Dataset Information

Adult body mass index and risk of ovarian cancer by subtype: a Mendelian randomization study.

ABSTRACT:

Background

Observational studies have reported a positive association between body mass index (BMI) and ovarian cancer risk. However, questions remain as to whether this represents a causal effect, or holds for all histological subtypes. The lack of association observed for serous cancers may, for instance, be due to disease-associated weight loss. Mendelian randomization (MR) uses genetic markers as proxies for risk factors to overcome limitations of observational studies. We used MR to elucidate the relationship between BMI and ovarian cancer, hypothesizing that genetically predicted BMI would be associated with increased risk of non-high grade serous ovarian cancers (non-HGSC) but not HGSC.

Methods

We pooled data from 39 studies (14 047 cases, 23 003 controls) in the Ovarian Cancer Association Consortium. We constructed a weighted genetic risk score (GRS, partial F-statistic = 172), summing alleles at 87 single nucleotide polymorphisms previously associated with BMI, weighting by their published strength of association with BMI. Applying two-stage predictor-substitution MR, we used logistic regression to estimate study-specific odds ratios (OR) and 95% confidence intervals (CI) for the association between genetically predicted BMI and risk, and pooled these using random-effects meta-analysis.

Results

Higher genetically predicted BMI was associated with increased risk of non-HGSC (pooled OR?=?1.29, 95% CI 1.03-1.61 per 5 units BMI) but not HGSC (pooled OR?=?1.06, 95% CI 0.88-1.27). Secondary analyses stratified by behaviour/subtype suggested that, consistent with observational data, the association was strongest for low-grade/borderline serous cancers (OR?=?1.93, 95% CI 1.33-2.81).

Conclusions

Our data suggest that higher BMI increases risk of non-HGSC, but not the more common and aggressive HGSC subtype, confirming the observational evidence.

SUBMITTER: Dixon SC

PROVIDER: S-EPMC5644573 | biostudies-literature | 2016 Jun

REPOSITORIES: biostudies-literature

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Publications

Adult body mass index and risk of ovarian cancer by subtype: a Mendelian randomization study.

Dixon Suzanne C SC Nagle Christina M CM Thrift Aaron P AP Pharoah Paul Dp PD Pearce Celeste Leigh CL Zheng Wei W Painter Jodie N JN Chenevix-Trench Georgia G Fasching Peter A PA Beckmann Matthias W MW Lambrechts Diether D Vergote Ignace I Lambrechts Sandrina S Van Nieuwenhuysen Els E Rossing Mary Anne MA Doherty Jennifer A JA Wicklund Kristine G KG Chang-Claude Jenny J Rudolph Anja A Moysich Kirsten B KB Odunsi Kunle K Goodman Marc T MT Wilkens Lynne R LR Thompson Pamela J PJ Shvetsov Yurii B YB Dörk Thilo T Park-Simon Tjoung-Won TW Hillemanns Peter P Bogdanova Natalia N Butzow Ralf R Nevanlinna Heli H Pelttari Liisa M LM Leminen Arto A Modugno Francesmary F Ness Roberta B RB Edwards Robert P RP Kelley Joseph L JL Heitz Florian F Karlan Beth Y BY Kjær Susanne K SK Høgdall Estrid E Jensen Allan A Goode Ellen L EL Fridley Brooke L BL Cunningham Julie M JM Winham Stacey J SJ Giles Graham G GG Bruinsma Fiona F Milne Roger L RL Southey Melissa C MC Hildebrandt Michelle A T MA Wu Xifeng X Lu Karen H KH Liang Dong D Levine Douglas A DA Bisogna Maria M Schildkraut Joellen M JM Berchuck Andrew A Cramer Daniel W DW Terry Kathryn L KL Bandera Elisa V EV Olson Sara H SH Salvesen Helga B HB Thomsen Liv Cecilie LC Kopperud Reidun K RK Bjorge Line L Kiemeney Lambertus A LA Massuger Leon F A G LF Pejovic Tanja T Cook Linda S LS Le Nhu D ND Swenerton Kenneth D KD Brooks-Wilson Angela A Kelemen Linda E LE Lubiński Jan J Huzarski Tomasz T Gronwald Jacek J Menkiszak Janusz J Wentzensen Nicolas N Brinton Louise L Yang Hannah H Lissowska Jolanta J Høgdall Claus K CK Lundvall Lene L Song Honglin H Tyrer Jonathan P JP Campbell Ian I Eccles Diana D Paul James J Glasspool Rosalind R Siddiqui Nadeem N Whittemore Alice S AS Sieh Weiva W McGuire Valerie V Rothstein Joseph H JH Narod Steven A SA Phelan Catherine C Risch Harvey A HA McLaughlin John R JR Anton-Culver Hoda H Ziogas Argyrios A Menon Usha U Gayther Simon A SA Ramus Susan J SJ Gentry-Maharaj Aleksandra A Wu Anna H AH Pike Malcolm C MC Tseng Chiu-Chen CC Kupryjanczyk Jolanta J Dansonka-Mieszkowska Agnieszka A Budzilowska Agnieszka A Spiewankiewicz Beata B Webb Penelope M PM

International journal of epidemiology 20160601 3

<h4>Background</h4>Observational studies have reported a positive association between body mass index (BMI) and ovarian cancer risk. However, questions remain as to whether this represents a causal effect, or holds for all histological subtypes. The lack of association observed for serous cancers may, for instance, be due to disease-associated weight loss. Mendelian randomization (MR) uses genetic markers as proxies for risk factors to overcome limitations of observational studies. We used MR to ...[more]

PMID: 27401727

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Project description:BackgroundEndometrial cancer is the most common gynaecological cancer in high-income countries. Elevated body mass index (BMI) is an established modifiable risk factor for this condition and is estimated to confer a larger effect on endometrial cancer risk than any other cancer site. However, the molecular mechanisms underpinning this association remain unclear. We used Mendelian randomization (MR) to evaluate the causal role of 14 molecular risk factors (hormonal, metabolic and inflammatory markers) in endometrial cancer risk. We then evaluated and quantified the potential mediating role of these molecular traits in the relationship between BMI and endometrial cancer using multivariable MR.MethodsGenetic instruments to proxy 14 molecular risk factors and BMI were constructed by identifying single-nucleotide polymorphisms (SNPs) reliably associated (P < 5.0 × 10-8) with each respective risk factor in previous genome-wide association studies (GWAS). Summary statistics for the association of these SNPs with overall and subtype-specific endometrial cancer risk (12,906 cases and 108,979 controls) were obtained from a GWAS meta-analysis of the Endometrial Cancer Association Consortium (ECAC), Epidemiology of Endometrial Cancer Consortium (E2C2) and UK Biobank. SNPs were combined into multi-allelic models and odds ratios (ORs) and 95% confidence intervals (95% CIs) were generated using inverse-variance weighted random-effects models. The mediating roles of the molecular risk factors in the relationship between BMI and endometrial cancer were then estimated using multivariable MR.ResultsIn MR analyses, there was strong evidence that BMI (OR per standard deviation (SD) increase 1.88, 95% CI 1.69 to 2.09, P = 3.87 × 10-31), total testosterone (OR per inverse-normal transformed nmol/L increase 1.64, 95% CI 1.43 to 1.88, P = 1.71 × 10-12), bioavailable testosterone (OR per natural log transformed nmol/L increase: 1.46, 95% CI 1.29 to 1.65, P = 3.48 × 10-9), fasting insulin (OR per natural log transformed pmol/L increase: 3.93, 95% CI 2.29 to 6.74, P = 7.18 × 10-7) and sex hormone-binding globulin (SHBG, OR per inverse-normal transformed nmol/L increase 0.71, 95% CI 0.59 to 0.85, P = 2.07 × 10-4) had a causal effect on endometrial cancer risk. Additionally, there was suggestive evidence that total serum cholesterol (OR per mg/dL increase 0.90, 95% CI 0.81 to 1.00, P = 4.01 × 10-2) had an effect on endometrial cancer risk. In mediation analysis, we found evidence for a mediating role of fasting insulin (19% total effect mediated, 95% CI 5 to 34%, P = 9.17 × 10-3), bioavailable testosterone (15% mediated, 95% CI 10 to 20%, P = 1.43 × 10-8) and SHBG (7% mediated, 95% CI 1 to 12%, P = 1.81 × 10-2) in the relationship between BMI and endometrial cancer risk.ConclusionsOur comprehensive MR analysis provides insight into potential causal mechanisms linking BMI with endometrial cancer risk and suggests targeting of insulinemic and hormonal traits as a potential strategy for the prevention of endometrial cancer.

Dataset Information

Adult body mass index and risk of ovarian cancer by subtype: a Mendelian randomization study.

Background

Methods

Results

Conclusions

Publications

Adult body mass index and risk of ovarian cancer by subtype: a Mendelian randomization study.

Similar Datasets

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