TY - JOUR

T1 - Adult body mass index and risk of ovarian cancer by subtype

T2 - a Mendelian randomization study

AU - Dixon, Suzanne C

AU - Nagle, Christina M

AU - Thrift, Aaron P

AU - Pharoah, Paul Dp

AU - Pearce, Celeste Leigh

AU - Zheng, Wei

AU - Painter, Jodie N

AU - Chenevix-Trench, Georgia

AU - Fasching, Peter A

AU - Beckmann, Matthias W

AU - Lambrechts, Diether

AU - Vergote, Ignace

AU - Lambrechts, Sandrina

AU - Van Nieuwenhuysen, Els

AU - Rossing, Mary Anne

AU - Doherty, Jennifer A

AU - Wicklund, Kristine G

AU - Chang-Claude, Jenny

AU - Rudolph, Anja

AU - Moysich, Kirsten B

AU - Odunsi, Kunle

AU - Goodman, Marc T

AU - Wilkens, Lynne R

AU - Thompson, Pamela J

AU - Shvetsov, Yurii B

AU - Dörk, Thilo

AU - Park-Simon, Tjoung-Won

AU - Hillemanns, Peter

AU - Bogdanova, Natalia

AU - Butzow, Ralf

AU - Nevanlinna, Heli

AU - Pelttari, Liisa M

AU - Leminen, Arto

AU - Modugno, Francesmary

AU - Ness, Roberta B

AU - Edwards, Robert P

AU - Kelley, Joseph L

AU - Heitz, Florian

AU - Karlan, Beth Y

AU - Kjær, Susanne Krüger

AU - Høgdall, Estrid Vilma Solyom

AU - Jensen, Allan

AU - Goode, Ellen L

AU - Fridley, Brooke L

AU - Cunningham, Julie M

AU - Winham, Stacey J

AU - Giles, Graham G

AU - Bruinsma, Fiona

AU - Milne, Roger L

AU - Høgdall, Claus Kim

AU - AOCS Group & Australian Cancer Study (Ovarian Cancer)

N1 - © The Author 2016; all rights reserved. Published by Oxford University Press on behalf of the International Epidemiological Association.

PY - 2016/7

Y1 - 2016/7

N2 - 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.

AB - 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.

KW - Journal Article

U2 - 10.1093/ije/dyw158

DO - 10.1093/ije/dyw158

M3 - Journal article

C2 - 27401727

VL - 45

SP - 884

EP - 895

JO - International Journal of Epidemiology

JF - International Journal of Epidemiology

SN - 0300-5771

IS - 3

ER -