faecal detected occult blood
      (FOBT) and colonoscopy has led to 16% decline in overall mortality rate without affecting
      incidence. However, FOBT has reduced sensitivity for advanced adenomas and CRC which may
      improve with newly implemented immunochemical testing (qFiT). With the pressures on service
      from the Covid-19 pandemic, qFIT has been implemented into the Two-Week Pathway to attempt to
      stratify patients at highest risk of colorectal cancer and the NICE-qFiT Study publication is
      awaited.

      Biomarkers are molecular patterns that can be used as a tool for early cancer detection and
      individualized CRC treatment. They can be divided into diagnostic, prognostic, or predictive
      categories. Thus, biomarkers provide utility at different stages of the disease to determine
      disease progression, recurrence, as well as providing a personalized indicator for
      therapeutic effectiveness.

      Firstly, early diagnosis in asymptomatic patients remains a key target to achieve favourable
      survival outcomes through identification of early CRC as well as pre-malignant lesions
      including high risk polyps. This forms the basis of the National Bowel Screening Programme.
      The sensitivity for detecting CRC using current qFIT testing (100ng/mL) is 73.8% versus 92.3%
      for a stool-based DNA assay screening KRAS, aberrant NDRG4 and BMP3 methylation. Furthermore,
      qFIT testing sensitivity for advanced precancerous lesions is 23.8% versus 42.4% with stool
      DNA testing. Moreover, the rate of detection of polyps with high-grade dysplasia is 46.2%
      with qFIT testing verses 69.2% with stool DNA testing, whereas the detection rate of serrated
      sessile polyps measuring >1 cm is only 5.1% (qFIT) versus 42.4% with stool DNA sampling.
      These findings highlight the limits of current diagnostic screening and difficulty in
      establishing appropriate surrogate markers for early disease detection in asymptomatic
      individuals.

      Current non-invasive screening stools are not sensitive to detect pre-cancerous lesions and
      regularly miss significant early CRC.

      As outlined, the investigator currently have a low threshold in symptomatic patients for
      colonoscopy in these patients and further tools are required to support identifying early
      pre-malignant lesions (adenomas) and CRC .

      The investigator knows from the recognition of the adenoma - carcinoma sequence and the
      impact of hyper- and hypomethylation that the local environment that there are a number of
      steps both in carcinogenesis and the associated risks.

      At an epigenetic level, DNA methylation changes is one of the hallmark events in
      carcinogenesis, characterized by global hypomethylation and paradoxical gene-specific
      hypermethylation. Hypomethylation is primarily involved in chromosomal instability and global
      loss of imprinting, while gene-specific hypermethylation anchors to promoters, it causes
      transcriptional silencing of tumour suppressor genes and consequently sets the stage for
      neoplastic transformation. Deregulated DNA methylation is well known to be associated with
      CRC. The first evidence of DNA methylation contributing to CRC was presented, in which a
      global loss in DNA methylation was identified. Then, extensive efforts have been made in
      identifying aberrant hypermethylation in promoters of CRC-related suppressor genes, such as
      APC, SFRP2, SEPT, and CDH1. Remarkably, a near universal phenomenon that gene-specific
      hypermethylation occurred in both pre-neoplastic and neoplastic phase of colorectal cancer
      was observed. This might shed light on the process of tumorigenesis. However, few studies
      have defined precisely the hierarchy of methylation events during the transformation from
      normal epithelial cells to malignant cells in colorectal carcinogenesis.

      It is becoming increasingly apparent that the occurrence of molecular alterations could be
      found not only in tumour tissue but also in histological normal-appearing tissue adjacent to
      the tumour. The presence of such molecular alterations in histological normal-appearing
      tissue is commonly known as field cancerization or field effect. This has been thought to
      constitute the earliest clone in the carcinogenesis process. In colorectal carcinogenesis, a
      few numbers of gene-specific hypermethylation events have been reported in normal-appearing
      colonic mucosa from CRC patients (such as APC, DKKI, MGMT, CDKN2A, and SFRP4). In addition,
      previous studies have also demonstrated the effect of aberrant DNA methylation on suppressor
      genes such as MINT1, MINT31, SLC5A8, and MGMT, during adenoma-carcinoma sequence. These
      findings suggest that the presence of field effect in methylation might be a useful
      intermediate biomarker in etiologic studies. A better understanding of when these epigenetic
      tags occur and how they take part in colorectal progression may represent a practical
      opportunity for colorectal cancer risk assessment. The use of a unique biological material
      capture device with genomic and epigenetic assessment of the retrieved specimen is the basis
      of the trial.
    

Observational model: Cohort
Time perspective: Prospective
Sampling method: Non-Probability Sample
Study population: 
        Subjects with known or suspected gastrointestinal disease(s).
      
Biospecimen description: 
      Banked DNA retrieved from specimen taken from bowel lumen