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

Suzanne C Dixon; Christina M Nagle; Aaron P Thrift; Paul Dp Pharoah; Celeste Leigh Pearce; Wei Zheng; Jodie N Painter; Georgia Chenevix-Trench; Peter A Fasching; Matthias W Beckmann; Diether Lambrechts; Ignace Vergote; Sandrina Lambrechts; Els Van Nieuwenhuysen; Mary Anne Rossing; Jennifer A Doherty; Kristine G Wicklund; Jenny Chang-Claude; Anja Rudolph; Kirsten B Moysich; Kunle Odunsi; Marc T Goodman; Lynne R Wilkens; Pamela J Thompson; Yurii B Shvetsov; Thilo Dörk; Tjoung-Won Park-Simon; Peter Hillemanns; Natalia Bogdanova; Ralf Butzow; Heli Nevanlinna; Liisa M Pelttari; Arto Leminen; Francesmary Modugno; Roberta B Ness; Robert P Edwards; Joseph L Kelley; Florian Heitz; Beth Y Karlan; Susanne Krüger Kjær; Estrid Vilma Solyom Høgdall; Allan Jensen; Ellen L Goode; Brooke L Fridley; Julie M Cunningham; Stacey J Winham; Graham G Giles; Fiona Bruinsma; Roger L Milne; Claus Kim Høgdall; AOCS Group & Australian Cancer Study (Ovarian Cancer)

doi:10.1093/ije/dyw158

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

Suzanne C Dixon, Christina M Nagle, Aaron P Thrift, Paul Dp Pharoah, Celeste Leigh Pearce, Wei Zheng, Jodie N Painter, Georgia Chenevix-Trench, Peter A Fasching, Matthias W Beckmann, Diether Lambrechts, Ignace Vergote, Sandrina Lambrechts, Els Van Nieuwenhuysen, Mary Anne Rossing, Jennifer A Doherty, Kristine G Wicklund, Jenny Chang-Claude, Anja Rudolph, Kirsten B MoysichKunle Odunsi, Marc T Goodman, Lynne R Wilkens, Pamela J Thompson, Yurii B Shvetsov, Thilo Dörk, Tjoung-Won Park-Simon, Peter Hillemanns, Natalia Bogdanova, Ralf Butzow, Heli Nevanlinna, Liisa M Pelttari, Arto Leminen, Francesmary Modugno, Roberta B Ness, Robert P Edwards, Joseph L Kelley, Florian Heitz, Beth Y Karlan, Susanne Krüger Kjær, Estrid Vilma Solyom Høgdall, Allan Jensen, Ellen L Goode, Brooke L Fridley, Julie M Cunningham, Stacey J Winham, Graham G Giles, Fiona Bruinsma, Roger L Milne, Claus Kim Høgdall, AOCS Group & Australian Cancer Study (Ovarian Cancer)

Department of Clinical Medicine

33 Citations (Scopus)

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.

Original language	English
Journal	International Journal of Epidemiology
Volume	45
Issue number	3
Pages (from-to)	884-895
Number of pages	12
ISSN	0300-5771
DOIs	https://doi.org/10.1093/ije/dyw158
Publication status	Published - Jun 2016

Keywords

Journal Article

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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Dixon, S. C., Nagle, C. M., Thrift, A. P., Pharoah, P. D., Pearce, C. L., Zheng, W., Painter, J. N., Chenevix-Trench, G., Fasching, P. A., Beckmann, M. W., Lambrechts, D., Vergote, I., Lambrechts, S., Van Nieuwenhuysen, E., Rossing, M. A., Doherty, J. A., Wicklund, K. G., Chang-Claude, J., Rudolph, A., ... AOCS Group & Australian Cancer Study (Ovarian Cancer) (2016). Adult body mass index and risk of ovarian cancer by subtype: a Mendelian randomization study. International Journal of Epidemiology, 45(3), 884-895. https://doi.org/10.1093/ije/dyw158

Dixon, SC, Nagle, CM, Thrift, AP, Pharoah, PD, Pearce, CL, Zheng, W, Painter, JN, Chenevix-Trench, G, Fasching, PA, Beckmann, MW, Lambrechts, D, Vergote, I, Lambrechts, S, Van Nieuwenhuysen, E, Rossing, MA, Doherty, JA, Wicklund, KG, Chang-Claude, J, Rudolph, A, Moysich, KB, Odunsi, K, Goodman, MT, Wilkens, LR, Thompson, PJ, Shvetsov, YB, Dörk, T, Park-Simon, T-W, Hillemanns, P, Bogdanova, N, Butzow, R, Nevanlinna, H, Pelttari, LM, Leminen, A, Modugno, F, Ness, RB, Edwards, RP, Kelley, JL, Heitz, F, Karlan, BY, Kjær, SK , Høgdall, EVS, Jensen, A, Goode, EL, Fridley, BL, Cunningham, JM, Winham, SJ, Giles, GG, Bruinsma, F, Milne, RL, Høgdall, CK & AOCS Group & Australian Cancer Study (Ovarian Cancer) 2016, 'Adult body mass index and risk of ovarian cancer by subtype: a Mendelian randomization study', International Journal of Epidemiology, vol. 45, no. 3, pp. 884-895. https://doi.org/10.1093/ije/dyw158

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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.",

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author = "Dixon, {Suzanne C} and Nagle, {Christina M} and Thrift, {Aaron P} and Pharoah, {Paul Dp} and Pearce, {Celeste Leigh} and Wei Zheng and Painter, {Jodie N} and Georgia Chenevix-Trench and Fasching, {Peter A} and Beckmann, {Matthias W} and Diether Lambrechts and Ignace Vergote and Sandrina Lambrechts and {Van Nieuwenhuysen}, Els and Rossing, {Mary Anne} and Doherty, {Jennifer A} and Wicklund, {Kristine G} and Jenny Chang-Claude and Anja Rudolph and Moysich, {Kirsten B} and Kunle Odunsi and Goodman, {Marc T} and Wilkens, {Lynne R} and Thompson, {Pamela J} and Shvetsov, {Yurii B} and Thilo D{\"o}rk and Tjoung-Won Park-Simon and Peter Hillemanns and Natalia Bogdanova and Ralf Butzow and Heli Nevanlinna and Pelttari, {Liisa M} and Arto Leminen and Francesmary Modugno and Ness, {Roberta B} and Edwards, {Robert P} and Kelley, {Joseph L} and Florian Heitz and Karlan, {Beth Y} and Kj{\ae}r, {Susanne Kr{\"u}ger} and H{\o}gdall, {Estrid Vilma Solyom} and Allan Jensen and Goode, {Ellen L} and Fridley, {Brooke L} and Cunningham, {Julie M} and Winham, {Stacey J} and Giles, {Graham G} and Fiona Bruinsma and Milne, {Roger L} and H{\o}gdall, {Claus Kim} and {AOCS Group & Australian Cancer Study (Ovarian Cancer)}",

year = "2016",

month = jun,

doi = "10.1093/ije/dyw158",

language = "English",

volume = "45",

pages = "884--895",

journal = "International Journal of Epidemiology",

issn = "0300-5771",

publisher = "Oxford University Press",

number = "3",

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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)

PY - 2016/6

Y1 - 2016/6

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

SN - 0300-5771

VL - 45

SP - 884

EP - 895

JO - International Journal of Epidemiology

JF - International Journal of Epidemiology

IS - 3

ER -

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

Abstract

Keywords

UN SDGs

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