Insulin-like growth factor-1, insulin-like growth factor-binding protein-3, and breast cancer risk: observational and Mendelian randomization analyses with ∼430 000 women

Murphy, Neil; Knüppel, Anika; Papadimitriou, Nikos; Martin, Richard M.; Tsilidis, Kostas; Smith-Byrne, Karl; Fensom, Georgina K.; Travis, Ruth C.; Key, Tim; Gunter, Marc J.

doi:10.1016/j.annonc.2020.01.066

Cited by 123 publications

(127 citation statements)

References 27 publications

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“…The findings of a likely causal effect of IGF-I in prostate cancer development may be due to its role in activating signalling pathways which regulate cell proliferation and apoptosis 2 . The positive relationship between IGF-I and incident prostate cancer observed is consistent with previous epidemiological evidence 4 , as well as associations observed with other cancers including breast and colorectal [35][36][37] . Further genetic epidemiology including fine mapping may help elucidate exactly by which mechanism variation at the IGF1 locus associates with risk prostate and some other cancers.…”

Section: Discussionsupporting

confidence: 91%

Circulating insulin-like growth factor-I, total and free testosterone concentrations and prostate cancer risk in 200,000 men in UK Biobank

Watts

Fensom

Smith-Byrne

et al. 2020

Preprint

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Background: Insulin-like growth factor-I (IGF-I) and testosterone have been implicated in prostate cancer aetiology. Using newly available data from a large prospective full-cohort with standardised assays and repeat blood measurements, and genetic data from an international consortium, we aimed to investigate the associations of circulating concentrations of IGF-I, sex hormone-binding globulin (SHBG), total and calculated free testosterone with prostate cancer risk. Patients and methods: For prospective analyses of prostate cancer incidence and mortality, we studied 199,698 male UK Biobank participants using Cox proportional hazards models. Multivariable-adjusted hazard ratios (HRs) were corrected for regression dilution bias using repeat hormone measurements from a subsample of up to 7,776 men. A 2-sample Mendelian randomization (MR) analysis of IGF-I and risk used genetic instruments identified from UK Biobank men and genetic outcome data from 79,148 cases and 61,106 controls from the PRACTICAL consortium. We used cis- and all (cis and trans) SNP MR approaches. Results: After a mean follow-up of 6.9 years, 5,402 men were diagnosed with and 295 died from prostate cancer. Higher circulating IGF-I was associated with an elevated risk (HR per 5 nmol/L increment=1.09, 95% CI 1.05-1.12) and prostate cancer mortality (HR per 5 nmol/L increment=1.15,1.02-1.29) in observational analyses. Cis- and all SNPs MR analyses also supported the role of IGF-I in prostate cancer diagnosis (cis-MR odds ratio per 5 nmol/L increment=1.34,1.07-1.68). In observational analyses, higher free testosterone was associated with a higher risk of prostate cancer (HR per 50 pmol/L increment=1.10,1.05-1.15), and higher SHBG was associated with a lower risk of prostate cancer (HR per 10 nmol/L increment=0.95,0.94-0.97), but neither was associated with prostate cancer mortality. Total testosterone was not associated with prostate cancer. Conclusion(s): These findings implicate IGF-I and free testosterone in prostate cancer development and/or progression.

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Section: Discussionsupporting

confidence: 91%

Circulating insulin-like growth factor-I, total and free testosterone concentrations and prostate cancer risk in 200,000 men in UK Biobank

Watts

Fensom

Smith-Byrne

et al. 2020

Preprint

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“…25 The present MR results for IGF-1 and breast cancer based on BCAC data are similar to those obtained from another MR study also based on BCAC data which showed an OR of 1.05 (95% CI 1.01-1.10) per 5 nmol/L increase of genetically predicted IGF-1 levels based on 265 SNPs associated with serum IGF-1 levels in women. 33 Another smaller case-control study (4647 cases and 4564 controls) found that the IGF-1-increasing allele of rs1520220 in the IGF1 gene was associated with higher odds of breast cancer. 34 We could not replicate an association between genetically predicted IGF-1 levels and breast cancer in UK Biobank, potentially owing to the lack of power to detect a weak association (41% and 93% power to detect an OR of 1.05 and 1.10, respectively), phenotyping differences, or younger participants in UK Biobank (eg some current controls in UK Biobank may eventually develop cancer later in their life).…”

Section: Discussionmentioning

confidence: 99%

Insulin‐like growth factor‐1 and site‐specific cancers: A Mendelian randomization study

et al. 2020

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Insulin‐like growth factor‐1 (IGF‐1) is involved in several processes relevant to carcinogenesis. We used 416 single‐nucleotide polymorphisms robustly associated with serum IGF‐1 levels to assess the potential causal associations between this hormone and site‐specific cancers through Mendelian randomization. Summary‐level genetic association estimates for prostate, breast, ovarian, and lung cancer were obtained from large‐scale consortia including individuals of European‐descent. Furthermore, we estimated genetic associations with 14 site‐specific cancers in European‐descent individuals in UK Biobank. Supplementary analyses were conducted for six site‐specific cancers using summary‐level data from the BioBank Japan Project. Genetically predicted serum IGF‐1 levels were associated with colorectal cancer. The odds ratio (OR) per standard deviation increase of IGF‐1 levels was 1.11 (95% confidence interval [CI] 1.01‐1.22; P = .03) in UK Biobank and 1.22 (95% CI 1.09‐1.36; P = 3.9 × 10−4) in the BioBank Japan Project. For prostate cancer, the corresponding OR was 1.10 (95% CI 1.01‐1.21; P = .04) in UK Biobank, 1.03 (95% CI 0.97‐1.09; P = .41) in the prostate cancer consortium, and 1.08 (95% CI 0.95‐1.22; P = .24) in the BioBank Japan Project. For breast cancer, the corresponding OR was 0.99 (95% CI 0.92‐1.07; P = .85) in UK Biobank and 1.08 (95% CI 1.02‐1.13; P = 4.4 × 10−3) in the Breast Cancer Association Consortium. There was no statistically significant association between genetically predicted IGF‐1 levels and 14 other cancers. This study found some support for a causal association between elevated serum IGF‐1 levels and increased risk of colorectal cancer. There was inconclusive or no evidence of a causal association of IGF‐1 levels with prostate, breast, and other cancers.

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“…Observational epidemiological studies have reported a positive link between circulating IGF-1 levels and increased risk of particular cancers, although associations vary between sites [73]. Evidence from MR studies implicate circulating IGFs in breast cancer [74] and prostate cancer risk and progression [75,76]. Another purported mechanism is that hyperinsulinaemia inhibits the production of sex hormone binding globulin (SHBG) in the liver, resulting in an elevation of free hormones (including oestrogen and testosterone), which are pro-proliferative and anti-apoptotic [77].…”

Section: Confoundersmentioning

confidence: 99%

“…No evidence for a causal association between T2DM and overall [52], pancreatic [51,89], endometrial [53], RCC [54] or ovarian [55] cancer No evidence for a causal association between glucose measures and lung [63], pancreatic [51,89] and endometrial cancer [53] and RCC [54]; some evidence of an association between 2 h glucose and breast cancer [64] Evidence for an association between higher levels of fasting insulin and risk of endometrial [53], breast [64], lung [63] and pancreatic cancer [51] and RCC [54] Some evidence implicating circulating IGFs in breast cancer [74] and prostate cancer risk [75,76] Some evidence implicating sex hormone levels and puberty timing with breast and endometrial cancer in women [78][79][80] and puberty timing in prostate cancer in men [78] Evidence for a causal association between adiposity measures and RCC [54] and endometrial [85], ovarian [55,86,87], oesophageal [88], pancreatic [51,89,90] and colorectal [87,91] cancer Cancer type investigated Fig. 3 Summary of evidence from MR studies supporting an association between type 2 diabetes (or associated metabolic traits) and cancer.…”

Section: Adipositymentioning

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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Insulin-like growth factor-1, insulin-like growth factor-binding protein-3, and breast cancer risk: observational and Mendelian randomization analyses with ∼430 000 women

Cited by 123 publications

References 27 publications

Circulating insulin-like growth factor-I, total and free testosterone concentrations and prostate cancer risk in 200,000 men in UK Biobank

Circulating insulin-like growth factor-I, total and free testosterone concentrations and prostate cancer risk in 200,000 men in UK Biobank

Insulin‐like growth factor‐1 and site‐specific cancers: A Mendelian randomization study

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

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