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Professor Andrew Silver, BSc, PhD

Andrew

Professor of Cancer Genetics

Profile

 

Andrew Silver graduated with First Class honours in Applied Biology from Bath University in 1980, which was followed by a CASE PhD studentship with ICI and the University of Reading. Following graduation in 1984, he undertook post-doctoral appointments with the MRC before entering the emerging field of molecular biology. In 1990, Andrew joined the National Radiation Protection Board heading the Tumour Biology and Genetics group before moving in 2003 to lead the laboratory at Cancer Research UK’s Colorectal Cancer Unit at St Mark’s Hospital. In 2006 he moved with his team, the Colorectal Cancer Genetics Group, to Barts and The London School of Medicine and Dentistry as Professor of Cancer Genetics.
 

 

Head, Colorectal Cancer Genetics
 
Co-director, National Centre for Bowel Research and Surgical Innovation

Editor, British Journal of Cancer; Editor, Pathology Research & Practice

Summary

 

Professor Silver’s group has made novel discoveries and important contributions to clinical cancer genetics including:
  • Identification of potential tumour suppressor genes in murine and human acute myeloid leukaemia
  • Localization of modifier genes of colorectal cancer
  • Understanding familial adenomatous polyposis, hereditary non-polyposis colorectal cancer, hyperplastic polyposis and Peutz-Jeghers syndrome.
  • Determining the role of the APC gene in the development of colorectal cancer.
  • Study of susceptibility variants for colorectal cancer and on the ‘just right hypothesis’ for the development of colorectal cancer and desmoids disease
  • Mutational profiling of sporadic colorectal cancer to identify biomarkers for use in the clinic.
 

Teaching

 

  • MBBS: Lectures, PBLs (Fundamental of medicine and locomotion) and mentoring. Genetics workshop
  • Intercalated BSc in Experimental Pathology: project supervision
  • MSc in Gastroenterology: lecture and project supervision 
Topics for PhD supervision:
Molecular genetics of colorectal cancer; identification of biomarkers for use in the clinic, particularly with regard to rectal cancer, surveillance of ulcerative colitis patients, understanding stenofibrosing disease in Crohn’s disease
 

Research

Research Interests:

 

Colorectal cancer; biomarkers for colorectal cancer patient management; inflammatory bowel disease; prevention and detection of dysplasia and cancer in ulcerative colitis patients; fibrosis in Crohns; diverticular disease
 
Recent and ongoing research projects:
 
A. Cancer
  • 1.0 Predicting tumour sensitivity to chemotherapy and radiotherapy in rectal cancer patients: combined chemotherapy and radiotherapy, given before removal of tumours (preoperatively) has a crucial role in the management of cancers found in the rectum. This is because chemotherapy and radiotherapy significantly increase cure rates. Whilst some rectal cancers are highly responsive to treatment, many are not and patients with non-responsive cancers have higher cancer recurrence rates. We have analyzed the genes and proteins expressed in rectal cancers from a large number of patients and now wish to expand this analysis into more patients, to identify genes and cancer proteins that will enable the prediction of which patients’ tumours will respond to standard therapy and which will not. This would then guide therapy and avoid toxic therapies for the patients that would not respond. Detailed analysis of genetic and molecular changes in cancers would enable us to identify novel targets for treatment that will allow individualised therapies.
  • 2.0 Identifying patients with bowel cancer who will not benefit from standard chemotherapy: The standard post-operative treatment for patients with bowel (colon and rectum) cancer is 5-Fluorouracil (5-FU) chemotherapy. Unfortunately, at least half of patients will have a cancer that is partly or completely resistant to this drug. Which patients will or will not benefit from 5-FU cannot yet be predicted, as our knowledge of which genes control resistance to drug treatment is incomplete. Consequently, many patients receive toxic treatments unnecessarily. Recently, microRNAs have been discovered in both cancer tissue and blood. These small RNA fragments control gene function. We have found a number of microRNAs, which control the genes involved in resistance to 5-FU in laboratory grown cells. We are now undertaking the same tests on cancers obtained from patients to determine whether the presence of specific miRNAs correlates with drug resistance. If this is the case then it will be possible to identify patients who will or will not benefit from 5-FU. This requires us to collect large numbers of cancers, to test the cancers for microRNAs and assess whether these correlate with response to chemotherapy. This will require close collaboration between laboratory, clinicians and statisticians.
  • 3.0 Improving outcome for patients with bowel cancer: We have identified a very large group of bowel cancers that have a unique group of inactivated (switched-off) genes. These genes, when switched on and functioning normally stop cancers growing. The cause of the gene inactivation is a process called methylation. We want to find out if switching these genes back on will stop cancer growth. In addition we want to find out about the behaviour of these tumours. Important questions are- what is the outcome for patients with this type of bowel cancer? If outcomes were good then some patients may not need chemotherapy, conversely if they are worse than normal, more aggressive chemotherapy treatments would reduce the chance of cancer recurrence. To do this we need to analyse significant numbers of cancers to find the best form of chemotherapy for patients. Our work will also lead to novel targets for therapy.

 

B. Inflammatory Bowel Disease.
 
  • 1.0 Early detection of tumours in patients with chronic ulcerative colitis: Ulcerative colitis is a common and serious inflammatory condition of the intestine affecting the large bowel (colon and rectum). The disease causes pain, diarrhoea and bleeding. Patients with long standing ulcerative colitis have a high risk of bowel cancer. To monitor the patient’s ulcerative colitis and to detect cancer early it is necessary to take multiple biopsies at colonoscopy when the bowel is viewed using an endoscope. Incorrect control of genes causes chronic inflammation, which can lead to cancer. MicroRNAs are involved in gene regulation and are found in inflamed and cancerous tissue and in blood. Our goal is to develop tests for particular microRNAs to identify those patients who require surgery to remove part of the bowel to prevent bowel cancer.
  • 2.0 Developing therapies to prevent bowel obstruction in Crohn's disease: Crohn’s Disease is an inflammatory condition of the bowel similar to ulcerative colitis. Patients with Crohn’s disease frequently develop obstruction of the bowel caused by narrowing of the bowel – stricturing - as a result of a build up of scar tissue (fibrosis) in the outer muscle layer of the intestine. This stricturing process often requires surgery. Unfortunately, there are no blood tests available to detect fibrosis or strictures and no therapies that prevent, delay or reverse it. Patients often require many x-ray based and endoscopic tests that can be uncomfortable and carry a small risk of harm in order to detect whether their symptoms are caused by strictures. A new class of gene regulatory elements called microRNAs has been discovered recently and we have found that there are changes in the expression of microRNAs in strictured regions of the gut compared to non-strictured areas. Also, we have shown that these miRNAs can be detected in blood samples, providing opportunities for minimally invasive patient surveillance. We now propose to develop new tests to measure the levels of microRNAs to help clinical decision-making and to find new therapies to prevent microRNAs causing fibrosis.
  • 3.0 Preventing fibrosis in complicated diverticular disease. Diverticular disease of the colon is a common problem among adults and complicated diverticular disease is associated with extensive structural changes of the bowel wall, including tissue degradation and fibrosis. Despite the disease being relatively common very little research is being conducted into diverticular disease. We plan to examine whether results from our studies on fibrosis in Crohn’s disease (see above) are applicable to diverticular disease and aim to develop new tests and therapies.
 

Publications

 

Silver A, Sengupta N, Propper D, Wilson P, Hagemann T, Patel A, Parker A, Ghosh A, Feakins R, Dorudi S, Suraweera N (2011). A Distinct DNA Methylation Profile associated with Microsatellite and Chromosomal Stable Sporadic Colorectal Cancers. International Journal of Cancer March 31 [Epub ahead of print].
 
Lai C, Robinson J, Clark S, Stamp G, Poulsom R, Silver A (2011). Elevation of WNT5A expression in polyp formation in Lkb+/- mice and Peutz-Jeghers syndrome. J Pathol 223:584-92.
 
Mcdonald S, Silver A. (2011). On target? Strategies and progress in developing therapies for colorectal cancer targeted against WNT signalling. Colorectal Diseases 13:360-9.
 
Carvajal-Carmona L, Silver A, Tomlinson I (2010). Molecular Genetics of Familial Adenomatous polyposis. In, Hereditary Colorectal Cancer. M.D. Anderson Solid Tumour Oncology Series, Chapter 3 p.45-66. Springer.
 
Mcdonald S, Silver A. (2009). Wnt5a: opposing roles in cancer. British J. Cancer, 101:209-14.
 
Robinson J, Lai C, Martin A, Nye E, Tomlinson I, Silver A. (2009). Oral rapamycin reduces tumour burden and vascularisation in Lkb1+/- mice. J Pathol,
 
Pollard P, Deheragoda M, Segditsas S, Lewis A, Rowan A, Howarth K, Willis L, Nye E, McCart A, Mandir N, Silver A, Goodlad R, Stamp G, Cockman M, East P, Spencer-Dene B, Poulsom R, Wright N, Tomlinson I. (2009). The Apc(1322T) mouse develops severe polyposis associated with sub-maximal nuclear beta-catenin expression. Gastroenterology Feb 25. [Epub ahead of print]
 
Elahi E, Suraweera N, Volikos E, Haines J, Brown N, Davidson G, Churchman M, Ilyas M, Tomlinson I, Silver A. (2009). Five quantitative trait loci control radiation-induced adenoma multiplicity in Mom1R ApcMin/+ mice. PLoS ONE. 4:e4388.
 
Vickaryous N, Polanco-Echeverry G, Morrow S, Suraweera N, Thomas H, Tomlinson I, Silver A. (2008). Smooth-muscle myosin mutations in hereditary non-polyposis colorectal cancer syndrome. British J. Cancer. 99:1726-8.
 
Segditas S, Sieber O, Deheragoda M, East P, Rowan A, Jeffery R, Nye E, Clarke S, Spencer-Dene B, Stamp G, Poulsom R, Suraweera N, Silver A, Ilyas M, Tomlinson I. (2008). Putative direct and indirect Wnt targets identified through consistent gene expression changes in APC-mutant intestinal adenomas from humans and mice. Hum Mol Genet. 17:3864-75.
 
McCart AE, Vickaryous N, Silver A. (2008) Apc mice: models, modifiers and mutants. Pathology Research and Practice. 204:479-90.

View all Andrew Silver's Research Publications at: http://www.researchpublications.qmul.ac.uk

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