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

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Abstract

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?’

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The online version of this article (10.1007/s00125-020-05228-y) contains a slideset of the figures for download, which is available to authorised users.

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Fasting serum glucose level and cancer risk in Korean men and women.

Sun Jee, Heechoul Ohrr, Jae Sull … (2005)

Diabetes is a serious and costly disease that is becoming increasingly common in many countries. The role of diabetes as a cancer risk factor remains unclear. To examine the relationship between fasting serum glucose and diabetes and risk of all cancers and specific cancers in men and women in Korea. Ten-year prospective cohort study of 1,298,385 Koreans (829,770 men and 468,615 women) aged 30 to 95 years who received health insurance from the National Health Insurance Corp and had a biennial medical evaluation in 1992-1995 (with follow-up for up to 10 years). Death from cancer and registry-documented incident cancer or hospital admission for cancer. During the 10 years of follow-up, there were 20,566 cancer deaths in men and 5907 cancer deaths in women. Using Cox proportional hazards models and controlling for smoking and alcohol use, the stratum with the highest fasting serum glucose (> or =140 mg/dL [> or =7.8 mmol/L]) had higher death rates from all cancers combined (hazard ratio [HR], 1.29; 95% confidence interval [CI], 1.22-1.37 in men and HR, 1.23; 95% CI, 1.09-1.39 in women) compared with the stratum with the lowest level (<90 mg/dL [<5.0 mmol/L]). By cancer site, the association was strongest for pancreatic cancer, comparing the highest and lowest strata in men (HR, 1.91; 95% CI, 1.52-2.41) and in women (HR, 2.05; 95% CI, 1.43-2.93). Significant associations were also found for cancers of the esophagus, liver, and colon/rectum in men and of the liver and cervix in women, and there were significant trends with glucose level for cancers of the esophagus, colon/rectum, liver, pancreas, and bile duct in men and of the liver and pancreas in women. Of the 26,473 total cancer deaths in men and women, 848 were estimated as attributable to having a fasting serum glucose level of less than 90 mg/dL. For cancer incidence, the general patterns reflected those found for mortality. For persons with a diagnosis of diabetes or a fasting serum glucose level greater than 125 mg/dL (6.9 mmol/L), risks for cancer incidence and mortality were generally elevated compared with those without diabetes. In Korea, elevated fasting serum glucose levels and a diagnosis of diabetes are independent risk factors for several major cancers, and the risk tends to increase with an increased level of fasting serum glucose.

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Genomic analyses identify hundreds of variants associated with age at menarche and support a role for puberty timing in cancer risk

Felix Day, Deborah J Thompson, Hannes Helgason … (2017)

John Perry, Ken Ong and colleagues analyze genotype data on ∼370,000 women and identify 389 independent signals that associate with age at menarche, implicating ∼250 genes. Their analyses suggest causal inverse associations, independent of BMI, between puberty timing and risks for breast and endometrial cancers in women and prostate cancer in men.

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Adult weight change and risk of postmenopausal breast cancer.

Bernard A Rosner, G. A. Colditz, A. Eliassen … (2006)

Endogenous hormones are a primary cause of breast cancer. Adiposity affects circulating hormones, particularly in postmenopausal women, and may be a modifiable risk factor for breast cancer. To assess the associations of adult weight change since age 18 years and since menopause with the risk of breast cancer among postmenopausal women. Prospective cohort study within the Nurses' Health Study. A total of 87,143 postmenopausal women, aged 30 to 55 years and free of cancer, were followed up for up to 26 years (1976-2002) to assess weight change since age 18 years. Weight change since menopause was assessed among 49,514 women who were followed up for up to 24 years. Incidence of invasive breast cancer. Overall, 4393 cases of invasive breast cancer were documented. Compared with those who maintained weight, women who gained 25.0 kg or more since age 18 years were at an increased risk of breast cancer (relative risk [RR], 1.45; 95% confidence interval [CI], 1.27-1.66; P<.001 for trend), with a stronger association among women who have never taken postmenopausal hormones (RR,1.98; 95% CI, 1.55-2.53). Compared with weight maintenance, women who gained 10.0 kg or more since menopause were at an increased risk of breast cancer (RR, 1.18; 95% CI, 1.03-1.35; P = .002 for trend). Women who had never used postmenopausal hormones, lost 10.0 kg or more since menopause, and kept the weight off were at a lower risk than those who maintained weight (RR, 0.43; 95% CI, 0.21-0.86; P = .01 for weight loss trend). Overall, 15.0% (95% CI, 12.8%-17.4%) of breast cancer cases in this population may be attributable to weight gain of 2.0 kg or more since age 18 years and 4.4% (95% CI, 3.6%-5.5%) attributable to weight gain of 2.0 kg or more since menopause. Among those who did not use postmenopausal hormones, the population attributable risks are 24.2% (95% CI, 19.8%-29.1%) for a weight gain since age 18 years and 7.6% (95% CI, 5.9%-9.7%) for weight gain since menopause. These data suggest that weight gain during adult life, specifically since menopause, increases the risk of breast cancer among postmenopausal women, whereas weight loss after menopause is associated with a decreased risk of breast cancer. Thus, in addition to other known benefits of healthy weight, our results provide another reason for women approaching menopause to maintain or lose weight, as appropriate.

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Author and article information

Contributors

Emma E. Vincent:

ORCID: https://orcid.org/0000-0002-8917-7384

emma.vincent@bristol.ac.uk

Journal

Journal ID (nlm-ta): Diabetologia

Journal ID (iso-abbrev): Diabetologia

Title: Diabetologia

Publisher: Springer Berlin Heidelberg (Berlin/Heidelberg )

ISSN (Print): 0012-186X

ISSN (Electronic): 1432-0428

Publication date (Electronic): 23 July 2020

Publication date PMC-release: 23 July 2020

Publication date (Print): 2020

Volume: 63

Issue: 9

Pages: 1706-1717

Affiliations

[1 ]GRID grid.423000.5, ISNI 0000 0004 0627 3472, MRC Integrative Epidemiology Unit at the University of Bristol, Bristol, ; Bristol, UK

[2 ]GRID grid.5337.2, ISNI 0000 0004 1936 7603, Population Health Sciences, Bristol Medical School, , University of Bristol, ; Bristol, UK

[3 ]GRID grid.5337.2, ISNI 0000 0004 1936 7603, School of Cellular and Molecular Medicine, Biomedical Science Building, , University of Bristol, ; Bristol, BS8 1TW UK

[4 ]Genetics of Complex Traits, University of Exeter Medical School, Royal Devon & Exeter Hospital, Exeter, UK

[5 ]GRID grid.12896.34, ISNI 0000 0000 9046 8598, School of Life Sciences, College of Liberal Arts and Science, , University of Westminster, ; London, UK

[6 ]GRID grid.6926.b, ISNI 0000 0001 1014 8699, Division of Medical Sciences, Department of Health Sciences, , Luleå University of Technology, ; Luleå, Sweden

Author information

Emma E. Vincent https://orcid.org/0000-0002-8917-7384

Hanieh Yaghootkar https://orcid.org/0000-0001-9672-9477

Article

Publisher ID: 5228

DOI: 10.1007/s00125-020-05228-y

PMC ID: 7406536

PubMed ID: 32705315

SO-VID: d44bb1e8-1b3b-46fd-b32d-c9838a3b495f

License:

Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/.

History

Date received : 21 January 2020

Date accepted : 18 May 2020

Funding

Funded by: FundRef http://dx.doi.org/10.13039/501100000361, Diabetes UK;

Award ID: 17/0005587 and 17/0005594

Funded by: FundRef http://dx.doi.org/10.13039/501100000289, Cancer Research UK;

Award ID: C18281/A19169

Funded by: FundRef http://dx.doi.org/10.13039/501100000321, World Cancer Research Fund;

Award ID: IIG_2019_2009

Custom metadata

ScienceOpen disciplines: Endocrinology & Diabetes

Keywords: adiposity,cancer,diabetes,genetics,gwas,mendelian randomisation,review,type 2 diabetes

Data availability:

ScienceOpen disciplines: Endocrinology & Diabetes

Keywords: adiposity, cancer, diabetes, genetics, gwas, mendelian randomisation, review, type 2 diabetes

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

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Most cited references 76

Fasting serum glucose level and cancer risk in Korean men and women.

Genomic analyses identify hundreds of variants associated with age at menarche and support a role for puberty timing in cancer risk

Adult weight change and risk of postmenopausal breast cancer.

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