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Metabolic factors and cancer risk: prospective studies on prostate cancer, colorectal cancer, and cancer overall
Umeå University, Faculty of Medicine, Surgical and Perioperative Sciences, Urology and Andrology.
2009 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Background: A large number of prospective studies have shown that overweight and diabetes are related to an increased risk of many cancers, including colorectal cancer. In contrast, diabetes has been related to a decreased risk of prostate cancer, and overweight has been related to an increased risk of fatal, but not of incident, prostate cancer. Data from studies on metabolic factors related to overweight and diabetes, and the association with cancer risk, are limited.

 Aim: The aim of this thesis was to study metabolic factors in relation to risk of prostate cancer (paper I and III), colorectal cancer (paper II and V), and cancer overall (paper VI).

 Methods: Study designs were i) case-control studies, nested within the Northern Sweden Health and Disease Cohort (paper I and II), and ii) cohort studies of the Swedish Construction Workers cohort (paper III), and the Metabolic syndrome and Cancer project (Me-Can) comprising seven European cohorts (paper V and VI). Paper IV was a descriptive paper of Me-Can.

 Results, prostate cancer: In paper I, increasing levels of several factors related to insulin resistance (insulin, insulin resistance index, leptin, HbA1c, and glucose) were associated with a decreased risk of overall incident prostate cancer, and the associations were stronger for non-aggressive tumours. In paper III, increasing levels of blood pressure was associated with a significant decreased risk of overall incident prostate cancer and of non-aggressive tumours. Body mass index (BMI) was significantly positively related to fatal prostate cancer. 

 Results, colorectal cancer: In paper II, obesity, hypertension, and hyperglycaemia, were associated with an increased risk of colorectal cancer, and presence of two or three of these factors was associated with a higher risk than the presence of one single factor. In paper V, BMI was associated with a significant linear positive association with risk of colorectal cancer in men and women, and significant positive associations were also found in men for blood pressure and triglycerides. A high metabolic syndrome score, based on levels of BMI, blood pressure, glucose, cholesterol, and triglycerides, was associated with a significant increased risk of colorectal cancer in men and women. The association was stronger than for any of the factors in single, but there was no evidence of a positive interaction between these metabolic factors.

 Results, cancer overall: Blood glucose was significantly positively associated with risk of incident and fatal cancer overall, and at several specific sites. The associations were stronger in women than in men, and for fatal than for incident cancer.

 Conclusions: Results from these studies indicate that elevated blood glucose is related to an increased risk of cancer overall and at several specific sites, and further, that overweight and metabolic aberrations increase the risk of colorectal cancer in an additive way. The association with prostate cancer seems to be more complex; insulin resistance and high blood pressure were in our studies related to a decreased risk of overall incident prostate cancer and of non-aggressive tumours, whereas overweight increased the risk of fatal prostate cancer.

Place, publisher, year, edition, pages
Umeå: Institutionen för kirurgi och perioperativ vetenskap , 2009. , 90 p.
Series
Umeå University medical dissertations, ISSN 0346-6612 ; 1267
National Category
Urology and Nephrology
Research subject
Epidemiology
Identifiers
URN: urn:nbn:se:umu:diva-22567ISBN: 978-91-7264-784-8 (print)OAI: oai:DiVA.org:umu-22567DiVA: diva2:217149
Distributor:
Urologi och andrologi, 901 85, Umeå
Public defence
2009-06-05, Sal B, byggnad 1 D, Umeå Universitetssjukhus, Umeå, 13:15 (English)
Opponent
Supervisors
Available from: 2009-05-19 Created: 2009-05-13 Last updated: 2010-03-26Bibliographically approved
List of papers
1. Insulin resistance is inversely related to prostate cancer: a prospective study in Northern Sweden
Open this publication in new window or tab >>Insulin resistance is inversely related to prostate cancer: a prospective study in Northern Sweden
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2007 (English)In: International Journal of Cancer, ISSN 0020-7136, E-ISSN 1097-0215, Vol. 120, no 12, 2678-2686 p.Article in journal (Refereed) Published
Abstract [en]

Factors related to insulin resistance have been implicated in prostate cancer development, however, few analytical studies support such an association. We performed a case control study on 392 prostate cancer cases and 392 matched controls nested in a prospective cohort in Northern Sweden. Plasma concentrations of C-peptide, leptin, glycated haemoglobin (HbA1c) and fasting and post-load glucose were analysed and homeostatic model assessment of insulin resistance (HOMA-IR) was calculated. Conditional logistic regression analyses were used to calculate odds ratios (OR) of prostate cancer. High levels of C-peptide, HOMA-IR, leptin and HbA1c were associated with significant decreases in risk of prostate cancer, with ORs for top vs. bottom quartile for C-peptide of 0.59 (95% Confidence Interval [CI], 0.40-0.89; ptrend = 0.008), HOMA-IR 0.60 (95% CI, 0.38-0.94; ptrend = 0.03), leptin 0.55 (95% CI, 0.36-0.84; ptrend = 0.006) and HbA1c 0.56 (95% CI, 0.35-0.91; ptrend = 0.02). All studied factors were strongly inversely related to risk among men less than 59 years of age at blood sampling, but not among older men, with a significant heterogeneity between the groups for leptin (pheterogeneity = 0.006) and fasting glucose (pheterogeneity = 0.03). C-peptide and HOMA-IR were strongly inversely related to non-aggressive cancer but were non-significantly positively related to risk of aggressive disease (pheterogeneity = 0.007 and 0.01, respectively). Our data suggest that androgens, which are inversely associated with insulin resistance, are important in the early prostate cancer development, whereas insulin resistance related factors may be important for tumour progression.

Place, publisher, year, edition, pages
John Wiley & Sons, 2007
Keyword
prostatic neoplasms, insulin resistance, blood glucose, C-peptide, leptin
National Category
Cancer and Oncology
Research subject
Epidemiology
Identifiers
urn:nbn:se:umu:diva-22551 (URN)10.1002/ijc.22587 (DOI)000245873000020 ()17278097 (PubMedID)
Available from: 2009-05-13 Created: 2009-05-13 Last updated: 2017-12-13Bibliographically approved
2. Components of the metabolic syndrome and colorectal cancer risk: a prospective study
Open this publication in new window or tab >>Components of the metabolic syndrome and colorectal cancer risk: a prospective study
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2008 (English)In: International Journal of Obesity, ISSN 0307-0565, E-ISSN 1476-5497, Vol. 32, no 2, 304-314 p.Article in journal (Refereed) Published
Abstract [en]

Objective: To examine the relation of well-known factors of the metabolic syndrome (MetS) as well as related circulating factors, with risk of colorectal cancer.

Methods: We performed a case control study of 306 colorectal cancer cases and 595 matched controls nested in the Northern Sweden Health and Disease Cohort. Levels of C-peptide, glycated haemoglobin (HbA1c), leptin and adiponectin were measured in cryopreserved samples. Body mass index (BMI), systolic and diastolic blood pressure and fasting and post-load plasma glucose, had been measured in a subcohort. Conditional logistic regression was used to calculate odds ratios (OR) of disease, including risk assessments for the MetS factors: obesity (BMI>30 kg m-2), hypertension (blood pressure 140/90 mmHg or use of anti-hypertensive drugs) and hyperglycaemia (fasting glucose 6.1 mmol l-1 or post-load glucose in capillary plasma 8.9 mmol l-1).

Results: None of the studied variables were significantly associated with risk across quartiles. Presence of obesity, hypertension and hyperglycaemia significantly increased the risk of colorectal cancer; OR for three vs null factors was 2.57 (95% Confidence Interval [CI] 1.20–5.52; P trend=0.0021), as compared to a 30 to 70% increased risk for the factors in single. Similarly, top decile levels of C-peptide, HbA1c and leptin/adiponectin ratio were associated with an increased risk; ORs for top vs deciles 1–9 were 1.56 (95% CI 0.93–2.62; P=0.090), 1.83 (95% CI 1.00–3.36; P=0.051) and 1.50 (95% CI 0.83–2.71; P=0.18), respectively.

Conclusions: Our study support the view that components of the MetS increase risk of colorectal cancer, and further suggests that only very high levels of metabolic factors confer an increased risk.

Keyword
colorectal neoplasms, insulin resistance, blood glucose, C-peptide, leptin
Identifiers
urn:nbn:se:umu:diva-17962 (URN)10.1038/sj.ijo.0803713 (DOI)17878894 (PubMedID)
Available from: 2008-08-14 Created: 2008-08-14 Last updated: 2017-12-14Bibliographically approved
3. Blood pressure, body size and prostate cancer risk in the Swedish Construction Workers cohort.
Open this publication in new window or tab >>Blood pressure, body size and prostate cancer risk in the Swedish Construction Workers cohort.
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2010 (English)In: International Journal of Cancer, ISSN 0020-7136, E-ISSN 1097-0215, Vol. 127, no 7, 1660-1668 p.Article in journal (Refereed) Published
Abstract [en]

Data from prospective studies on blood pressure and prostate cancer risk are limited, and results are inconclusive. Baseline measurements of height, weight and blood pressure were available in 336,159 men in the Swedish Construction Workers cohort. During an average of 22.2 years of follow-up, 10,002 incident cases and 2,601 fatal cases of prostate cancer were identified in National registers. For 5,219 cases, tumor characteristics were available; 2,817 tumors were classified as nonaggressive and 2,402 as aggressive. Relative risks of disease were estimated from Cox regression models, using attained age as time-scale, and adjusting for birth year, smoking status and body mass index (BMI). Top compared to bottom quintile level of systolic or diastolic blood pressure was associated with a significant 15-20% decreased risk of incident prostate cancer (p for trend: systolic < 0.0001, diastolic = 0.3), but blood pressure was not significantly associated with risk of fatal prostate cancer. BMI was not associated with prostate cancer incidence, but was positively associated with fatal prostate cancer; men in the top quintile had a 30% increased risk (p for trend = 0.0004). The associations between blood pressure and BMI and nonaggressive tumors were similar to those of incident prostate cancer, and associations with aggressive tumors were similar to those of fatal prostate cancer. Data from our study suggest that hypertension is associated with a decreased risk of incident prostate cancer, but the explanation for this finding is unclear. Our study support a positive association between overweight and risk of fatal prostate cancer.

Keyword
prostatic neoplasms, cohort studies, blood pressure, overweight, body size
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:umu:diva-32700 (URN)10.1002/ijc.25171 (DOI)000281340200017 ()20087861 (PubMedID)
Note
Articles online in advance of printAvailable from: 2010-03-22 Created: 2010-03-22 Last updated: 2017-12-12Bibliographically approved
4. Cohort profile: the metabolic syndrome and cancer project (Me-Can)
Open this publication in new window or tab >>Cohort profile: the metabolic syndrome and cancer project (Me-Can)
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2010 (English)In: International Journal of Epidemiology, ISSN 0300-5771, E-ISSN 1464-3685, Vol. 39, no 3, 660-667 p.Article in journal (Refereed) Published
Place, publisher, year, edition, pages
Oxford University Press, 2010
Research subject
Epidemiology
Identifiers
urn:nbn:se:umu:diva-22558 (URN)10.1093/ije/dyp186 (DOI)000278438500005 ()19380371 (PubMedID)
Available from: 2009-05-13 Created: 2009-05-13 Last updated: 2017-12-13Bibliographically approved
5. Metabolic factors and risk of colorectal cancer in the metabolic syndrome and cancer project (Me-Can)
Open this publication in new window or tab >>Metabolic factors and risk of colorectal cancer in the metabolic syndrome and cancer project (Me-Can)
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2011 (English)In: Cancer, ISSN 0008-543X, E-ISSN 1097-0142, Vol. 117, no 11, 2398-2407 p.Article in journal (Refereed) Published
Abstract [en]

Background

The metabolic syndrome (MetS) has been related to an increased risk of colorectal cancer in some small studies, but it is unknown which factors in the MetS that are most strongly related to risk, and if there is an interaction between factors.

Methods and Findings

In the Metabolic syndrome and Cancer project (Me-Can), data on body mass index (BMI), blood pressure, and blood levels of glucose, cholesterol, and triglycerides were available in 289,866 men and 288,834 women. Mean age at baseline was 44.0 years and mean follow-up time was 12.0 years. During follow-up, 2,834 men and 1,861 women were diagnosed with colorectal cancer. We used Cox regression models to calculate relative risk (RR) of colorectal cancer by exposures transformed into Z scores (mean = 0, standard deviation = 1), and for a MetS Z score, and used regression calibration to correct exposure levels for random error in measurement. Significant increases in risk per one unit increment of factors were observed in men for BMI, RR 1.07 (95% confidence interval, 1.02-1.13), blood pressure, RR 1.10 (1.02-1.18), and triglycerides, RR 1.17 (1.06-1.28), and in women for BMI, RR 1.08 (1.01-1.15). The RR of colorectal cancer per one unit increment of the MetS Z score was 1.24 (1.18-1.31) in men, and 1.14 (1.06-1.22) in women. There was no significant positive interaction for any combination of two metabolic factors. Associations between metabolic factors and risk of fatal colorectal cancer were similar to those for incident cancer.

Conclusions

Our data add further evidence for an association between factors in the MetS, in single and combined, and risk of colorectal cancer. Our data do not support an interaction between factors in the MetS on risk.

Keyword
epidemiology, cohort studies, colorectal neoplasms, overweight, blood pressure, blood glucose, cholesterol, triglycerides, metabolic syndrome X
National Category
Cancer and Oncology
Research subject
Epidemiology
Identifiers
urn:nbn:se:umu:diva-22559 (URN)10.1002/cncr.25772 (DOI)21171019 (PubMedID)
Available from: 2009-12-22 Created: 2009-05-13 Last updated: 2017-12-13Bibliographically approved
6. Blood glucose and risk of incident and fatal cancer in the metabolic syndrome and cancer project (Me-Can): analysis of six prospective cohorts.
Open this publication in new window or tab >>Blood glucose and risk of incident and fatal cancer in the metabolic syndrome and cancer project (Me-Can): analysis of six prospective cohorts.
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2009 (English)In: PLoS Medicine, ISSN 1549-1277, E-ISSN 1549-1676, Vol. 6, no 12, e1000201- p.Article in journal (Refereed) Published
Abstract [en]

 Background

Prospective studies have indicated that elevated blood glucose levels may increase the risk of cancer, but the strength of the association is unclear. We examined the association between blood glucose and cancer risk in a prospective study of six European cohorts. Methods and Findings The Metabolic syndrome and Cancer project (Me-Can) includes cohorts from Norway, Austria, and Sweden; the current study included 274,126 men and 275,818 women. Mean age at baseline was 44.8 years and mean follow-up time was 10.4 years. Excluding the first year of follow-up, 18,621 men and 11,664 women were diagnosed with cancer, and 6,973 men and 3,088 women died of cancer. We used Cox regression models to calculate relative risk (RR) for glucose levels, and included adjustment for body mass index (BMI) and smoking  status in the analyses. RRs were corrected for regression dilution ratio of glucose. RR (95% confidence interval) per 1 mmol/l increment of glucose for overall incident cancer was 1.05 (1.01-1.10) in men and 1.11 (1.05-1.16) in women, and corresponding RRs for fatal cancer were 1.15 (1.07-1.22) and 1.21 (1.11-1.33), respectively. Significant increases in risk among men were found for incident and fatal cancer of the liver, gallbladder and respiratory tract, for incident thyroid cancer and multiple myeloma, and for fatal rectal cancer. In women, significant associations were found for incident and fatal cancer of the pancreas, for incident urinary bladder cancer, and for fatal cancer of the uterine corpus, cervix uteri, and stomach.

Conclusions

Data from our study indicate that abnormal glucose metabolism, independently of BMI, is associated with an increased risk of cancer overall and at several cancer sites. Our data showed stronger associations among women than among men, and for fatal cancer compared to incident cancer.

 

Keyword
cohort studies, neoplasms, blood glucose
National Category
Cancer and Oncology
Research subject
Epidemiology
Identifiers
urn:nbn:se:umu:diva-22562 (URN)10.1371/journal.pmed.1000201 (DOI)000273060600015 ()20027213 (PubMedID)
Available from: 2009-12-22 Created: 2009-05-13 Last updated: 2017-12-13Bibliographically approved

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