Development of a better screening test for bowel cancer.

Colorectal cancer (CRC) is the second leading cause of death from cancer despite the fact that the disease is curable when detected in its early stages. Furthermore, CRC is preventable by a number of methods which include adenoma detection and removal Studies of faecal occult blood testing have demonstrated that annual screening with such tests leads to a reduction in mortality Studies clearly show that screening can also lower cancer incidence through the early detection and removal of precancerous polyps including adenomas. Based on this evidence, to effectively decrease incidence at the population level, we need to identify and remove adenomas. The current methods for identifying people likely to have adenomas are largely ad hoc and limited. Conversely, a sensitive and specific marker with strong positive predictive value for colorectal adenomas would provide an effective selection process for individuals to undergo colonoscopy, and polypectomy when an adenoma is found. The literature now describes a number of molecular characteristics of adenomas that may be useful in this setting but none of these has been explored for its value in blood or faeces. In addition, preliminary molecular studies here at Flinders University using materials from the tissue bank have identified approximately 67 genes that show promise differentiating adenomas from normal tissue. We now have a need to establish a clinical bank of relevant target clinical materials (specifically faeces and blood), that would allow us to determine the presence of these markers in faeces and blood and to relate them to the neoplastic status of patients. Phase 1 research and research by others has identified several colorectal neoplasia-associated biomarkers in blood that may be useful, individually or together, for the development of new screening tests for early detection of colorectal neoplasia. Phase 2 of the research will evaluate the accuracy in larger population samples of several candidate biomarkers for detection of screen-relevant colorectal neoplasia, relative to a proven immunochemical faecal occult blood test (iFOBT, FIT) and the diagnostic test colonoscopy. The panel includes at least one candidate biomarker, KIAA1199, highly expressed in colorectal neoplasia relative to normal colonic epithelium, and which is also detectable in blood of CRC patients. To evaluate the accuracy of a panel of blood-based candidate biomarkers for detection of screen-relevant colorectal neoplasia, relative findings at colonoscopy, a commercial blood based test for CRC and to a proven faecal occult blood test (FOBT). We will invite participants who are scheduled for a colonoscopy to complete an FOBT (Faecal Occult Blood Test), on one occasion only, prior to their colonoscopy. The participant will be asked to collect a sample of approximately 0.5 g of stool using provided scoop and transfer the scoop with faeces into a double sealed, self-contained transport vessel that stabilizes and disperses the faecal sample for storage and transport. We will take one blood sample only just prior to the participant’s colonoscopy procedure. We will view the results (histopathology) of colonoscopy or/and any ensuing colorectal surgery Phase 2b Some patients resected for CRC will be subsequently diagnosed with further (recurrent) cancer, not necessarily located within the bowel. Some current simple methods to monitor patients for recurrence of CRC, such as CEA, are not optimal. A blood test using the biomarker panel may more sensitive for detection of recurrent cancers and blood samples will be assayed for our markers during monitoring as approved for serial sampling after diagnosis. To explore this possibility, we first need to determine whether the CRC biomarkers we have identified are detectable in tumour tissues from both an initial and any subsequent cancer from the same patient. We propose an initial small retrospective observational sub-study within BiBCoN to determine the pattern of expression of the markers across time and tumour locations. One or both of the tumour samples would be derived from the Joint RGH and FMC Tissue Bank where patients have consented for tissue to be accessed for research. Where possible the level of expression of other clinical biomarkers for recurrent cancer may be determined on the same tissue samples. If both samples from the same patient prove to be positive for the biomarker test panel in a small initial sample, further prospective studies using tissues and blood from patients with recurrent cancer will be proposed to explore the feasibility of the blood test to detect cancer recurrence.Each patient will be followed for 2 years. Phase 3 Patients aged between 18 - 85 who are diagnosed with a primary adenocarcinoma of the bowel, and those who attend clinic appointments at Flinders Medical Centre, will be enrolled into the study after obtaining informed consent. Blood will be collected through venepuncture (4 x 9mL K3-EDTA tubes) by trained nurses prior to any type of cancer treatment (ie. prior to chemotherapy, radiotherapy and surgery). Whole blood samples will be centrifuged, and plasma and serum will be isolated and stored in cryovial aliquots at -80 degrees until analysis for concentrations of methylated BCAT1 and IKZF1 and other novel biomarkers. For patients that undergo cancer resection prior to chemotherapy or radiotherapy, consent will be asked to obtain some tissue samples from any excess specimen from surgery (a cancer specimen and adjacent normal tissue). The collection of this tissue will be stored in the Flinders Medical Centre tissue bank. Tissue will have DNA extracted for analysis of biomarker levels to allow direct comparison to blood biomarker levels within the same patient. Cancer pathology details (including stage of disease, pathological features) will be recorded. Other blood indicators that have been taken as part of clinical care prior to surgery will be recorded. Patients will be interviewed by nurses to record current medications and other medical conditions, as well as any previous cancers. Levels of methylated BCAT1 and IKZF1 in the blood and surgical tissue will be determined for all samples. Each patient will be followed up for 3 years, for any signs of CRC recurrence. Information related to routine CRC surveillance will be collected and patients may be asked to provide further blood samples, (2 x 9mL K3-EDTA tubes) during neoadjuvant/adjuvant treatment, at 6 weeks post treatment, then at 6 monthly intervals or whenever attending doctors appointments at Flinders Medical Centre. Genomic material (DNA or RNA) will be extracted from blood and/or tissue samples for genetic sequencing analysis to uncover genomic locations that are associated with the patient’s tumour, that are commonly found in adenocarcinomas.