Professor Richard Martin
School of Social and Community Medicine
University of Bristol
Bristol, UK
Project title (1)
Association of factors in the folate metabolic pathway with prostate cancer incidence and progression. (2007/07)
Scientific abstract (1)
Epidemiological studies examining the relationship of folate with prostate cancer reveal mixed results, and biological mechanisms exist whereby folate could plausibly decrease or increase risk. Prostate cancer is one of the commonest male cancers worldwide. It is clearly of considerable public health importance, therefore, to understand the relationship of folate and related metabolites (e.g. homocysteine and B12) with prostate cancer incidence and progression, since many countries either already legislate for folic acid supplementation of some foods or are planning to do so.
Previous epidemiological studies have been small and have generally utilised dietary measures of folate intake, which are known to have high levels of measurement error. This current case control study is nested within the intensive population-based case finding phase (involving 115,000 PSA tested men from 500 general practices accross the UK) of the ProtecT trial (Prostate Testing for Cancer and Treatment). The study is based on 1500 screen detected prostate cancer cases and 1500 controls, and will also exploit the active monitoring arm of the ProtecT trial to investigate associations with disease progression.
The aim of the proposed research is to investigate associations of plasma folate, associated metabolites and genetic polymorphisms influencing folate metabolism pathways on risk of screen detected prostate cancer, on prostate cancer stage and on risk of progression of localised prostate cancer.
Project title (2)
Association of circulating vitamin D metabolite levels with incidence and progression of screen-detected prostate cancer (2006/15)
Scientific abstract (2)
Point estimates from case-control/nested cohort studies indicate a 12-42% reduction in prostate cancer associated with vitamin D. These studies are small, with wide confidence intervals, limiting the evidence-base to currently justify large-scale intervention trials. Few studies investigate possible differential effects of vitamin D metabolites (biologically more active 1,25-dihydroxyvitamin D (1,25(OH)2D) versus circulating 25-hydroxyvitamin D (25(OH)D)) or whether associations vary by cancer stage, histology or progression.
To assess the potential of vitamin D in prostate cancer primary and secondary prevention, this study will relate circulating 25(OH)D and 1,25(OH)2D levels with prostate cancer incidence, stage (localised/advanced) and progression using a case-control study nested within the population-based case-finding phase (involving 115,000 PSA tested men from 500 general practices in 9 UK areas) of the ProtecT trial (Prostate Testing for Cancer and Treatment). The study will be based on 1500 screen-detected incident prostate cancer cases and 1500 controls, making it the largest single study to date on vitamin D and prostate cancer.
Project title (3)
The causal role of the nutritionally regulated insulin-like growth factor system in prostate cancer: Mendelian randomization study (2011/419)
Scientific abstract (3)
Prostate cancer mortality is several-fold greater in 'western' than Asian countries, generating speculation that 'westernisation’ (involving high meat, milk, alcohol intakes; low exercise; and obesity) is important in the aetiology of prostate cancer. A metabolic endpoint of westernisation is hyperinsulinaemia and perturbations of the insulin-like growth factor (IGF) system, and this is a potential mechanism linking diet and obesity to cancer. The nutritionally-regulated IGFs and their binding proteins (IGFBPs) play a key role in somatic growth, but they also activate intracellular signalling networks involved in carcinogenesis. There are positive associations of circulating IGFs/IGFBPs with prostate cancer but results are inconsistent - whether elevated IGFs cause prostate cancer or reflect confounding or reverse causality is unclear. The objective of this research is to clarify the causal role of the circulating IGF system in prostate cancer and its progression, using Mendelian randomization and to investigate associations of dietary and lifestyle exposures with those IGFs/IGFBPs shown to be causally associated with prostate cancer.
Employing genes associated with circulating IGFs/IGFBPs as surrogates for circulating ligands Mendelian randomization enables causal inference about whether IGF-I causes prostate cancer or is, instead, a tumour marker, because genetic association studies are not subject to reverse causality and confounding seen in observational studies that measure phenotypes. Population-based case-control study of the IGF-system in screen-detected disease (ProtecT), in which 2,000 prostate cancer cases and 2,000 controls have already been phenotyped for circulating IGF-I, IGF-II, IGFBP-2 and IGFBP-3 will be used. DNA from the samples will be used for targeted genotyping to perform Mendelian randomization instrumental variables analysis and establish causality. (SNPs) for the analyses will be selected through a two stage procedure. Firstly literature and web-based bioinformatics searches to identify potentially functional common variants in IGF-related genes, which are associated with circulating IGFs. Secondly by investigation of associations of the SNPs identified above with IGFs amongst the 2317 in ProtecT who have already been typed for > 2.5 million genome-wide SNPs (GWAS, test-sample); those SNPs associated with IGFs will then be genotyped amongst 1,683 additional men to determine whether associations are replicated (validation-sample). Relationships between replicated SNPs and prostate cancer, will be undertaken. Mendelian randomization analysis, in the whole sample will also be conducted. Data on diet and lifestyle will be used to investigate associations of dietary and lifestyle exposures with those IGFs that are causally associated with prostate cancer.
If the results shows that IGF-prostate cancer associations are causal, this would suggest that the IGF system may mediate associations of dietary, lifestyle and metabolic factors with prostate cancer and suggest that nutritional and/or behavioural interventions to reduce IGFs could be indicated for the prevention of prostate cancer or its progression.
Project 1 plain language abstract
Folate is a type of B vitamin which is necessary for the normal synthesis, repair, and functioning of genetic material (DNA). There have been claims that folate could either decrease or increase the risk of prostate cancer, but previous studies have generally been small, had poor measures of folate status, and were unable to assess the role of folate in the progression, as well as the development, of prostate cancer Prostate cancer is one of the commonest male cancers worldwide and, since many countries either already legislate for folic acid supplementation of some foods or are planning to do so, it is clearly of considerable public health importance to understand the relationship of folate and associated factors with the development and progression of prostate cancer. We plan to undertake a case-control study nested within the intensive population-based case finding phase (involving 115,000 men from 500 general practices across the UK) of the ProtecT trial (Prostate Testing for Cancer and Treatment). The study will be based on 1500 screen detected prostate cancer cases and 1500 controls, and will also investigate associations of folate with the progression of localised to more advanced cancers.
Project 2 plain language abstract
An individual’s risk of cancer is influenced by their diet and lifestyle as well as their genes. Laboratory evidence suggests that blood vitamin D levels may protect against prostate cancer. However, few studies in human populations have been conducted and those that have provide promising but inconclusive evidence. This is because the studies are too small to reach robust conclusions. To assess the potential of vitamin D in prostate cancer prevention, we will relate blood vitamin D levels with the development and progression of prostate cancer. The study will involve 1500 men with prostate cancer and 1500 men without, making it the largest single study to date on vitamin D and prostate cancer. The study sample will be based on a large population-based case-finding study involving 115,000 men from 500 general practices across the UK. Prostate cancer is fast becoming the most common cancer in men but screening and treatment of localised disease offer only limited benefits, especially when set aside the complications of current treatments. If our study suggests that vitamin D is protective, then this could indicate that prostate cancer or its progression may be preventable by increasing vitamin D exposure through dietary or therapeutic means.
Project 3: Plain language abstract
Background: Hormones that regulate how tall we grow and the normal development of our organs in early life circulate in high concentrations in our bodies. Levels of these hormones vary considerably (due to differences in our genetic make-up, diet and other reasons), and partly explain differences in height between individuals. However, in adulthood, after we have finished growing, people who have raised levels of these hormones seem to have an increased risk of cancer, including prostate cancer. The possible reasons for this finding, which has been shown in many studies, are unclear and the picture is currently confusing. Some people assume that the finding occurs because high levels of these hormones cause imbalances in the normal growth and production of cells and tissues in adulthood, which ultimately leads to the development of abnormal cells that become cancers. Others argue that the hormones don't cause cancers to develop, but high levels can cause those that have already started growing to become more aggressive/serious and to spread around the body. Another explanation is that the cancers themselves produce these hormones. Thus, raised levels of these hormones may not cause cancer or its progression, but are an indication that a cancer may be present. The final explanation is that these findings are nothing to do with the hormones, but are due to other factors that are in some way related to them.
Aims & Goals: This research aims to understand why men with prostate cancer appear to have raised growth-related hormone levels.
How it will be done: The researchers will assess whether men with a genetic make-up that causes a rise in these hormones also have an increased risk of prostate cancer developing or progressing, or whether raised hormone levels are due to the presence of tumour. Hormone levels in 2000 men with prostate cancer and 2000 healthy men will be studied.
Potential impact: The research is important, because if growth-related hormones cause prostate cancer or its progression, then treatments that lower hormone levels in order to prevent the initiation or progression of prostate cancer could be potentially designed. Nutritional interventions may be relatively straightforward to develop as the nutritional determinants (e.g. milk) of growth-related hormones as a number of them are already known. If, instead, it is the cancers that cause a rise in the levels of these hormones, then this information could be used to develop clinical blood tests to diagnose the presence and aggressiveness of prostate cancer and to monitor the response of prostate cancers to treatment.
Institution and location |
Degree |
Year |
Scientific Field |
|---|---|---|---|
University of Nottingham, UK |
BMedSci |
1988 |
Medical Sciences |
University of Nottingham, UK |
BM BS |
1990 |
Medicine |
Royal College of GPs, UK |
MRCGP |
1994 |
General Practice |
London School of Hygiene & Tropical Medicine, UK |
MSc (with distinction) |
1999 |
Epidemiology |
Faculty of Public Health Medicine |
MFPHM |
2003 |
Public Health |
University of Bristol, UK |
PhD |
2004 |
Epidemiology |
| From 2008-current | Professor of Clinical Epidemiology |
| 2004-2008 | Consultant Senior Lecturer, then Reader in Clinical Epidemiology, Department of Social Medicine, Bristol University |
| 2001–2004 | Wellcome Trust Training Fellow in Clinical Epidemiology, Department of Social Medicine, Bristol University: |
| 1999–2001 | Lecturer in Epidemiology & Public Health, Department of Social Medicine, Bristol University |
| 1997–1999 | Clinical Research Fellow & GP, Drug Safety Research Unit |
| 1995–1997 | Clinical Research Fellow & GP, St George’s Medical School |
| 1991–1995 | General Practice Training Scheme, Canterbury & Thanet GP Training Scheme |
Research interests
Prostate cancer epidemiology.
