The role of genomics in global cancer prevention Ginsburg, Ophira; Ashton-Prolla, Patricia; Cantor, Anna ...
Nature reviews. Clinical oncology,
02/2021, Letnik:
18, Številka:
2
Journal Article
Recenzirano
Despite improvements in the understanding of cancer causation, much remains unknown regarding the mechanisms by which genomic and non-genomic factors initiate carcinogenesis, drive cell invasion and ...metastasis, and enable cancer to develop. Technological advances have enabled the analysis of whole genomes, comprising thousands of tumours across populations worldwide, with the aim of identifying mutation signatures associated with particular tumour types. Large collaborative efforts have resulted in the identification and improved understanding of causal factors, and have shed light on new opportunities to prevent cancer. In this new era in cancer genomics, discoveries from studies conducted on an international scale can inform evidence-based strategies in cancer control along the cancer care continuum, from prevention to treatment. In this Review, we present the relevant history and emerging frontiers of cancer genetics and genomics from the perspective of global cancer prevention. We highlight the importance of local context in the adoption of new technologies and emergent evidence, with illustrative examples from worldwide. We emphasize the challenges in implementing important genomic findings in clinical settings with disparate resource availability and present a conceptual framework for the translation of such findings into clinical practice, and evidence-based policies in order to maximize the utility for a population.
Objective
To assess the associations of blood biomarkers of carbohydrate, lipid, and apolipoprotein metabolisms with the future risk of amyotrophic lateral sclerosis (ALS).
Methods
In the ...Apolipoprotein‐related MOrtality RISk study, we enrolled 636,132 men and women during 1985–1996 in Stockholm, Sweden, with measurements of serum glucose, total cholesterol, triglycerides, apolipoprotein B (apoB), and apolipoprotein A‐I (apoA‐I). Serum low‐density lipoprotein cholesterol (LDL‐C) and high‐density lipoprotein cholesterol (HDL‐C) were either directly measured or calculated from total cholesterol, triglycerides, and apoA‐I. The cohort was followed until the end of 2011. We used Cox models and mixed‐effects models to, first, estimate the associations between these biomarkers and ALS incidence and, second, to assess the changes of these biomarkers during the 20 years before ALS diagnosis.
Results
One‐unit increase of LDL‐C (hazard ratio HR = 1.14; 95% confidence interval CI = 1.02–1.27), apoB (HR = 1.68; 95% CI = 1.17–2.42), and apoB/apoA‐I ratio (HR = 1.90; 95% CI = 1.29–2.78) was associated with a higher incidence of ALS. High glucose level (≥6.11mmol/L) was associated with a lower incidence (HR = 0.62; 95% CI = 0.42–0.93), whereas high LDL‐C/HDL‐C (≥3.50; HR = 1.50; 95% CI = 1.15–1.96) and high apoB/apoA‐I (≥0.90 for men, ≥0.8 for women; HR = 1.41; 95% CI = 1.04–1.90) ratios were associated with a higher incidence. During the 10 years before diagnosis, ALS patients had increasing levels of LDL‐C, HDL‐C, apoB, and apoA‐I, whereas gradually decreasing levels of LDL‐C/HDL‐C and apoB/apoA‐I ratios.
Interpretation
Alterations in the carbohydrate, lipid, and apolipoprotein metabolisms are associated with ALS risk and may serve as prodromal symptoms decades before ALS diagnosis. The imbalance between apoB and apoA‐I as well as between LDL‐C and HDL‐C may be an etiological mechanism for ALS and needs to be further studied. Ann Neurol 2017;81:718–728
Obesity is considered a chronic inflammatory state characterized by continued secretion of adipokines and cytokines. Experimental and epidemiological evidence indicates that circulating adipokines ...may be associated with the development of obesity‐related cancers, but it is unclear if these associations are causal or confounded. We examined potential causal associations of specific adipokines (adiponectin, leptin, soluble leptin receptor sOB‐R and plasminogen activator inhibitor‐1 PAI‐1) with five obesity‐related cancers (colorectal, pancreatic, renal cell carcinoma RCC, ovarian and endometrial) using Mendelian randomization (MR) methods. We used summary‐level data from large genetic consortia for 114 530 cancer cases and 245 284 controls. We constructed genetic instruments using 18 genetic variants for adiponectin, 2 for leptin and 4 for both sOB‐R and PAI‐1 (P value for inclusion<5 × 10−8). Causal estimates were obtained using two‐sample MR methods. In the inverse‐variance weighted models, we found an inverse association between adiponectin and risk of colorectal cancer (odds ratio per 1 μg/mL increment in adiponectin concentration: 0.90 95% confidence interval = 0.84‐0.97; P = .01); but, evidence of horizontal pleiotropy was detected and the association was not present when this was taken into consideration. No association was found for adiponectin and risks of pancreatic cancer, RCC, ovarian cancer and endometrial cancer. Leptin, sOB‐R and PAI‐1 were also similarly unrelated to risk of obesity‐related cancers. Despite the large sample size, our MR analyses do not support causal effects of circulating adiponectin, leptin, sOB‐R and PAI‐1 concentrations on the development of five obesity‐related cancers.
What's new?
Chronic inflammation attributed to obesity may influence cancer development. However, little is known about the relationship between oncogenesis and changes in adipokine secretion stemming from immune cell infiltration in adipose tissue. Here, large‐scale Mendelian randomization analysis was used to assess possible causal associations of adipokine concentrations influenced by genetic variation and risk of five obesity‐related cancers, including renal cell carcinoma and colorectal, pancreatic, ovarian and endometrial cancer. In general, no association was detected between adipokines and the five malignancies, suggesting that adipokine levels have no causal influence on these cancers.
Dietary factors are assumed to play an important role in cancer risk, apparent in consensus recommendations for cancer prevention that promote nutritional changes. However, the evidence in this field ...has been generated predominantly through observational studies, which may result in biased effect estimates because of confounding, exposure misclassification, and reverse causality. With major geographical differences and rapid changes in cancer incidence over time, it is crucial to establish which of the observational associations reflect causality and to identify novel risk factors as these may be modified to prevent the onset of cancer and reduce its progression. Mendelian randomization (MR) uses the special properties of germline genetic variation to strengthen causal inference regarding potentially modifiable exposures and disease risk. MR can be implemented through instrumental variable (IV) analysis and, when robustly performed, is generally less prone to confounding, reverse causation and measurement error than conventional observational methods and has different sources of bias (discussed in detail below). It is increasingly used to facilitate causal inference in epidemiology and provides an opportunity to explore the effects of nutritional exposures on cancer incidence and progression in a cost-effective and timely manner. Here, we introduce the concept of MR and discuss its current application in understanding the impact of nutritional factors (e.g., any measure of diet and nutritional intake, circulating biomarkers, patterns, preference or behaviour) on cancer aetiology and, thus, opportunities for MR to contribute to the development of nutritional recommendations and policies for cancer prevention. We provide applied examples of MR studies examining the role of nutritional factors in cancer to illustrate how this method can be used to help prioritise or deprioritise the evaluation of specific nutritional factors as intervention targets in randomised controlled trials. We describe possible biases when using MR, and methodological developments aimed at investigating and potentially overcoming these biases when present. Lastly, we consider the use of MR in identifying causally relevant nutritional risk factors for various cancers in different regions across the world, given notable geographical differences in some cancers. We also discuss how MR results could be translated into further research and policy. We conclude that findings from MR studies, which corroborate those from other well-conducted studies with different and orthogonal biases, are poised to substantially improve our understanding of nutritional influences on cancer. For such corroboration, there is a requirement for an interdisciplinary and collaborative approach to investigate risk factors for cancer incidence and progression.
Observational studies have linked childhood obesity with elevated risk of colorectal cancer; however, it is unclear if this association is causal or independent from the effects of obesity in ...adulthood on colorectal cancer risk.
We conducted Mendelian randomization (MR) analyses to investigate potential causal relationships between self-perceived body size (thinner, plumper, or about average) in early life (age 10) and measured body mass index in adulthood (mean age 56.5) with risk of colorectal cancer. The total and independent effects of body size exposures were estimated using univariable and multivariable MR, respectively. Summary data were obtained from a genome-wide association study of 453,169 participants in UK Biobank for body size and from a genome-wide association study meta-analysis of three colorectal cancer consortia of 125,478 participants.
Genetically predicted early life body size was estimated to increase odds of colorectal cancer (odds ratio OR per category change: 1.12, 95% confidence interval CI: 0.98-1.27), with stronger results for colon cancer (OR: 1.16, 95% CI: 1.00-1.35), and distal colon cancer (OR: 1.25, 95% CI: 1.04-1.51). After accounting for adult body size using multivariable MR, effect estimates for early life body size were attenuated towards the null for colorectal cancer (OR: 0.97, 95% CI: 0.77-1.22) and colon cancer (OR: 0.97, 95% CI: 0.76-1.25), while the estimate for distal colon cancer was of similar magnitude but more imprecise (OR: 1.27, 95% CI: 0.90-1.77). Genetically predicted adult life body size was estimated to increase odds of colorectal (OR: 1.27, 95% CI: 1.03, 1.57), colon (OR: 1.32, 95% CI: 1.05, 1.67), and proximal colon (OR: 1.57, 95% CI: 1.21, 2.05).
Our findings suggest that the positive association between early life body size and colorectal cancer risk is likely due to large body size retainment into adulthood.
The nature of the association between levels of physical activity and risk of heart failure is little known. We investigated nonlinear associations of total and leisure time physical activity with ...risk of heart failure.
In 1997, 39 805 persons without heart failure completed a questionnaire of lifestyle factors and medical history. We used Cox regression models to investigate total (adjusting for education and previous myocardial infarction) and direct (multivariable-adjusted) effects of self-reported total and leisure time physical activity on risk of heart failure of any cause and heart failure of nonischemic origin. Heart failure diagnoses were obtained until December 31, 2010. Higher leisure time physical activity was associated with lower risk of heart failure of any cause; hazard ratio of the total effect of leisure time physical activity was for fifth versus first quintile 0.54; 95% confidence interval was 0.44 to 0.66. The direct effect was similar. High total daily physical activity level was associated with lower risk of heart failure, although the effect was less pronounced than for leisure time physical activity (total effect hazard ratio, 0.81; 95% confidence interval, 0.69-0.95; fifth versus first quintile). A similar direct effect observed.
Leisure time physical activity was inversely related to risk of developing heart failure in a dose-response fashion. This was reflected in a similar but less pronounced association of total physical activity with risk of heart failure. Only part of the effects appeared to be mediated by traditional risk factors.
Purpose
Partial stomach partitioning gastrojejunostomy (PSPGJ) was introduced as a palliative treatment for malignant gastric outlet obstruction (MGO) caused by unresectable gastric or periampullary ...cancers and suggested to offer advantages over conventional gastrojejunostomy (CGJ) in reducing the risk for delayed gastric emptying (DGE). However, insufficient evidence is available to allow a comprehensive view of the true value of PSPGJ. The present study aimed to show the advantages of PSPGJ in terms of alleviating DGE and improving postoperative recovery compared to CGJ.
Methods
A systematic literature search was performed, and studies comparing DGE and other perioperative and postoperative data including operation time, blood loss, total postoperative complications, anastomotic leak, postoperative period before oral intake, and/or hospital stay between PSPGJ and CGJ for MGO were incorporated. Risk ratio (RR) for binary variables and weighted mean difference (WMD) for continuous variables were calculated, and meta-analyses were performed.
Results
Seven studies containing 207 patients were included. The risk for DGE was significantly lower after PSPGJ (RR 0.32; 95%CI 0.17 to 0.60;
P
< 0.001). PSPGJ significantly reduced the postoperative hospital stay (WMD −6.1 days; 95%CI −8.9 to −3.3 days;
P
< 0.001). No significant differences were observed in the other variables between the groups.
Conclusions
PSPGJ for MGO seems to offer significant advantages in terms of alleviating DGE and improving postoperative recovery compared to CGJ.
Bilirubin, an endogenous antioxidant, may play a protective role in cancer development. We applied two-sample Mendelian randomization to investigate whether genetically raised bilirubin levels are ...causally associated with the risk of ten cancers (pancreas, kidney, endometrium, ovary, breast, prostate, lung, Hodgkin's lymphoma, melanoma, and neuroblastoma). The number of cases and their matched controls of European descent ranged from 122,977 and 105,974 for breast cancer to 1200 and 6417 for Hodgkin's lymphoma, respectively. A total of 115 single-nucleotide polymorphisms (SNPs) associated (
< 5 × 10
) with circulating total bilirubin, extracted from a genome-wide association study in the UK Biobank, were used as instrumental variables. One SNP (rs6431625) in the promoter region of the uridine-diphosphoglucuronate glucuronosyltransferase1A1 (
gene explained 16.9% and the remaining 114 SNPs (non-
SNPs) explained 3.1% of phenotypic variance in circulating bilirubin levels. A one-standarddeviation increment in circulating bilirubin (≈ 4.4 µmol/L), predicted by non-
SNPs, was inversely associated with risk of squamous cell lung cancer and Hodgkin's lymphoma (odds ratio (OR) 0.85, 95% confidence interval (CI) 0.73-0.99,
0.04 and OR 0.64, 95% CI 0.42-0.99,
0.04, respectively), which was confirmed after removing potential pleiotropic SNPs. In contrast, a positive association was observed with the risk of breast cancer after removing potential pleiotropic SNPs (OR 1.12, 95% CI 1.04-1.20,
0.002). There was little evidence for robust associations with the other seven cancers investigated. Genetically raised bilirubin levels were inversely associated with risk of squamous cell lung cancer as well as Hodgkin's lymphoma and positively associated with risk of breast cancer. Further studies are required to investigate the utility of bilirubin as a low-cost clinical marker to improve risk prediction for certain cancers.
Preclinical and genetic studies suggest that impaired glucose-dependent insulinotropic polypeptide receptor (GIPR) signaling worsens glycemic control. The relationship between GIPR signaling and the ...risk of cancers influenced by impaired glucose homeostasis is unclear. We examined the association of a variant in GIPR, rs1800437 (E354Q), shown to impair long-term GIPR signaling and lower circulating glucose-dependent insulinotropic peptide concentrations, with risk of 6 cancers influenced by impaired glucose homeostasis (breast, colorectal, endometrial, lung, pancreatic, and renal) in up to 235,698 cases and 333,932 controls. Each copy of E354Q was associated with a higher risk of overall and luminal A-like breast cancer and this association was consistent in replication and colocalization analyses. E354Q was also associated with higher postprandial glucose concentrations but diminished insulin secretion and lower testosterone concentrations. Our human genetics analysis suggests an adverse effect of the GIPR E354Q variant on breast cancer risk, supporting further evaluation of GIPR signaling in breast cancer prevention.
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•GIPR signaling may influence cancer risk•We tested the effect of a functional variant in GIPR (E354Q) on risk of 6 cancers•E354Q was associated with increased risk of overall and luminal A-like breast cancer•Further evaluation of GIPR signaling in breast cancer prevention is warranted
Health sciences; Genetics; Cancer
Background and purpose
Energy metabolism is altered in patients with amyotrophic lateral sclerosis (ALS) but the role of diabetes is largely unknown.
Methods
A population‐based case−control study was ...conducted of 5108 ALS cases and 25 540 individually matched population controls during 1991–2010. Information on ALS and pre‐existing diabetes was retrieved from the Swedish Patient Register to explore the association of ALS with diabetes overall and with insulin‐dependent or non‐insulin‐dependent diabetes specifically. Variation of the association by diabetes duration and age was also studied.
Results
In total, 224 ALS cases (4.39%) and 1437 controls (5.63%) had diabetes before the index date, leading to an overall inverse association between diabetes and ALS risk odds ratio (OR) 0.79, 95% confidence interval (CI) 0.68–0.91. The association was strong for non‐insulin‐dependent diabetes (OR 0.66, 95% CI 0.53–0.81) but not for insulin‐dependent diabetes (OR 0.83, 95% CI 0.60–1.15) and varied as a function of diabetes duration, with the strongest association observed around 6 years after first ascertainment of diabetes. The association was age‐specific; the inverse association was noted only amongst individuals aged 70 or older. In contrast, for younger individuals (<50 years), pre‐existing insulin‐dependent diabetes was associated with a higher ALS risk (OR 5.38, 95% CI 1.87–15.51).
Conclusions
Our study suggests that there is an association between diabetes and ALS, and highlights the importance of taking into account age, insulin dependence and diabetes duration. Future studies should explore whether the association is independent of body mass index.
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