Commentary: What can Mendelian randomization tell us about causes of cancer?

Mariosa, Daniela; Carreras‐Torres, Robert; Martin, Richard M.; Brennan, Paul

doi:10.1093/ije/dyz151

Cited by 27 publications

(28 citation statements)

References 29 publications

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“…Several MR studies support a causal association between higher body fatness and risk of six obesity-related cancers [ 84 ], renal cell carcinoma [ 54 ], endometrial [ 85 ], ovarian [ 55 , 86 , 87 ], oesophageal [ 88 ], pancreatic [ 51 , 89 , 90 ] and colorectal cancer [ 87 , 91 ] and reduced survival in oestrogen receptor-positive (ER+) breast cancer [ 92 ]. Higher body fatness has also been found to be causally associated with lung cancer [ 63 , 87 ], a cancer not observationally associated with higher adiposity or type 2 diabetes.…”

Section: Vertical Pleiotropy: Using Genetic Variants To Investigate Amentioning

confidence: 99%

Using genetics to decipher the link between type 2 diabetes and cancer: shared aetiology or downstream consequence?

Vincent

Yaghootkar

2020

Diabetologia

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Recent developments in the field of genetics have accelerated our understanding of the aetiology of complex diseases. Type 2 diabetes mellitus and cancer are no exception, with large-scale genome-wide association studies (GWAS) facilitating exploration of the underlying pathology. Here, we discuss how genetics studies can be used to investigate the relationship between these complex diseases. Observational epidemiological studies consistently report that people with type 2 diabetes have a higher risk of several types of cancer. Indeed, type 2 diabetes and cancer share many common risk factors, such as obesity, ageing, poor diet and low levels of physical activity. However, questions remain regarding the biological mechanisms that link these two diseases. Large-scale GWAS of type 2 diabetes and cancer allow us to consider the evidence for shared genetic architecture. Several shared susceptibility genes have been identified, yet tissue specificity and direction of effect must be taken into account when considering common genetic aetiology. We also consider how GWAS, and associated techniques such as Mendelian randomisation, allow us to dissect the link between the two diseases and address questions such as 'Does type 2 diabetes cause cancer or is the increased risk observed driven by higher adiposity or another associated metabolic feature?' Keywords Adiposity. Cancer. Diabetes. Genetics. GWAS. Mendelian randomisation. Review. Type 2 diabetes Abbreviations GRS Genetic risk score GWAS Genome-wide association studies HNF1B Hepatocyte nuclear factor 1 homeobox B IGF-1 Insulin-like growth factor 1 JAZF1 JAZF zinc finger 1 KLF14 Kruppel-like factor 14 MR Mendelian randomisation PPARγ Peroxisome proliferator-activated receptor γ RCT Randomised controlled trial TCF7L2 Transcription factor 7 like 2

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Section: Vertical Pleiotropy: Using Genetic Variants To Investigate Amentioning

confidence: 99%

Using genetics to decipher the link between type 2 diabetes and cancer: shared aetiology or downstream consequence?

Vincent

Yaghootkar

2020

Diabetologia

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“…For cancers, our results do not provide any clear additional insight into the likely mechanisms, with potentially stronger effects for BMI and UFA compared to body fat percentage in some analyses hard to explain biologically. The reasons why higher BMI is associated with cancers is uncertain, although several MR studies indicate that the association with many is causal 54,55 , and that central adiposity may play a role 56 . Exposure to higher insulin levels are a plausible mechanism and some studies have used MR to test insulin directly [57][58][59][60][61] .…”

Section: Other Diseasesmentioning

confidence: 99%

Using genetics to uncouple higher adiposity from its adverse metabolic effects and understand its role in metabolic and non-metabolic disease.

Martin

Tyrrell

Thomas

et al. 2021

Preprint

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To understand the consequences of higher adiposity uncoupled from its adverse metabolic effects, we selected 37 diseases associated with obesity and genetic variants associated with different aspects of excess weight including metabolically “favourable adiposity” (FA) and “unfavourable adiposity” (UFA). Mendelian randomisation (MR) identified two sets of diseases. First, 12 conditions where the metabolic effect of higher adiposity is the likely primary cause of the disease. Here MR with the FA and UFA genetics showed opposing effects on risk of disease, including colorectal and ovarian cancer, and gout. Second, 7 conditions where the non-metabolic effects of excess weight (e.g. mechanical effect) is likely a cause. Here MR with the FA genetics, despite leading to lower metabolic risk, and MR with the UFA genetics, were both associated with higher disease risk, including osteoarthritis and venous thromboembolism. Individuals with high BMI are at higher risk of some diseases despite being relatively metabolically healthy.

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“…Indeed, >900 independent single nucleotide polymorphisms have been shown to have some effect on obesity 34 . These variants have be used to generate a weighted genetic predictor of obesity, and this genetic proxy for obesity, commonly referred as a genetic instrument, has been evaluated in relation to a variety of common cancers using cancer GWAS results and two-sample Mendelian randomization methods, revealing a strong causal link between obesity and cancer usually greater than the effect previously seen in epidemiological studies 35,36 (with ORs 1.05-1.50) 37 . These results suggest that researchers might have underestimated the effect of BMI on the risk of many common cancers.…”

Section: Key Pointsmentioning

confidence: 99%