Imperial College London

Dr David C Muller

Faculty of MedicineSchool of Public Health

Lecturer in Cancer Epidemiology and Biostatistics
 
 
 
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Contact

 

+44 (0)20 7594 0856david.muller

 
 
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Location

 

VC2Norfolk PlaceSt Mary's Campus

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Summary

 

Publications

Publication Type
Year
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100 results found

Mariosa D, Smith-Byrne K, Richardson TG, Ferrari P, Gunter MJ, Papadimitriou N, Murphy N, Christakoudi S, Tsilidis KK, Riboli E, Muller D, Purdue MP, Chanock SJ, Hung RJ, Amos CI, O'Mara TA, Amiano P, Pasanisi F, Rodriguez-Barranco M, Krogh V, Tjønneland A, Halkjær J, Perez-Cornago A, Chirlaque M-D, Skeie G, Rylander C, Borch KB, Aune D, Heath AK, Ward HA, Schulze M, Bonet C, Weiderpass E, Smith GD, Brennan P, Johansson Met al., 2022, Body size at different ages and risk of six cancers: a Mendelian randomization and prospective cohort study, JNCI: Journal of the National Cancer Institute, ISSN: 0027-8874

It is unclear if body weight in early life affects cancer risk independently of adult body weight. To investigate this question for six obesity-related cancers, we performed univariable and multivariable analyses using i) Mendelian randomization (MR) analysis and ii) longitudinal analyses in prospective cohorts. Both the MR and longitudinal analyses indicated that larger body size at age 10 was associated with higher risk of endometrial (ORMR=1.61, 95%CI = 1.23–2.11) and kidney cancer (ORMR=1.40, 95%CI = 1.09–1.80). These associations were attenuated after accounting for adult body size in both the MR and cohort analyses. Early life BMI was not consistently associated with the other investigated cancers. The lack of clear independent risk associations suggests that early life BMI influences endometrial and kidney cancer risk mainly through pathways that are common with adult BMI.

Journal article

Cairat M, Rinaldi S, Navionis A-S, Romieu I, Biessy C, Viallon V, Olsen A, Tjonneland A, Fournier A, Severi G, Kvaskoff M, Fortner RT, Kaaks R, Aleksandrova K, Schulze MB, Masala G, Tumino R, Sieri S, Grasso C, Mattiello A, Gram IT, Olsen KS, Agudo A, Etxezarreta PA, Sanchez M-J, Santiuste C, Barricarte A, Monninkhof E, Hiensch AE, Muller D, Merritt MA, Travis RC, Weiderpass E, Gunter MJ, Dossus Let al., 2022, Circulating inflammatory biomarkers, adipokines and breast cancer risk-a case-control study nested within the EPIC cohort, BMC MEDICINE, Vol: 20, ISSN: 1741-7015

Journal article

Clasen JL, Heath AK, Van Puyvelde H, Huybrechts I, Park JY, Ferrari P, Scelo G, Ulvik A, Midttun Ø, Ueland PM, Overvad K, Eriksen AK, Tjønneland A, Kaaks R, Katzke V, Schulze MB, Palli D, Agnoli C, Chiodini P, Tumino R, Sacerdote C, Zamora-Ros R, Rodriguez-Barranco M, Santiuste C, Ardanaz E, Amiano P, Schmidt JA, Weiderpass E, Gunter M, Riboli E, Cross AJ, Johansson M, Muller DCet al., 2022, Biomarkers of the transsulfuration pathway and risk of renal cell carcinoma in the European Prospective Investigation into Cancer and Nutrition (EPIC) study, International Journal of Cancer, ISSN: 0020-7136

Previous studies have suggested that components of one-carbon metabolism, particularly circulating vitamin B6, have an etiological role in renal cell carcinoma (RCC). Vitamin B6 is a cofactor in the transsulfuration pathway. We sought to holistically investigate the role of the transsulfuration pathway in RCC risk. We conducted a nested case-control study (455 RCC cases and 455 matched controls) within the European Prospective Investigation into Cancer and Nutrition (EPIC) study. Plasma samples from the baseline visit were analyzed for metabolites of the transsulfuration pathway, including pyridoxal 5'-phosphate (PLP, the biologically active form of vitamin B6), homocysteine, serine, cystathionine, and cysteine, in addition to folate. Bayesian conditional logistic regression was used to estimate associations of metabolites with RCC risk as well as interactions with established RCC risk factors. Circulating PLP and cysteine were inversely associated with RCC risk, and these association were not attenuated after adjustment for other transsulfuration metabolites (odds ratio (OR) and 90% credible interval (CrI) per 1 SD increase in log concentration: 0.76 [0.66, 0.87]; 0.81 [0.66, 0.96], respectively). A comparison of joint metabolite profiles suggested substantially greater RCC risk for the profile representative of low overall transsulfuration function compared with high function (OR 2.70 [90% CrI 1.26, 5.70]). We found some statistical evidence of interactions of cysteine with body mass index, and PLP and homocysteine with smoking status, on their associations with RCC risk. In conclusion, we found evidence suggesting that the transsulfuration pathway may play a role in metabolic dysregulation leading to RCC development. This article is protected by copyright. All rights reserved.

Journal article

Papadimitriou N, Bouras E, van den Brandt PA, Muller DC, Papadopoulou A, Heath AK, Critselis E, Gunter MJ, Vineis P, Ferrari P, Weiderpass E, Boeing H, Bastide N, Merritt MA, Lopez DS, Bergmann MM, Perez-Cornago A, Schulze M, Skeie G, Srour B, Eriksen AK, Boden S, Johansson I, Nøst TH, Lukic M, Ricceri F, Ericson U, Huerta JM, Dahm CC, Agnoli C, Amiano PE, Tjønneland A, Gurrea AB, Bueno-de-Mesquita B, Ardanaz E, Berntsson J, Sánchez M-J, Tumino R, Panico S, Katzke V, Jakszyn P, Masala G, Derksen JWG, Quirós JR, Severi G, Cross AJ, Riboli E, Tzoulaki I, Tsilidis KKet al., 2022, A prospective diet-wide association study for risk of colorectal cancer in EPIC, Clinical Gastroenterology and Hepatology, Vol: 20, Pages: 864-873.e13, ISSN: 1542-3565

BACKGROUND & AIMS: Evidence regarding the association of dietary exposures with colorectal cancer (CRC) risk is not consistent with a few exceptions. Therefore, we conducted a diet-wide association study (DWAS) in the European Prospective Investigation into Cancer and Nutrition (EPIC) to evaluate the associations between several dietary exposures with CRC risk. METHODS: The association of 92 food and nutrient intakes with CRC risk was assessed in 386,792 participants, 5,069 of whom developed incident CRC. Correction for multiple comparisons was performed using the false discovery rate, and emerging associations were examined in the Netherlands Cohort Study (NLCS). Multiplicative gene-nutrient interactions were also tested in EPIC based on known CRC-associated loci. RESULTS: In EPIC, alcohol, liquor/spirits, wine, beer/cider, soft drinks, and pork were positively associated with CRC, whereas milk, cheese, calcium, phosphorus, magnesium, potassium, riboflavin, vitamin B6, beta-carotene, fruit, fibre, non-white bread, banana, and total protein intakes were inversely associated. Of these 20 associations, 13 were replicated in NLCS, for which a meta-analysis was performed, namely alcohol (summary HR per 1 SD increment in intake: 1.07; 95%CI:1.04-1.09), liquor/spirits (1.04; 1.02-1.06), wine (1.04;1.02-1.07), beer/cider (1.06;1.04-1.08), milk (0.95;0.93-0.98), cheese (0.96;0.94-0.99), calcium (0.93;0.90-0.95), phosphorus (0.92;0.90-0.95), magnesium (0.95;0.92-0.98), potassium (0.96;0.94-0.99), riboflavin (0.94;0.92-0.97), beta-carotene (0.96;0.93-0.98), and total protein (0.94;0.92-0.97). None of the gene-nutrient interactions were significant after adjustment for multiple comparisons. CONCLUSIONS: Our findings confirm a positive association for alcohol and an inverse association for dairy products and calcium with CRC risk, and also suggest a lower risk at higher dietary intakes of phosphorus, magnesium, potassium, riboflavin, beta-carotene and total protein.

Journal article

Guida F, Tan VY, Corbin LJ, Smith-Byrne K, Alcala K, Langenberg C, Stewart ID, Butterworth AS, Surendran P, Achaintre D, Adamski J, Amiano Exezarreta P, Bergmann MM, Bull CJ, Dahm CC, Gicquiau A, Giles GG, Gunter MJ, Haller T, Langhammer A, Larose TL, Ljungberg B, Metspalu A, Milne RL, Muller DC, Nøst TH, Pettersen Sørgjerd E, Prehn C, Riboli E, Rinaldi S, Rothwell JA, Scalbert A, Schmidt JA, Severi G, Sieri S, Vermeulen R, Vincent EE, Waldenberger M, Timpson NJ, Johansson Met al., 2021, The blood metabolome of incident kidney cancer: A case-control study nested within the MetKid consortium, PLoS Medicine, Vol: 18, ISSN: 1549-1277

BACKGROUND: Excess bodyweight and related metabolic perturbations have been implicated in kidney cancer aetiology, but the specific molecular mechanisms underlying these relationships are poorly understood. In this study, we sought to identify circulating metabolites that predispose kidney cancer and to evaluate the extent to which they are influenced by body mass index (BMI). METHODS AND FINDINGS: We assessed the association between circulating levels of 1,416 metabolites and incident kidney cancer using pre-diagnostic blood samples from up to 1,305 kidney cancer case-control pairs from 5 prospective cohort studies. Cases were diagnosed on average 8 years after blood collection. We found 25 metabolites robustly associated with kidney cancer risk. In particular, 14 glycerophospholipids (GPLs) were inversely associated with risk, including 8 phosphatidylcholines (PCs) and 2 plasmalogens. The PC with the strongest association was PC ae C34:3 with an odds ratio (OR) for 1 standard deviation (SD) increment of 0.75 (95% confidence interval [CI]: 0.68 to 0.83, p = 2.6 × 10-8). In contrast, 4 amino acids, including glutamate (OR for 1 SD = 1.39, 95% CI: 1.20 to 1.60, p = 1.6 × 10-5), were positively associated with risk. Adjusting for BMI partly attenuated the risk association for some-but not all-metabolites, whereas other known risk factors of kidney cancer, such as smoking and alcohol consumption, had minimal impact on the observed associations. A mendelian randomisation (MR) analysis of the influence of BMI on the blood metabolome highlighted that some metabolites associated with kidney cancer risk are influenced by BMI. Specifically, elevated BMI appeared to decrease levels of several GPLs that were also found inversely associated with kidney cancer risk (e.g., -0.17 SD change [ßBMI] in 1-(1-enyl-palmitoyl)-2-linoleoyl-GPC (P-16:0/18:2) levels per SD change in BMI, p = 3.4 × 10-5). BMI was also associated with increased levels of glutamate (&sz

Journal article

Clasen J, Heath AK, Van Puyvelde H, Huybrechts I, Johansson M, Ferrari P, Park JY, Brennan P, Riboli E, Muller DCet al., 2021, Vitamin B6 intake, its active form pyridoxal 5'phosphate, and markers of B6 activity and catabolism, IEA WORLD CONGRESS OF EPIDEMIOLOGY 2021, Publisher: Oxford University Press, Pages: 1-1, ISSN: 0300-5771

BackgroundSeveral biological pathways implicated in cancer risk rely on vitamin B6, which can be measured in its active form pyridoxal 5’-phosphate (PLP). Functional markers of B6 enzymatic activity have been proposed, including the homocysteine:cysteine ratio (Hcy:Cys, a marker of transsulfuration), 3-hydroxykynurenine ratio (HKr, a marker of tryptophan catabolism), and the 4-pyridoxic acid ratio (PAr, a marker of B6 catabolism). We investigated the extent to which these markers are associated with B6 intake.MethodsData from 4,750 participants in the European Prospective Investigation into Cancer and Nutrition (EPIC) study were included. We estimated the expected percentage change in each of the markers (PLP, Hcy:Cys, HKr, and PAr) for a doubling in B6 intake using log-linear Bayesian hierarchical regression models with log-transformed intake and biomarker data.ResultsThe percent change (posterior mean [95% Credible Interval (CrI)]) for a doubling of B6 intake was 61.0 [51.2, 71.8] for PLP, -12.7 [-15.2, -9.9] for Hcy:Cys, -12.9 [-15.7, -9.9] for HKr, and 1.3 [-3.5, 6.2] for PAr.ConclusionsB6 intake is most strongly associated with PLP, but is also associated with functional markers of transsulfuration and tryptophan catabolism, in the direction of increased activity in these pathways. There is no evidence of a linear association between vitamin B6 intake and catabolism.Key messagesOur results show differing sensitivity of PLP, markers of tryptophan catabolism and transsulfuration, and vitamin B6 catabolism to B6 intake.

Conference paper

Heath A, Clasen J, Riboli E, Scelo G, Muller Det al., 2021, Investigation of the obesity paradox in kidney cancer: mystifying association or myth?, World Congress of Epidemiology 2021, Publisher: Oxford University Press, ISSN: 0300-5771

Conference paper

Clasen J, Heath A, Van Puyvelde H, Huybrechts I, Young Park J, Ferrari P, Johansson M, Scelo G, Midttun Ø, Magne Ueland P, Dahm C, Halkjær J, Olsen A, Johnson T, Katzke V, Schulze M, Masala G, Segrado F, Santucci de Magistris M, Sacerdote C, Ocké M, Luján-Barroso L, Ching-López A, Huerta JM, Ardanaz E, Amiano P, Ericson U, Manjer J, Gylling B, Johansson I, Schmidt J, Weiderpass E, Riboli E, Cross A, Muller Det al., 2021, A comparison of complementary measures of vitamin B6 status, function, and metabolism in the European Prospective Investigation into Cancer and Nutrition (EPIC) study, American Journal of Clinical Nutrition, Vol: 114, Pages: 338-347, ISSN: 0002-9165

BackgroundVitamin B6 insufficiency has been linked to increased risk of cancer and other chronic diseases. The circulating concentration of pyridoxal 5′-phosphate (PLP) is a commonly used measure of vitamin B6 status. Ratios of substrates indicating PLP coenzymatic function and metabolism may be useful complementary measures to further explore the role of vitamin B6 in health.ObjectivesWe explored the sensitivity of 5 outcomes, namely PLP concentration, homocysteine:cysteine (Hcy:Cys), cystathionine:cysteine (Cysta:Cys), the 3´-hydroxykynurenine ratio (HKr), and the 4-pyridoxic acid ratio (PAr) to vitamin B6 intake as well as personal and lifestyle characteristics.MedthodsDietary intake and biomarker data were collected from participants from 3 nested case-control studies within the European Prospective Investigation into Cancer and Nutrition (EPIC). Bayesian regression models assessed the associations of the 5 biomarker outcomes with vitamin B6 intake and personal and lifestyle covariates. Analogous models examined the relations of Hcy:Cys, Cysta:Cys, and HKr with PLP.ResultsIn total, 4608 participants were included in the analyses. Vitamin B6 intake was most strongly associated with PLP, moderately associated with Hcy:Cys, Cysta:Cys, and HKr, and not associated with PAr (fold change in marker given a doubling of vitamin B6 intake: PLP 1.60 [95% credible interval (CrI): 1.50, 1.71]; Hcy:Cys 0.87 [95% CrI: 0.84, 0.90]; Cysta:Cys 0.89 [95% CrI: 0.84, 0.94]; HKr 0.88 [95% CrI: 0.85, 0.91]; PAr 1.00 [95% CrI: 0.95, 1.05]). PAr was most sensitive to age, and HKr was least sensitive to BMI and alcohol intake. Sex and menopause status were strongly associated with all 5 markers.ConclusionsWe found that 5 different markers, capturing different aspects of vitamin B6–related biological processes, varied in their associations with vitamin B6 intake and personal and lifestyle predictors.

Journal article

Hageman S, Pennells L, Ojeda F, Kaptoge S, Kuulasmaa K, de Vries T, Xu Z, Kee F, Chung R, Wood A, McEvoy JW, Veronesi G, Bolton T, Dendale P, Ference BA, Halle M, Timmis A, Vardas P, Danesh J, Graham I, Salomaa V, Visseren F, De Bacquer D, Blankenberg S, Dorresteijn J, Di Angelantonio E, Achenbach S, Aleksandrova K, Amiano P, Amouyel P, Andersson J, Bakker SJL, Costa RBDP, Beulens JWJ, Blaha M, Bobak M, Boer JMA, Bonet C, Bonnet F, Boutron-Ruault M-C, Braaten T, Brenner H, Brunner F, Brunner EJ, Brunstrom M, Buring J, Butterworth AS, Capkova N, Cesana G, Chrysohoou C, Colorado-Yohar S, Cook NR, Cooper C, Dahm CC, Davidson K, Dennison E, Di Castelnuovo A, Donfrancesco C, Doerr M, Dorynska A, Eliasson M, Engstrom G, Ferrari P, Ferrario M, Ford I, Fu M, Gansevoort RT, Giampaoli S, Gillum RF, de la Camara AG, Grassi G, Hansson P-O, Huculeci R, Hveem K, Iacoviello L, Ikram MK, Jorgensen T, Joseph B, Jousilahti P, Jukema JW, Kaaks R, Katzke V, Kavousi M, Kiechl S, Klotsche J, Koenig W, Kronmal RA, Kubinova R, Kucharska-Newton A, Lall K, Lehmann N, Leistner D, Linneberg A, Lora Pablos D, Lorenz T, Lu W, Luksiene D, Lyngbakken M, Magnussen C, Malyutina S, Marin Ibanez A, Masala G, Mathiesen EB, Matsushita K, Meade TW, Melander O, Meyer HE, Moons KGM, Moreno-Iribas C, Muller D, Muenzel T, Nikitin Y, Nordestgaard BG, Omland T, Onland C, Overvad K, Packard C, Pajak A, Palmieri L, Panagiotakos D, Panico S, Perez-Cornago A, Peters A, Pietila A, Pikhart H, Psaty BM, Quarti-Trevano F, Quiros Garcia JR, Riboli E, Ridker PM, Rodriguez B, Rodriguez-Barranco M, Rosengren A, Roussel R, Sacerdote C, Sans S, Sattar N, Schiborn C, Schmidt B, Schoettker B, Schulze M, Schwartz JE, Selmer RM, Shea S, Shipley MJ, Sieri S, Soderberg S, Sofat R, Tamosiunas A, Thorand B, Tillmann T, Tjonneland A, Tong TYN, Trichopoulou A, Tumino R, Tunstall-Pedoe H, Tybjaerg-Hansen A, Tzoulaki J, van der Heijden A, van der Schouw YT, Verschuren WMM, Voelzke H, Waldeyer C, Wareham NJ, Weiderpass E, Weidinger F Wet al., 2021, SCORE2 risk prediction algorithms: new models to estimate 10-year risk of cardiovascular disease in Europe, EUROPEAN HEART JOURNAL, Vol: 42, Pages: 2439-2454, ISSN: 0195-668X

Journal article

Van Puyvelde H, Papadimitriou N, Clasen J, Muller D, Biessy C, Ferrari P, Halkjaer J, Overvad K, Tjonneland A, Fortner RT, Katzke V, Schulze MB, Chiodini P, Masala G, Pala V, Sacerdote C, Tumino R, Bakker MF, Agudo A, Ardanaz E, Chirlaque Lopez MD, Sanchez M-J, Ericson U, Gylling B, Karlsson T, Manjer J, Schmidt JA, Nicolas G, Casagrande C, Weiderpass E, Heath AK, Godderis L, Van Herck K, De Bacquer D, Gunter MJ, Huybrechts Iet al., 2021, Dietary methyl-group donor intake and breast cancer risk in the European prospective investigation into cancer and nutrition (EPIC), Nutrients, Vol: 13, Pages: 1-15, ISSN: 2072-6643

(1) Background: Methyl-group donors (MGDs), including folate, choline, betaine, and methionine, may influence breast cancer (BC) risk through their role in one-carbon metabolism; (2) Methods: We studied the relationship between dietary intakes of MGDs and BC risk, adopting data from the European Prospective Investigation into Cancer and Nutrition (EPIC) cohort; (3) Results: 318,686 pre- and postmenopausal women were followed between enrolment in 1992–2000 and December 2013–December 2015. Dietary MGD intakes were estimated at baseline through food-frequency questionnaires. Multivariable Cox proportional hazards regression models were used to quantify the association between dietary intake of MGDs, measured both as a calculated score based on their sum and individually, and BC risk. Subgroup analyses were performed by hormone receptor status, menopausal status, and level of alcohol intake. During a mean follow-up time of 14.1 years, 13,320 women with malignant BC were identified. No associations were found between dietary intakes of the MGD score or individual MGDs and BC risk. However, a potential U-shaped relationship was observed between dietary folate intake and overall BC risk, suggesting an inverse association for intakes up to 350 µg/day compared to a reference intake of 205 µg/day. No statistically significant differences in the associations were observed by hormone receptor status, menopausal status, or level of alcohol intake; (4) Conclusions: There was no strong evidence for an association between MGDs involved in one-carbon metabolism and BC risk. However, a potential U-shaped trend was suggested for dietary folate intake and BC risk. Further research is needed to clarify this association.

Journal article

Heath A, Clasen J, Jayanth N, Jenab M, Tjønneland A, Petersen K, Overvad K, Srour B, Katzke V, Bergmann M, Schulze M, Masala G, Krogh V, Tumino R, Catalano A, Pasanisi F, Brustad M, Standahl Olsen K, Skeie G, Luján-Barroso L, Rodríguez Barranco M, Amiano P, Santiuste C, Barricarte Gurrea A, Axelson H, Ramne S, Ljungberg B, Watts E, Huybrechts I, Weiderpass E, Riboli E, Muller Det al., 2021, Soft drink and juice consumption and renal cell carcinoma incidence and mortality in the European Prospective Investigation into Cancer and Nutrition, Cancer Epidemiology, Biomarkers and Prevention, Vol: 30, Pages: 1270-1274, ISSN: 1055-9965

Background: Renal cell carcinoma (RCC) accounts for more than 80% of kidney cancers in adults, and obesity is a known risk factor. Regular consumption of sweetened beverages has been linked to obesity and several chronic diseases, including some types of cancer. It is uncertain whether soft drink and juice consumption is associated with risk of RCC. We investigated the associations of soft drink and juice consumption with RCC incidence and mortality in the European Prospective Investigation into Cancer and Nutrition (EPIC).Methods: A total of 389,220 EPIC participants with median age of 52 years at recruitment (1991–2000) were included. Cox regression yielded adjusted HRs and 95% confidence intervals (CI) for RCC incidence and mortality in relation to intakes of juices and total, sugar-sweetened, and artificially sweetened soft drinks.Results: A total of 888 incident RCCs and 356 RCC deaths were identified. In models including adjustment for body mass index and energy intake, there was no higher risk of incident RCC associated with consumption of juices (HR per 100 g/day increment = 1.03; 95% CI, 0.97–1.09), total soft drinks (HR = 1.01; 95% CI, 0.98–1.05), sugar-sweetened soft drinks (HR = 0.99; 95% CI, 0.94–1.05), or artificially sweetened soft drinks (HR = 1.02; 95% CI, 0.96–1.08). In these fully adjusted models, none of the beverages was associated with RCC mortality (HR, 95% CI per 100 g/day increment 1.06, 0.97–1.16; 1.03, 0.98–1.09; 0.97, 0.89–1.07; and 1.06, 0.99–1.14, respectively).Conclusions: Consumption of juices or soft drinks was not associated with RCC incidence or mortality after adjusting for obesity.

Journal article

Christakoudi S, Pagoni P, Ferrari P, Cross AJ, Tzoulaki I, Muller DC, Weiderpass E, Freisling H, Murphy N, Dossus L, Fortner RT, Agudo A, Overvad K, Perez-Cornago A, Key TJ, Brennan P, Johansson M, Tjønneland A, Halkjær J, Boutron-Ruault M-C, Artaud F, Severi G, Kaaks R, Schulze MB, Bergmann MM, Masala G, Grioni S, Simeon V, Tumino R, Sacerdote C, Skeie G, Rylander C, Borch KB, Quirós JR, Rodriguez-Barranco M, Chirlaque M-D, Ardanaz E, Amiano P, Drake I, Stocks T, Häggström C, Harlid S, Ellingjord-Dale M, Riboli E, Tsilidis KKet al., 2021, Weight change in middle adulthood and risk of cancer in the European Prospective Investigation into Cancer and Nutrition (EPIC) cohort, International Journal of Cancer, Vol: 148, Pages: 1637-1651, ISSN: 0020-7136

Obesity is a risk factor for several major cancers. Associations of weight change in middle adulthood with cancer risk, however, are less clear. We examined the association of change in weight and body mass index (BMI) category during middle adulthood with 42 cancers, using multivariable Cox proportional hazards models in the European Prospective Investigation into Cancer and Nutrition cohort. Of 241,323 participants (31% men), 20% lost and 32% gained weight (>0.4 to 5.0 kg/year) during 6.9 years (average). During 8.0 years of follow-up after the second weight assessment, 20,960 incident cancers were ascertained. Independent of baseline BMI, weight gain (per one kg/year increment) was positively associated with cancer of the corpus uteri (hazard ratio HR=1.14; 95% confidence interval: 1.05-1.23). Compared to stable weight (+/-0.4 kg/year), weight gain (>0.4 to 5.0 kg/year) was positively associated with cancers of the gallbladder and bile ducts (HR=1.41; 1.01-1.96), post-menopausal breast (HR=1.08, 1.00-1.16) and thyroid (HR=1.40; 1.04-1.90). Compared to maintaining normal weight, maintaining overweight or obese BMI (World Health Organization categories) was positively associated with most obesity-related cancers. Compared to maintaining the baseline BMI category, weight gain to a higher BMI category was positively associated with cancers of the post-menopausal breast (HR=1.19; 1.06-1.33), ovary (HR=1.40; 1.04-1.91), corpus uteri (HR=1.42; 1.06-1.91), kidney (HR=1.80; 1.20-2.68) and pancreas in men (HR=1.81; 1.11-2.95). Losing weight to a lower BMI category, however, was inversely associated with cancers of the corpus uteri (HR=0.40; 0.23-0.69) and colon (HR=0.69; 0.52-0.92). Our findings support avoiding weight gain and encouraging weight loss in middle adulthood.

Journal article

Singleton RK, Heath AK, Clasen JL, Scelo G, Johansson M, Le Calvez-Kelm F, Weiderpass E, Liedberg F, Ljungberg B, Harbs J, Olsen A, Tjønneland A, Dahm CC, Kaaks R, Fortner RT, Panico S, Tagliabue G, Masala G, Tumino R, Ricceri F, Gram IT, Santiuste C, Bonet C, Rodriguez-Barranco M, Schulze MB, Bergmann MM, Travis RC, Tzoulaki I, Riboli E, Muller Det al., 2021, Risk prediction for renal cell carcinoma: results from the European Prospective Investigation into Cancer and Nutrition (EPIC) prospective cohort study, Cancer Epidemiology, Biomarkers and Prevention, ISSN: 1055-9965

Journal article

Thomas M, Sakoda LC, Hoffmeister M, Rosenthal EA, Lee JK, van Duijnhoven FJB, Platz EA, Wu AH, Dampier CH, de la Chapelle A, Wolk A, Joshi AD, Burnett-Hartman A, Gsur A, Lindblom A, Castells A, Kowin A, Namjou B, Van Guelpen B, Tangen CM, He Q, Li CI, Schafmayer C, Joshu CE, Ulrich CM, Bishop DT, Buchanan DD, Schaid D, Drew DA, Muller DC, Duggan D, Crosslin DR, Albanes D, Giovannucci EL, Larson E, Qu F, Mentch F, Giles GG, Hakonarson H, Hampel H, Stanaway IB, Figueiredo JC, Huyghe JR, Minnier J, Chang-Claude J, Hampe J, Harley JB, Visvanathan K, Curtis KR, Offit K, Li L, Le Marchand L, Vodickova L, Gunter MJ, Jenkins MA, Slattery ML, Lemire M, Woods MO, Song M, Murphy N, Lindor NM, Dikilitas O, Pharoah PDP, Campbell PT, Newcomb PA, Milne RL, MacInnis RJ, Castellvi-Bel S, Ogino S, Berndt SI, Bezieau S, Thibodeau SN, Gallinger SJ, Zaidi SH, Harrison TA, Keku TO, Hudson TJ, Vymetalkova V, Moreno V, Martin V, Arndt V, Wei W-Q, Chung W, Su Y-R, Hayes RB, White E, Vodicka P, Casey G, Gruber SB, Schoen RE, Chan AT, Potter JD, Brenner H, Jarvik GP, Corley DA, Peters U, Hsu Let al., 2021, Response to Li and Hopper, AMERICAN JOURNAL OF HUMAN GENETICS, Vol: 108, Pages: 527-529, ISSN: 0002-9297

Journal article

Laskar RS, Li P, Ecsedi S, Abedi-Ardekani B, Durand G, Robinot N, Hubert J-N, Janout V, Zaridze D, Mukeria A, Mates D, Holcatova I, Foretova L, Swiatkowska B, Dzamic Z, Milosavljevic S, Olaso R, Boland A, Deleuze J-F, Muller DC, McKay JD, Brennan P, Le Calvez-Kelm F, Scelo G, Chanudet Eet al., 2021, Sexual dimorphism in cancer: insights from transcriptional signatures in kidney tissue and renal cell carcinoma, HUMAN MOLECULAR GENETICS, Vol: 30, Pages: 343-355, ISSN: 0964-6906

Journal article

Chadeau M, Bodinier B, Vermeulen R, Karimi M, Zuber V, Castagne R, Elliott J, Muller D, Petrovic D, Whitaker M, Stringhini S, Tzoulaki I, Kivimaki M, Vineis P, Elliott P, Kelly-Irving M, Delpierre Cet al., 2020, Education, biological ageing, all-cause and cause-specific mortality and morbidity: UK Biobank Cohort Study, EClinicalMedicine, Vol: 29-30, ISSN: 2589-5370

BackgroundSocioeconomic position as measured by education may be embodied and affect the functioning of key physiological systems. Links between social disadvantage, its biological imprint, and cause-specific mortality and morbidity have not been investigated in large populations, and yet may point towards areas for public health interventions beyond targeting individual behaviours.MethodsUsing data from 366,748 UK Biobank participants with 13 biomarker measurements, we calculated a Biological Health Score (BHS, ranging from 0 to 1) capturing the level of functioning of five physiological systems. Associations between BHS and incidence of cardiovascular disease (CVD) and cancer, and mortality from all, CVD, cancer, and external causes were examined. We explored the role of education in these associations. Mendelian randomisation using genetic evidence was used to triangulate these findings.FindingsAn increase in BHS of 0.1 was associated with all-cause (HR = 1.14 [1.12–1.16] and 1.09 [1.07–1.12] in men and women respectively), cancer (HR = 1.11 [1.09–1.14] and 1.07 [1.04–1.10]) and CVD (HR = 1.25 [1.20–1.31] and 1.21 [1.11–1.31]) mortality, CVD incidence (HR = 1.15 [1.13–1.16] and 1.17 [1.15–1.19]). These associations survived adjustment for education, lifestyle-behaviours, body mass index (BMI), co-morbidities and medical treatments. Mendelian randomisation further supported the link between the BHS and CVD incidence (HR = 1.31 [1.21–1.42]). The BHS contributed to CVD incidence prediction (age-adjusted C-statistic = 0.58), other than through education and health behaviours.InterpretationThe BHS captures features of the embodiment of education, health behaviours, and more proximal unknown factors which all complementarily contribute to all-cause, cancer and CVD morbidity and premature death.

Journal article

Clasen J, Heath AK, Scelo G, Muller DCet al., 2020, Components of one-carbon metabolism and renal cell carcinoma: A systematic review and meta-analysis, European Journal of Nutrition, Vol: 59, Pages: 3801-3813, ISSN: 0044-264X

PurposeLittle is known about the aetiology of renal cell carcinoma (RCC). Components of one-carbon (1C) metabolism, which are required for nucleotide synthesis and methylation reactions, may be related to risk of RCC but existing evidence is inconclusive. We conducted a systematic review and independent exposure-specific meta-analyses of dietary intake and circulating biomarkers of 1C metabolites and RCC risk.MethodsMedline and Embase databases were searched for observational studies investigating RCC or kidney cancer incidence or mortality in relation to components of 1C metabolism and 12 eligible articles were included in the meta-analyses. We used Bayesian meta-analyses to estimate summary relative risks (RRs) and 95% credible intervals (CrIs) comparing the highest versus lowest categories as well as the between-study heterogeneity.ResultsWe did not find convincing evidence of an association between any exposure (riboflavin, vitamin B6, folate, vitamin B12, methionine, homocysteine, choline, or betaine) and RCC risk. However, vitamin B6 biomarker status did have a protective (RR = 0.62) but imprecise (95% CrI 0.39–1.14) effect estimate and folate intake had a notable association as well (RR = 0.85, 95% CrI 0.71–1.01).ConclusionThere was a lack of precision due largely to the low number of studies. Further investigation is warranted, especially for folate and vitamin B6, which had consistent suggestive evidence of a protective effect for both dietary intake and biomarker status. A unique strength of this review is the use of Bayesian meta-analyses which allowed for robust estimation of between-study heterogeneity.

Journal article

Sanikini H, Muller DC, Chadeau-Hyam M, Murphy N, Gunter MJ, Cross AJet al., 2020, Anthropometry, body fat composition and reproductive factors and risk of oesophageal and gastric cancer by subtype and subsite in the UK Biobank cohort, PLoS One, Vol: 15, Pages: 1-22, ISSN: 1932-6203

BackgroundObesity has been positively associated with upper gastrointestinal cancers, but prospective data by subtype/subsite are limited. Obesity influences hormonal factors, which may play a role in these cancers. We examined anthropometry, body fat and reproductive factors in relation to oesophageal and gastric cancer by subtype/subsite in the UK Biobank cohort.MethodsAmong 458,713 UK Biobank participants, 339 oesophageal adenocarcinomas, 124 oesophageal squamous cell carcinomas, 137 gastric cardia and 92 gastric non-cardia cancers were diagnosed during a mean of 6.5 years follow-up. Cox models estimated multivariable hazard ratios (HRs) and 95% confidence intervals (CIs).ResultsBody mass index (BMI), hip circumference, waist circumference, waist-to-hip ratio, waist-to-height ratio, total body fat and trunk fat were positively associated with oesophageal adenocarcinoma (highest vs lowest category: HR = 2.33, 95%-CI:1.65–3.28; HR = 1.56, 95%-CI:1.15–2.13; HR = 2.30, 95%-CI:1.47–3.57; HR = 1.71, 95%-CI:1.01–2.90; HR = 2.87, 95%-CI:1.88–4.38; HR = 1.96, 95%-CI:1.30–2.96; HR = 2.34, 95%-CI:1.70–3.22, respectively). Although there were no statistically significant associations in combined sex analyses, BMI (HR = 1.83, 95%-CI:1.00–3.37), waist circumference (HR = 2.21, 95%-CI:1.27–3.84) and waist-to-hip ratio (HR = 1.92, 95%-CI:1.11–3.29) were associated with gastric cardia cancer in men; however, mutual adjustment attenuated the associations for BMI and waist-to-hip ratio. For oesophageal squamous cell carcinoma, statistically significant inverse associations were observed among women for BMI, hip circumference, waist circumference, waist-to-height ratio, total body fat and trunk fat, although they were based on small numbers. In addition, older age at first (HR = 0.44, 95%-CI:0.22–0.88) and last live birth (HR = 0.44, 95%-CI:0.22–0.87) were inversely associated with oesophageal squamous cell carc

Journal article

Thomas M, Sakoda LC, Hoffmeister M, Rosenthal EA, Lee JK, van Duijnhoven FJB, Platz EA, Wu AH, Dampier CH, de la Chapelle A, Wolk A, Joshi AD, Burnett-Hartman A, Gsur A, Lindblom A, Castells A, Win AK, Namjou B, Van Guelpen B, Tangen CM, He Q, Li C, Schafmayer C, Joshu CE, Ulrich CM, Bishop DT, Buchanan DD, Schaid D, Drew DA, Muller DC, Duggan D, Crosslin DR, Albanes D, Giovannucci EL, Larson E, Qu F, Mentch F, Giles GG, Hakonarson H, Hampel H, Stanaway IB, Figueiredo JC, Huyghe JR, Minnier J, Chang-Claude J, Hampe J, Harley JB, Visvanathan K, Curtis KR, Offit K, Li L, Le Marchand L, Vodickova L, Gunter MJ, Jenkins MA, Slattery ML, Lemire M, Woods MO, Song M, Murphy N, Lindor NM, Dikilitas O, Pharoah PDP, Campbell PT, Newcomb PA, Milne RL, MacInnis RJ, Castellvi-Bel S, Ogino S, Berndt S, Bezieau S, Thibodeau SN, Gallinger SJ, Zaidi SH, Harrison TA, Keku TO, Hudson TJ, Vymetalkova V, Moreno V, Martin V, Arndt V, Wei W-Q, Chung W, Su Y-R, Hayes RB, White E, Vodicka P, Casey G, Gruber SB, Schoen RE, Chan AT, Potter JD, Brenner H, Jarvik GP, Corley DA, Peters U, Hsu Let al., 2020, Genome-wide Modeling of Polygenic Risk Score in Colorectal Cancer Risk, AMERICAN JOURNAL OF HUMAN GENETICS, Vol: 107, Pages: 432-444, ISSN: 0002-9297

Journal article

Christakoudi S, Tsilidis KK, Muller DC, Freisling H, Weiderpass E, Overvad K, Söderberg S, Häggström C, Pischon T, Dahm CC, Zhang J, Tjønneland A, Halkjær J, MacDonald C, Boutron-Ruault M-C, Mancini FR, Kühn T, Kaaks R, Schulze MB, Trichopoulou A, Karakatsani A, Peppa E, Masala G, Pala V, Panico S, Tumino R, Sacerdote C, Quirós JR, Agudo A, Sánchez M-J, Cirera L, Barricarte-Gurrea A, Amiano P, Memarian E, Sonestedt E, Bueno-de-Mesquita B, May AM, Khaw K-T, Wareham NJ, Tong TYN, Huybrechts I, Noh H, Aglago EK, Ellingjord-Dale M, Ward HA, Aune D, Riboli Eet al., 2020, ABSI (A Body Shape Index) achieves better mortality risk stratification than alternative indices of abdominal obesity: results from a large European cohort, Scientific Reports, Vol: 10, ISSN: 2045-2322

Abdominal and general adiposity are independently associated with mortality, but there is no consensus on how best to assess abdominal adiposity. We compared the ability of alternative waist indices to complement body mass index (BMI) when assessing all-cause mortality. We used data from 352,985 participants in the European Prospective Investigation into Cancer and Nutrition (EPIC) and Cox proportional hazards models adjusted for other risk factors. During a mean follow-up of 16.1 years, 38,178 participants died. Combining in one model BMI and a strongly correlated waist index altered the association patterns with mortality, to a predominantly negative association for BMI and a stronger positive association for the waist index, while combining BMI with the uncorrelated A Body Shape Index (ABSI) preserved the association patterns. Sex-specific cohort-wide quartiles of waist indices correlated with BMI could not separate high-risk from low-risk individuals within underweight (BMI<18.5 kg/m2) or obese (BMI≥30 kg/m2) categories, while the highest quartile of ABSI separated 18%-39% of the individuals within each BMI category, which had 22%-55% higher risk of death. In conclusion, only a waist index independent of BMI by design, such as ABSI, complements BMI and enables efficient risk stratification, which could facilitate personalisation of screening, treatment and monitoring.

Journal article

Loveday C, Sud A, Jones ME, Broggio J, Scott S, Gronthound F, Torr B, Garrett A, Nicol DL, Jhanji S, Boyce SA, Williams M, Barry C, Riboli E, Kipps E, McFerran E, Muller DC, Lyratzopoulos G, Lawler M, Abulafi M, Houlston RS, Turnbull Cet al., 2020, Prioritisation by FIT to mitigate the impact of delays in the 2-week wait colorectal cancer referral pathway during the COVID-19 pandemic: a UK modelling study, Gut, Vol: 70, Pages: 1053-1060, ISSN: 0017-5749

OBJECTIVE: To evaluate the impact of faecal immunochemical testing (FIT) prioritisation to mitigate the impact of delays in the colorectal cancer (CRC) urgent diagnostic (2-week-wait (2WW)) pathway consequent from the COVID-19 pandemic. DESIGN: We modelled the reduction in CRC survival and life years lost resultant from per-patient delays of 2-6 months in the 2WW pathway. We stratified by age group, individual-level benefit in CRC survival versus age-specific nosocomial COVID-19-related fatality per referred patient undergoing colonoscopy. We modelled mitigation strategies using thresholds of FIT triage of 2, 10 and 150 µg Hb/g to prioritise 2WW referrals for colonoscopy. To construct the underlying models, we employed 10-year net CRC survival for England 2008-2017, 2WW pathway CRC case and referral volumes and per-day-delay HRs generated from observational studies of diagnosis-to-treatment interval. RESULTS: Delay of 2/4/6 months across all 11 266 patients with CRC diagnosed per typical year via the 2WW pathway were estimated to result in 653/1419/2250 attributable deaths and loss of 9214/20 315/32 799 life years. Risk-benefit from urgent investigatory referral is particularly sensitive to nosocomial COVID-19 rates for patients aged >60. Prioritisation out of delay for the 18% of symptomatic referrals with FIT >10 µg Hb/g would avoid 89% of these deaths attributable to presentational/diagnostic delay while reducing immediate requirement for colonoscopy by >80%. CONCLUSIONS: Delays in the pathway to CRC diagnosis and treatment have potential to cause significant mortality and loss of life years. FIT triage of symptomatic patients in primary care could streamline access to colonoscopy, reduce delays for true-positive CRC cases and reduce nosocomial COVID-19 mortality in older true-negative 2WW referrals. However, this strategy offers benefit only in short-term rationalisation of limited endoscopy services: the a

Journal article

Sud A, Torr B, Jones M, Broggio J, Scott S, Loveday C, Garrett A, Gronthoud F, Nicol D, Jhanji S, Boyce S, Williams M, Riboli E, Muller D, Kipps E, Larkin J, Navani N, Swanton C, Lyratzopoulos G, McFerran E, Lawler M, Houlston R, Turnbull Cet al., 2020, Effect of delays in the UK two-week wait cancer referral pathway during the COVID-19 pandemic on cancer survival: a modelling study, The Lancet Oncology, Vol: 21, Pages: 1035-1044, ISSN: 1213-9432

Background: During the COVID-19 lockdown, referrals via the 2 Week Wait (2WW) urgent pathway for suspected cancer in England are reported to have dropped by up to 84%. We aimed to examine the impact on cancer survival of different scenarios of lockdown accumulated-backlog. We also aimed to examine by tumour-referral-group and age, survival benefit per referred patient considering survival decrement from delayed referral versus risk of death from nosocomial SARS-CoV-2 infection.Methods: To construct the underlying models, we used age- and stage-stratified 10 year cancer survival estimates for England 2007-2017 for 20 common tumour-types. We applied per-day hazard ratios for cancer progression generated from observational studies of delay to-treatment. We quantified the annual numbers of cancers diagnosed via the 2WW-pathway using the 2WW age- and stage-specific breakdowns. From these, for per-patient delays of 1- 6 months, we estimated aggregate number of lives lost and life-years lost in England. Using referral-to-diagnosis conversion rates and COVID-19 case fatality rates, we also estimated the survival increment per patient referred. Findings: Per month across England in 2013-2016, on average 6,281 patients with Stage 1- 3 cancer were diagnosed via the 2WW pathway of whom 1,691 would be predicted to die within 10 years from their disease. We estimated 2WW-pathway presentational-delay from three months of lockdown will result in total in 181/361/542 attributable additional deaths (if % reduction in referrals was 25/50/75% respectively). Limited diagnostic capacity to address the backlog may result in additional delays: 401/811/1,231 attributable additional deaths are estimated if additional diagnostic capacity is delayed until months 3-8 post-lockdown. 2-month delay in 2WW investigatory referral results in average loss of life-years per-referred-patient of between 0 and 0.7, depending on age and tumour-type. Interpretation: Prompt provision of additional capacity f

Journal article

Elliott P, Muller DC, Schneider-Luftman D, Pazoki R, Evangelou E, Dehghan A, Neal B, Tzoulaki Iet al., 2020, Estimated 24-hour urinary sodium excretion and incident cardiovascular disease and mortality among 398 628 individuals in UK biobank., Hypertension, Vol: 76, Pages: 1-9, ISSN: 0194-911X

We report on an analysis to explore the association between estimated 24-hour urinary sodium excretion (surrogate for sodium intake) and incident cardiovascular disease (CVD) and mortality. Data were obtained from 398 628 UK Biobank prospective cohort study participants (40-69 years) recruited between 2006 and 2010, with no history of CVD, renal disease, diabetes mellitus or cancer, and cardiovascular events and mortality recorded during follow-up. Hazard ratios between 24-hour sodium excretion were estimated from spot urinary sodium concentrations across incident CVD and its components and all-cause and cause-specific mortality. In restricted cubic splines analyses, there was little evidence for an association between estimated 24-hour sodium excretion and CVD, coronary heart disease, or stroke; hazard ratios for CVD (95% CIs) for the 15th and 85th percentiles (2.5 and 4.2 g/day, respectively) compared with the 50th percentile of estimated sodium excretion (3.2 g/day) were 1.05 (1.01-1.10) and 0.96 (0.92-1.00), respectively. An inverse association was observed with heart failure, but that was no longer apparent in sensitivity analysis. A J-shaped association was observed between estimated sodium excretion and mortality. Our findings do not support a J-shaped association of estimated sodium excretion with CVD, although such an association was apparent for all-cause and cause-specific mortality across a wide range of diseases. Reasons for these differences are unclear; methodological limitations, including the use of estimating equations based on spot urinary data, need to be considered in interpreting our findings.

Journal article

Maric T, Kanu C, Muller DC, Tzoulaki I, Johnson MR, Savvidou MDet al., 2020, Fetal growth and fetoplacental circulation in pregnancies following bariatric surgery: a prospective study, Publisher: WILEY, Pages: 839-846, ISSN: 1470-0328

Conference paper

Ji X, Mukherjee S, Landi MT, Bosse Y, Joubert P, Zhu D, Gorlov I, Xiao X, Han Y, Gorlova O, Hung RJ, Brhane Y, Carreras-Torres R, Christiani DC, Caporaso N, Johansson M, Liu G, Bojesen SE, Le Marchand L, Albanes D, Bickeböller H, Aldrich MC, Bush WS, Tardon A, Rennert G, Chen C, Byun J, Dragnev KH, Field JK, Kiemeney LF, Lazarus P, Zienolddiny S, Lam S, Schabath MB, Andrew AS, Bertazzi PA, Pesatori AC, Diao N, Su L, Song L, Zhang R, Leighl N, Johansen JS, Mellemgaard A, Saliba W, Haiman C, Wilkens L, Fernandez-Somoano A, Fernandez-Tardon G, Heijden EHFMVD, Kim JH, Davies MPA, Marcus MW, Brunnström H, Manjer J, Melander O, Muller DC, Overvad K, Trichopoulou A, Tumino R, Goodman GE, Cox A, Taylor F, Woll P, Wichmann E, Muley T, Risch A, Rosenberger A, Grankvist K, Johansson M, Shepherd F, Tsao M-S, Arnold SM, Haura EB, Bolca C, Holcatova I, Janout V, Kontic M, Lissowska J, Mukeria A, Ognjanovic S, Orlowski TM, Scelo G, Swiatkowska B, Zaridze D, Bakke P, Skaug V, Butler LM, Offit K, Srinivasan P, Bandlamudi C, Hellmann MD, Solit DB, Robson ME, Rudin CM, Stadler ZK, Taylor BS, Berger MF, Houlston R, McLaughlin J, Stevens V, Nickle DC, Obeidat M, Timens W, Artigas MS, Shete S, Brenner H, Chanock S, Brennan P, McKay JD, Amos CIet al., 2020, Protein-altering germline mutations implicate novel genes related to lung cancer development., Nature Communications, Vol: 11, Pages: 1-14, ISSN: 2041-1723

Few germline mutations are known to affect lung cancer risk. We performed analyses of rare variants from 39,146 individuals of European ancestry and investigated gene expression levels in 7,773 samples. We find a large-effect association with an ATM L2307F (rs56009889) mutation in adenocarcinoma for discovery (adjusted Odds Ratio = 8.82, P = 1.18 × 10-15) and replication (adjusted OR = 2.93, P = 2.22 × 10-3) that is more pronounced in females (adjusted OR = 6.81 and 3.19 and for discovery and replication). We observe an excess loss of heterozygosity in lung tumors among ATM L2307F allele carriers. L2307F is more frequent (4%) among Ashkenazi Jewish populations. We also observe an association in discovery (adjusted OR = 2.61, P = 7.98 × 10-22) and replication datasets (adjusted OR = 1.55, P = 0.06) with a loss-of-function mutation, Q4X (rs150665432) of an uncharacterized gene, KIAA0930. Our findings implicate germline genetic variants in ATM with lung cancer susceptibility and suggest KIAA0930 as a novel candidate gene for lung cancer risk.

Journal article

Elliott J, Bodinier B, Bond TA, Chadeau-Hyam M, Evangelou E, Moons KGM, Dehghan A, Muller DC, Elliott P, Tzoulaki Iet al., 2020, Predictive accuracy of a polygenic risk score-enhanced prediction model vs a clinical risk score for coronary artery disease, JAMA: Journal of the American Medical Association, Vol: 323, Pages: 636-645, ISSN: 0098-7484

Importance The incremental value of polygenic risk scores in addition to well-established risk prediction models for coronary artery disease (CAD) is uncertain.Objective To examine whether a polygenic risk score for CAD improves risk prediction beyond pooled cohort equations.Design, Setting, and Participants Observational study of UK Biobank participants enrolled from 2006 to 2010. A case-control sample of 15 947 prevalent CAD cases and equal number of age and sex frequency–matched controls was used to optimize the predictive performance of a polygenic risk score for CAD based on summary statistics from published genome-wide association studies. A separate cohort of 352 660 individuals (with follow-up to 2017) was used to evaluate the predictive accuracy of the polygenic risk score, pooled cohort equations, and both combined for incident CAD.Exposures Polygenic risk score for CAD, pooled cohort equations, and both combined.Main Outcomes and Measures CAD (myocardial infarction and its related sequelae). Discrimination, calibration, and reclassification using a risk threshold of 7.5% were assessed.Results In the cohort of 352 660 participants (mean age, 55.9 years; 205 297 women [58.2%]) used to evaluate the predictive accuracy of the examined models, there were 6272 incident CAD events over a median of 8 years of follow-up. CAD discrimination for polygenic risk score, pooled cohort equations, and both combined resulted in C statistics of 0.61 (95% CI, 0.60 to 0.62), 0.76 (95% CI, 0.75 to 0.77), and 0.78 (95% CI, 0.77 to 0.79), respectively. The change in C statistic between the latter 2 models was 0.02 (95% CI, 0.01 to 0.03). Calibration of the models showed overestimation of risk by pooled cohort equations, which was corrected after recalibration. Using a risk threshold of 7.5%, addition of the polygenic risk score to pooled cohort equations resulted in a net reclassification improvement of 4.4% (95% CI, 3.5% to 5.3%) for cases and −0.4% (95% CI, &

Journal article

Sanikini H, Muller DC, Sophiea M, Rinaldi S, Agudo A, Duell EJ, Weiderpass E, Overvad K, Tjønneland A, Halkjaer J, Boutron-Ruault M-C, Carbonnel F, Cervenka I, Boeing H, Kaaks R, Kühn T, Trichopoulou A, Martimianaki G, Karakatsani A, Pala V, Palli D, Mattiello A, Tumino R, Sacerdote C, Skeie G, Rylander C, López MDC, Sánchez M-J, Ardanaz E, Regnér S, Stocks T, Bueno-de-Mesquita B, Vermeulen RCH, Aune D, Tong TYN, Kliemann N, Murphy N, Chadeau-Hyam M, Gunter MJ, Cross AJet al., 2020, Anthropometric and reproductive factors and risk of esophageal and gastric cancer by subtype and subsite: results from the European Prospective Investigation into Cancer and Nutrition (EPIC) cohort, International Journal of Cancer, Vol: 146, Pages: 929-942, ISSN: 0020-7136

Obesity has been associated with upper gastrointestinal cancers; however, there are limited prospective data on associations by subtype/subsite. Obesity can impact hormonal factors, which have been hypothesized to play a role in these cancers. We investigated anthropometric and reproductive factors in relation to esophageal and gastric cancer by subtype and subsite for 476,160 participants from the European Prospective Investigation into Cancer and Nutrition cohort. Multivariable hazard ratios (HRs) and 95% confidence intervals (CIs) were estimated using Cox models. During a mean follow‐up of 14 years, 220 esophageal adenocarcinomas (EA), 195 esophageal squamous cell carcinomas, 243 gastric cardia (GC) and 373 gastric noncardia (GNC) cancers were diagnosed. Body mass index (BMI) was associated with EA in men (BMI ≥30 vs. 18.5–25 kg/m2: HR = 1.94, 95% CI: 1.25–3.03) and women (HR = 2.66, 95% CI: 1.15–6.19); however, adjustment for waist‐to‐hip ratio (WHR) attenuated these associations. After mutual adjustment for BMI and HC, respectively, WHR and waist circumference (WC) were associated with EA in men (HR = 3.47, 95% CI: 1.99–6.06 for WHR >0.96 vs. <0.91; HR = 2.67, 95% CI: 1.52–4.72 for WC >98 vs. <90 cm) and women (HR = 4.40, 95% CI: 1.35–14.33 for WHR >0.82 vs. <0.76; HR = 5.67, 95% CI: 1.76–18.26 for WC >84 vs. <74 cm). WHR was also positively associated with GC in women, and WC was positively associated with GC in men. Inverse associations were observed between parity and EA (HR = 0.38, 95% CI: 0.14–0.99; >2 vs. 0) and age at first pregnancy and GNC (HR = 0.54, 95% CI: 0.32–0.91; >26 vs. <22 years); whereas bilateral ovariectomy was positively associated with GNC (HR = 1.87, 95% CI: 1.04–3.36). These findings support a role for hormonal pathways in upper gastrointestinal cancers.

Journal article

Heath A, Muller D, van den Brandt P, Papadimitriou N, Critselis E, Gunter M, Vineis P, Weiderpass E, Fagherazzi G, Boeing H, Ferrari P, Olsen A, Tjønneland A, Arveux P, Boutron-Ruault M-C, Romana Mancini F, Kühn T, Turzanski-Fortner R, Schulze M, Karakatsani A, Thriskos P, Trichopoulou A, Masala G, Contiero P, Ricceri F, Panico S, Bueno-de-Mesquita B, Bakker M, van Gils C, Standahl Olsen K, Skeie G, Lasheras C, Agudo A, Rodríguez-Barranco M, Sánchez M-J, Amiano P, Chirlaque M-D, Barricarte A, Drake I, Ericson U, Johansson I, Winkvist A, Key T, Freisling H, His M, Huybrechts I, Christakoudi S, Ellingjord-Dale M, Riboli E, Tsilidis K, Tzoulaki Iet al., 2020, Nutrient-wide association study of 92 foods and nutrients and breast cancer risk, Breast Cancer Research, Vol: 22, ISSN: 1465-542X

Background: Several dietary factors have been reported to be associated with risk of breast cancer, but to date unequivocal evidence only exists for alcohol consumption. We sought to systematically assess the association between intake of 92 foods and nutrients and breast cancer risk using a nutrient-wide association study. Methods: Using data from 272,098 women participating in the European Prospective Investigation into Cancer and Nutrition (EPIC) study, we assessed dietary intake of 92 foods and nutrients estimated by dietary questionnaires. Cox regression was used to quantify the association between each food/nutrient and risk of breast cancer. A false discovery rate (FDR) of 0.05 was used to select the set of foods and nutrients to be replicated in the independent Netherlands Cohort Study (NLCS). Results: Six foods and nutrients were identified as associated with risk of breast cancer in the EPIC study (10,979 cases). Higher intake of alcohol overall was associated with a higher risk of breast cancer (hazard ratio (HR) for a 1 SD increment in intake = 1.05, 95% CI 1.03–1.07), as was beer/cider intake and wine intake (HRs per 1 SD increment = 1.05, 95% CI 1.03–1.06 and 1.04, 95% CI 1.02–1.06, respectively), whereas higher intakes of fibre, apple/pear, and carbohydrates were associated with a lower risk of breast cancer (HRs per 1 SD increment = 0.96, 95% CI 0.94–0.98; 0.96, 95% CI 0.94–0.99; and 0.96, 95% CI 0.95–0.98, respectively). When evaluated in the NLCS (2368 cases), estimates for each of these foods and nutrients were similar in magnitude and direction, with the exception of beer/cider intake, which was not associated with risk in the NLCS Conclusions: Our findings confirm a positive association of alcohol consumption andsuggest an inverse association of dietary fibre and possibly fruit intake with breast cancer risk.

Journal article

Freisling H, Viallon V, Lennon H, Bagnardi V, Ricci C, Butterworth AS, Sweeting M, Muller D, Romieu I, Bazelle P, Kvaskoff M, Arveux P, Severi G, Bamia C, Kühn T, Kaaks R, Bergmann M, Boeing H, Tjønneland A, Olsen A, Overvad K, Dahm CC, Menéndez V, Agudo A, Sánchez M-J, Amiano P, Santiuste C, Gurrea AB, Tong TYN, Schmidt JA, Tzoulaki I, Tsilidis KK, Ward H, Palli D, Agnoli C, Tumino R, Ricceri F, Panico S, Picavet HSJ, Bakker M, Monninkhof E, Nilsson P, Manjer J, Rolandsson O, Thysell E, Weiderpass E, Jenab M, Riboli E, Vineis P, Danesh J, Wareham NJ, Gunter MJ, Ferrari Pet al., 2020, Lifestyle factors and risk of multimorbidity of cancer and cardiometabolic diseases: a multinational cohort study, BMC Medicine, Vol: 18, Pages: 5-5, ISSN: 1741-7015

BACKGROUND: Although lifestyle factors have been studied in relation to individual non-communicable diseases (NCDs), their association with development of a subsequent NCD, defined as multimorbidity, has been scarcely investigated. The aim of this study was to investigate associations between five lifestyle factors and incident multimorbidity of cancer and cardiometabolic diseases. METHODS: In this prospective cohort study, 291,778 participants (64% women) from seven European countries, mostly aged 43 to 58 years and free of cancer, cardiovascular disease (CVD), and type 2 diabetes (T2D) at recruitment, were included. Incident multimorbidity of cancer and cardiometabolic diseases was defined as developing subsequently two diseases including first cancer at any site, CVD, and T2D in an individual. Multi-state modelling based on Cox regression was used to compute hazard ratios (HR) and 95% confidence intervals (95% CI) of developing cancer, CVD, or T2D, and subsequent transitions to multimorbidity, in relation to body mass index (BMI), smoking status, alcohol intake, physical activity, adherence to the Mediterranean diet, and their combination as a healthy lifestyle index (HLI) score. Cumulative incidence functions (CIFs) were estimated to compute 10-year absolute risks for transitions from healthy to cancer at any site, CVD (both fatal and non-fatal), or T2D, and to subsequent multimorbidity after each of the three NCDs. RESULTS: During a median follow-up of 11 years, 1910 men and 1334 women developed multimorbidity of cancer and cardiometabolic diseases. A higher HLI, reflecting healthy lifestyles, was strongly inversely associated with multimorbidity, with hazard ratios per 3-unit increment of 0.75 (95% CI, 0.71 to 0.81), 0.84 (0.79 to 0.90), and 0.82 (0.77 to 0.88) after cancer, CVD, and T2D, respectively. After T2D, the 10-year absolute risks of multimorbidity were 40% and 25% for men and women, respectively, with unhealthy lifestyle, and 30% and 18

Journal article

Sasamoto N, Babic A, Rosner BA, Fortner RT, Vitonis AF, Yamamoto H, Fichorova RN, Titus LJ, Tjonneland A, Hansen L, Kvaskoff M, Fournier A, Mancini FR, Boeing H, Trichopoulou A, Peppa E, Karakatsani A, Palli D, Grioni S, Mattiello A, Tumino R, Fiano V, Onland-Moret NC, Weiderpass E, Gram IT, Quiros JR, Lujan-Barroso L, Sanchez M-J, Colorado-Yohar S, Barricarte A, Amiano P, Idahl A, Lundin E, Sartor H, Khaw K-T, Key TJ, Muller D, Riboli E, Gunter M, Dossus L, Trabert B, Wentzensen N, Kaaks R, Cramer DW, Tworoger SS, Terry KLet al., 2019, Development and validation of circulating CA125 prediction models in postmenopausal women, Journal of Ovarian Research, Vol: 12, Pages: 1-12, ISSN: 1757-2215

BackgroundCancer Antigen 125 (CA125) is currently the best available ovarian cancer screening biomarker. However, CA125 has been limited by low sensitivity and specificity in part due to normal variation between individuals. Personal characteristics that influence CA125 could be used to improve its performance as screening biomarker.MethodsWe developed and validated linear and dichotomous (≥35 U/mL) circulating CA125 prediction models in postmenopausal women without ovarian cancer who participated in one of five large population-based studies: Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial (PLCO, n = 26,981), European Prospective Investigation into Cancer and Nutrition (EPIC, n = 861), the Nurses’ Health Studies (NHS/NHSII, n = 81), and the New England Case Control Study (NEC, n = 923). The prediction models were developed using stepwise regression in PLCO and validated in EPIC, NHS/NHSII and NEC.ResultThe linear CA125 prediction model, which included age, race, body mass index (BMI), smoking status and duration, parity, hysterectomy, age at menopause, and duration of hormone therapy (HT), explained 5% of the total variance of CA125. The correlation between measured and predicted CA125 was comparable in PLCO testing dataset (r = 0.18) and external validation datasets (r = 0.14). The dichotomous CA125 prediction model included age, race, BMI, smoking status and duration, hysterectomy, time since menopause, and duration of HT with AUC of 0.64 in PLCO and 0.80 in validation dataset.ConclusionsThe linear prediction model explained a small portion of the total variability of CA125, suggesting the need to identify novel predictors of CA125. The dichotomous prediction model showed moderate discriminatory performance which validated well in independent dataset. Our dichotomous model could be valuable in identifying healthy women who may have elevated CA125 lev

Journal article

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