Causal association between physical activity and breast cancer subtype; a Mendelian randomization study (MSc Research)

Breast cancer is the second most common cancer in women worldwide accounting for approximately 25 percent of all new cases of cancer in women. Sedentary behavior could increase cancer risk through various mechanisms for example a compromised immune system and enhanced insulin-resistance and inflammation. Physical-activity (PA) is a modifiable lifestyle risk factor and increased physical-activity may lower the risk of breast cancer by reducing metabolic hormones (e.g., insulin resistance) and systemic inflammation (e.g., C-reactive protein) and increasing immune cell components (e.g., T-helper cells). There is strong evidence that higher levels of physical activity are linked to lower risk of several types of cancer. We have previously applied two-sample Mendelian randomization (MR) and the results showed that physical activity can reduce the risk of breast cancer.

The aim of this project (MSc Research) is to investigate the causal link between physical activity and triple-negative breast cancer (TNBC) using a MR approach. TNBC can develop in women of any age and ethnicity but it is more common in women under forty years old and in black women. MR is a methodological approach that has been increasingly used to find evidence of causality using genetic data. The student will systematically examine whether biomarkers within the inflammatory pathway e.g., CRP and IL6 mediate the effect of physical activity on the risk of breast specifically TNBC using two-step MR. For causal biomarkers, the student will also carry-out mediation analyses to determine the extent to which the physical activity influences cancer risk via the inflammatory biomarkers.

The student will be expected to perform MR analyses to underpin the causal relationship between physical activity and TNBC and to understand the causal mechanisms in particular inflammatory pathways underpinning associations of physical activity with risk of breast cancer including TNBC.

i)                   Using genetic instruments for physical activity perform two sample MR analyses to identify whether there is a causal relationship of physical activity with TNBC.

ii)                 Identify single nucleotide polymorphisms (SNPs) associated with the inflammatory biomarkers.

iii)               Using genetic instruments for physical activity and intermediates (i.e., the inflammatory biomarkers) carry-out two-step Mendelian randomization analyses to determine whether intermediates are on the casual pathway between physical activity and breast cancer risk.

iv)               Apply several sensitivity analyses including weighted median, weighted mode, MR-Egger regression, MR-PRESSO and colocalization analyses to rule out pleiotropy.

v)                 For intermediates found to be on the casual pathway between physical activity and cancer risk carry-out mediation analysis to determine the proportion of the risk which can be attributed to the particular intermediate.

The student will be supervised by Dr Nabila Kazmi (University of Bristol) who has expertise in Genetic Epidemiology and Mendelian randomization analysis and Professor Sarah Lewis (Professor of Molecular Epidemiology; University of Bristol) who has a well-established track record in cancer research, in particular through the application of causal inference analysis to understand the aetiology of cancer and to identify lifestyle risk factors for cancer.

Funding

Funding is through the Opportunity Bristol scheme, which aims to widen participation in postgraduate research programmes, funding including a stipend may be available for those who self-identify as being from a Black, African, Black British, or Caribbean, or mixed background. In other cases, there is no identified funding, but this would be suitable for those who can self-fund their studies.

A prospective student must be accepted for entry to a research-related, master's-level programme (as defined by Faculties and specified above) in Academic Year 2021-22;

How do I apply?

Candidates who wish to apply for this 1 year funded MSc (Research) opportunity should first complete the online application for entry to their preferred programme on the main postgraduate study application page noting their interest in the Opportunity Bristol programme within their application if applicable. Please choose Population Health MSc (Research). This funding is only available to UK applicants. EU and International students may apply but would need to provide their own funding.

The student stipend will be £15,609 and there will be a £1000 consumables budget.

Candidates who wish to be considered for these awards must submit a complete, online application by 12 Noon on 31 May 2021.

Informal initial enquiries are welcomed at nabila.kazmi@bristol.ac.uk