Imperial College London

Professor Amanda Cross

Faculty of MedicineSchool of Public Health

Professor of Cancer Epidemiology
 
 
 
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Contact

 

+44 (0)20 7594 3338amanda.cross

 
 
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Assistant

 

Mr Will Kay +44 (0)20 7594 3350

 
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Location

 

Norfolk PlaceSt Mary's Campus

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Summary

 

Publications

Publication Type
Year
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268 results found

Hanna GB, Cross AJ, 2021, Editorial: volatile organic compound analysis to improve faecal immunochemical testing in the detection of colorectal cancer, ALIMENTARY PHARMACOLOGY & THERAPEUTICS, Vol: 54, Pages: 504-505, ISSN: 0269-2813

Journal article

Tsilidis K, 2021, An umbrella review of the evidence associating diet and cancer risk at 11 anatomical sites, Nature Communications, Vol: 12, Pages: 1-10, ISSN: 2041-1723

There is evidence that diet and nutrition are modifiable risk factors for several cancers, but associations may be flawed due to inherent biases. Nutritional epidemiology studies have largely relied on a single assessment of diet using food frequency questionnaires. We conduct an umbrella review of meta-analyses of observational studies to evaluate the strength and validity of the evidence for the association between food/nutrient intake and risk of developing or dying from 11 primary cancers. It is estimated that only few single food/nutrient and cancer associations are supported by strong or highly suggestive meta-analytic evidence, and future similar research is unlikely to change this evidence. Alcohol consumption is positively associated with risk of postmenopausal breast, colorectal, esophageal, head & neck and liver cancer. Consumption of dairy products, milk, calcium and wholegrains are inversely associated with colorectal cancer risk. Coffee consumption is inversely associated with risk of liver cancer and skin basal cell carcinoma.

Journal article

Chan SSM, Chen Y, Casey K, Olen O, Ludvigsson JF, Carbonnel F, Oldenburg B, Gunter MJ, Tjønneland A, Grip O, DEFINe-IBD Investigators, Lochhead P, Chan AT, Wolk A, Khalili Het al., 2021, Obesity is Associated With Increased Risk of Crohn's disease, but not Ulcerative Colitis: A Pooled Analysis of Five Prospective Cohort Studies., Clin Gastroenterol Hepatol

BACKGROUND AND AIMS: It is unclear whether obesity is associated with the development of inflammatory bowel disease despite compelling data from basic science studies. We therefore examined the association between obesity and risk of Crohn's disease (CD) and ulcerative colitis (UC). METHODS: We conducted pooled analyses of 5 prospective cohorts with validated anthropometric measurements for body mass index (BMI) and waist-hip ratio and other lifestyle factors. Diagnoses of CD and UC were confirmed through medical records or ascertained using validated definitions. We used Cox proportional hazards modeling to calculate pooled multivariable-adjusted HRs (aHRs) and 95% confidence intervals (CIs). RESULTS: Among 601,009 participants (age range, 18-98 years) with 10,110,018 person-years of follow-up, we confirmed 563 incident cases of CD and 1047 incident cases of UC. Obesity (baseline BMI ≥30 kg/m2) was associated with an increased risk of CD (pooled aHR, 1.34; 95% CI, 1.05-1.71, I2 = 0%) compared with normal BMI (18.5 to <25 kg/m2). Each 5 kg/m2 increment in baseline BMI was associated with a 16% increase in risk of CD (pooled aHR, 1.16; 95% CI, 1.05-1.22; I2 = 0%). Similarly, with each 5 kg/m2 increment in early adulthood BMI (age, 18-20 years), there was a 22% increase in risk of CD (pooled aHR, 1.22; 95% CI, 1.05-1.40; I2 = 13.6%). An increase in waist-hip ratio was associated with an increased risk of CD that did not reach statistical significance (pooled aHR across quartiles, 1.08; 95% CI, 0.97-1.19; I2 = 0%). No associations were observed between measures of obesity and risk of UC. CONCLUSIONS: In an adult population, obesity as measured by BMI was associated with an increased risk of older-onset CD but not UC.

Journal article

Harewood R, Disney R, Kinross J, von Wagner C, Cross AJet al., 2021, Medication use and risk of proximal colon cancer: a systematic review of prospective studies with narrative synthesis and meta-analysis, CANCER CAUSES & CONTROL, Pages: 1-15, ISSN: 0957-5243

PurposeEvidence of differences in the etiology of, and poorer survival from, proximal colon compared to the distal colorectum, necessitates research into its risk factors. This systematic review summarizes the evidence on medication use and proximal colon cancer risk.MethodsMEDLINE and EMBASE were searched for prospective studies investigating nine medication groups, namely non-steroidal anti-inflammatory drugs (NSAIDs), exogenous hormones, i.e., hormone replacement therapy (HRT) or oral contraceptives (OCs), statins, proton pump inhibitors, anti-hypertensives, metformin (an antidiabetic), antidiarrheals or laxatives, and the risk of proximal colon cancer. Narrative synthesis and meta-analyses, using random effects models to estimate risk ratios (RRs) and 95% confidence intervals (CIs), were conducted.ResultsTwenty nine publications investigating NSAIDs (n = 13), exogenous hormones [HRT (n = 9) or OCs (n = 4)] statins (n = 5), anti-hypertensives (n = 1), and metformin (n = 1) were included. Summary RRs reported a protective effect of aspirin use (RR 0.80, 95% CI 0.73–0.89) but no associations between HRT (RR 0.92, 95% CI 0.83–1.02), OC (RR 1.06, 95% CI 0.98–1.14) or statin use (RR 0.94, 95% CI 0.67–1.31), and proximal colon cancer incidence compared to never/non-use. One study on metformin and one on anti-hypertensives reported no association. Sources of between-study heterogeneity included study design, period of exposure ascertainment, exposure source, and exposure comparison, but this exploration was hindered by the small numbers of studies.ConclusionDespite some studies on NSAID or HRT use, evidence on the impact of a range of medications on proximal colon cancer risk is limited. This highlights the need for more research to inform chemoprevention strategies.

Journal article

Iglesias-Vazquez L, Arija V, Aranda N, Aglago EK, Cross AJ, Schulze MB, Quintana Pacheco D, Kuhn T, Weiderpass E, Tumino R, Redondo-Sanchez D, de Magistris MS, Palli D, Ardanaz E, Laouali N, Sonestedt E, Drake I, Rizzolo L, Santiuste C, Sacerdote C, Quiros R, Amiano P, Agudo A, Jakszyn Pet al., 2021, Factors associated with serum ferritin levels and iron excess: results from the EPIC-EurGast study, European Journal of Nutrition, Pages: 1-14, ISSN: 0044-264X

PurposeExcess iron is involved in the development of non-communicable diseases such as cancer, type 2 diabetes and cardiovascular conditions. We aimed to describe the prevalence of excess iron and its determinants in healthy European adults.MethodsSociodemographic, lifestyle, iron status, dietary information, and HFE genotyping were obtained from controls from the nested case–control study EPIC-EurGast study. High sensitivity C-reactive protein (hsCRP) was measured to address possible systemic inflammation. Descriptive and multivariate analyses were used to assess iron status and its determinants.ResultsOut of the 828 participants (median age: 58.7 years), 43% were females. Median serum ferritin and prevalence of excess iron were 143.7 µg/L and 35.2% in males, respectively, and 77 µg/L and 20% in females, both increasing with latitude across Europe. Prevalence of HFE C282Y mutation was significantly higher in Northern and Central Europe (~ 11%) than in the South (5%). Overweight/obesity, age, and daily alcohol and heme iron intake were independent determinants for iron status, with sex differences even after excluding participants with hsCRP > 5 mg/L. Obese males showed a greater consumption of alcohol, total and red meat, and heme iron, compared with those normal weight.ConclusionObesity, higher alcohol and heme iron consumption were the main risk factors for excess iron in males while only age was associated with iron overload in females. Weight control and promoting healthy lifestyle may help prevent iron overload, especially in obese people. Further research is needed to clarify determinants of excess iron in the healthy adult population, helping to reduce the associated comorbidities.

Journal article

Dimou N, Mori N, Harlid S, Harbs J, Martin RM, Smith-Byrne K, Papadimitriou N, Bishop DT, Casey G, Colorado-Yohar SM, Cotterchio M, Cross AJ, Le Marchand L, Lin Y, Offit K, Onland-Moret NC, Peters U, Potter JD, Rohan TE, Weiderpass E, Gunter MJ, Murphy Net al., 2021, Circulating Levels of Testosterone, Sex Hormone Binding Globulin and Colorectal Cancer Risk: Observational and Mendelian Randomization Analyses, CANCER EPIDEMIOLOGY BIOMARKERS & PREVENTION, Vol: 30, Pages: 1336-1348, ISSN: 1055-9965

Journal article

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

Agudo A, Cayssials V, Bonet C, Tjønneland A, Overvad K, Boutron-Ruault M-C, Affret A, Fagherazzi G, Katzke V, Schubel R, Trichopoulou A, Karakatsani A, La Vecchia C, Palli D, Grioni S, Tumino R, Ricceri F, Panico S, Bueno-de-Mesquita B, Peeters PH, Weiderpass E, Skeie G, Nøst TH, Lasheras C, Rodríguez-Barranco M, Amiano P, Chirlaque M-D, Ardanaz E, Ohlsson B, Dias JA, Nilsson LM, Myte R, Khaw K-T, Perez-Cornago A, Gunter M, Huybrechts I, Cross AJ, Tsilidis K, Riboli E, Jakszyn Pet al., 2021, Inflammatory potential of the diet & risk of gastric cancer in the European Investigation into Cancer & Nutrition, American Journal of Clinical Nutrition, ISSN: 1938-3207

Journal article

Huyghe JR, Harrison TA, Bien SA, Hampel H, Figueiredo JC, Schmit SL, Conti DV, Chen S, Qu C, Lin Y, Barfield R, Baron JA, Cross AJ, Diergaarde B, Duggan D, Harlid S, Imaz L, Kang HM, Levine DM, Perduca V, Perez-Cornago A, Sakoda LC, Schumacher FR, Slattery ML, Toland AE, van Duijnhoven FJB, Van Guelpen B, Agudo A, Albanes D, Alonso MH, Anderson K, Arnau-Collell C, Arndt V, Banbury BL, Bassik MC, Berndt SI, Bézieau S, Bishop DT, Boehm J, Boeing H, Boutron-Ruault M-C, Brenner H, Brezina S, Buch S, Buchanan DD, Burnett-Hartman A, Caan BJ, Campbell PT, Carr PR, Castells A, Castellví-Bel S, Chan AT, Chang-Claude J, Chanock SJ, Curtis KR, de la Chapelle A, Easton DF, English DR, Feskens EJM, Gala M, Gallinger SJ, Gauderman WJ, Giles GG, Goodman PJ, Grady WM, Grove JS, Gsur A, Gunter MJ, Haile RW, Hampe J, Hoffmeister M, Hopper JL, Hsu W-L, Huang W-Y, Hudson TJ, Jenab M, Jenkins MA, Joshi AD, Keku TO, Kooperberg C, Kühn T, Küry S, Le Marchand L, Lejbkowicz F, Li CI, Li L, Lieb W, Lindblom A, Lindor NM, Männistö S, Markowitz SD, Milne RL, Moreno L, Murphy N, Nassir R, Offit K, Ogino S, Panico S, Parfrey PS, Pearlman R, Pharoah PDP, Phipps AI, Platz EA, Potter JD, Prentice RL, Qi L, Raskin L, Rennert G, Rennert HS, Riboli E, Schafmayer C, Schoen RE, Seminara D, Song M, Su Y-R, Tangen CM, Thibodeau SN, Thomas DC, Trichopoulou A, Ulrich CM, Visvanathan K, Vodicka P, Vodickova L, Vymetalkova V, Weigl K, Weinstein SJ, White E, Wolk A, Woods MO, Wu AH, Abecasis GR, Nickerson DA, Scacheri PC, Kundaje A, Casey G, Gruber SB, Hsu L, Moreno V, Hayes RB, Newcomb PA, Peters Uet al., 2021, Genetic architectures of proximal and distal colorectal cancer are partly distinct, Gut, Vol: 70, Pages: 1325-1334, ISSN: 0017-5749

OBJECTIVE: An understanding of the etiologic heterogeneity of colorectal cancer (CRC) is critical for improving precision prevention, including individualized screening recommendations and the discovery of novel drug targets and repurposable drug candidates for chemoprevention. Known differences in molecular characteristics and environmental risk factors among tumors arising in different locations of the colorectum suggest partly distinct mechanisms of carcinogenesis. The extent to which the contribution of inherited genetic risk factors for CRC differs by anatomical subsite of the primary tumor has not been examined. DESIGN: To identify new anatomical subsite-specific risk loci, we performed genome-wide association study (GWAS) meta-analyses including data of 48 214 CRC cases and 64 159 controls of European ancestry. We characterised effect heterogeneity at CRC risk loci using multinomial modelling. RESULTS: We identified 13 loci that reached genome-wide significance (p<5×10-8) and that were not reported by previous GWASs for overall CRC risk. Multiple lines of evidence support candidate genes at several of these loci. We detected substantial heterogeneity between anatomical subsites. Just over half (61) of 109 known and new risk variants showed no evidence for heterogeneity. In contrast, 22 variants showed association with distal CRC (including rectal cancer), but no evidence for association or an attenuated association with proximal CRC. For two loci, there was strong evidence for effects confined to proximal colon cancer. CONCLUSION: Genetic architectures of proximal and distal CRC are partly distinct. Studies of risk factors and mechanisms of carcinogenesis, and precision prevention strategies should take into consideration the anatomical subsite of the tumour.

Journal article

Cross AJ, Robbins EC, 2021, Reply, Clinical Gastroenterology and Hepatology, ISSN: 1542-3565

Journal article

Tsilidis KK, Papadimitriou N, Dimou N, Gill D, Lewis SJ, Martin RM, Murphy N, Markozannes G, Zuber V, Cross AJ, Burrows K, Lopez DS, Key TJ, Travis RC, Perez-Cornago A, Hunter DJ, van Duijnhoven FJB, Albanes D, Arndt V, Berndt SI, Bézieau S, Bishop DT, Boehm J, Brenner H, Burnett-Hartman A, Campbell PT, Casey G, Castellví-Bel S, Chan AT, Chang-Claude J, de la Chapelle A, Figueiredo JC, Gallinger SJ, Giles GG, Goodman PJ, Gsur A, Hampe J, Hampel H, Hoffmeister M, Jenkins MA, Keku TO, Kweon S-S, Larsson SC, Le Marchand L, Li CI, Li L, Lindblom A, Martín V, Milne RL, Moreno V, Nan H, Nassir R, Newcomb PA, Offit K, Pharoah PDP, Platz EA, Potter JD, Qi L, Rennert G, Sakoda LC, Schafmayer C, Slattery ML, Snetselaar L, Schenk J, Thibodeau SN, Ulrich CM, Van Guelpen B, Harlid S, Visvanathan K, Vodickova L, Wang H, White E, Wolk A, Woods MO, Wu AH, Zheng W, Bueno-de-Mesquita B, Boutron-Ruault M-C, Hughes DJ, Jakszyn P, Kühn T, Palli D, Riboli E, Giovannucci EL, Banbury BL, Gruber SB, Peters U, Gunter MJet al., 2021, Genetically predicted circulating concentrations of micronutrients and risk of colorectal cancer among individuals of European descent: a Mendelian randomization study, American Journal of Clinical Nutrition, Vol: 113, Pages: 1490-1502, ISSN: 0002-9165

BACKGROUND: The literature on associations of circulating concentrations of minerals and vitamins with risk of colorectal cancer is limited and inconsistent. Evidence from randomized controlled trials (RCTs) to support the efficacy of dietary modification or nutrient supplementation for colorectal cancer prevention is also limited. OBJECTIVES: To complement observational and RCT findings, we investigated associations of genetically predicted concentrations of 11 micronutrients (β-carotene, calcium, copper, folate, iron, magnesium, phosphorus, selenium, vitamin B-6, vitamin B-12, and zinc) with colorectal cancer risk using Mendelian randomization (MR). METHODS: Two-sample MR was conducted using 58,221 individuals with colorectal cancer and 67,694 controls from the Genetics and Epidemiology of Colorectal Cancer Consortium, Colorectal Cancer Transdisciplinary Study, and Colon Cancer Family Registry. Inverse variance-weighted MR analyses were performed with sensitivity analyses to assess the impact of potential violations of MR assumptions. RESULTS: Nominally significant associations were noted for genetically predicted iron concentration and higher risk of colon cancer [ORs per SD (ORSD): 1.08; 95% CI: 1.00, 1.17; P value = 0.05] and similarly for proximal colon cancer, and for vitamin B-12 concentration and higher risk of colorectal cancer (ORSD: 1.12; 95% CI: 1.03, 1.21; P value = 0.01) and similarly for colon cancer. A nominally significant association was also noted for genetically predicted selenium concentration and lower risk of colon cancer (ORSD: 0.98; 95% CI: 0.96, 1.00; P value = 0.05) and similarly for distal colon cancer. These associations were robust to sensitivity analyses. Nominally significant inverse associations were observed for zinc and risk of colorectal and distal colon cancers, but sensitivity analyses could not be performed. None of these findings survived correction for multiple testing. Genetica

Journal article

Iguacel I, Schmidt JA, Perez-Cornago A, Van Puyvelde H, Travis R, Stepien M, Scalbert A, Casagrande C, Weiderpass E, Riboli E, Schulze MB, Skeie G, Bodén S, Boeing H, Cross AJ, Harlid S, Jensen TE, Huerta JM, Katzke V, Kühn T, Lujan-Barroso L, Masala G, Rodriguez-Barranco M, Rostgaard-Hansen AL, van der Schouw YT, Vermeulen R, Tagliabue G, Tjønneland A, Trevisan M, Ferrari P, Gunter MJ, Huybrechts Iet al., 2021, Associations between dietary amino acid intakes and blood concentration levels, Clinical Nutrition, Vol: 40, Pages: 3772-3779, ISSN: 0261-5614

BACKGROUND AND AIMS: Emerging evidence suggests a role of amino acids (AAs) in the development of various diseases including renal failure, liver cirrhosis, diabetes and cancer. However, mechanistic pathways and the effects of dietary AA intakes on circulating levels and disease outcomes are unclear. We aimed to compare protein and AA intakes, with their respective blood concentrations in the European Prospective Investigation into Cancer and Nutrition (EPIC) cohort. METHODS: Dietary protein and AA intakes were assessed via the EPIC dietary questionnaires (DQ) and 24-h dietary recalls (24-HDR). A subsample of 3768 EPIC participants who were free of cancer had blood AA concentrations measured. To investigate how circulating levels relate to their respective intakes, dietary AA intake was examined in quintiles and ANOVA tests were run. Pearson correlations were examined for continous associations between intakes and blood concentrations. RESULTS: Dietary AA intakes (assessed with the DQ) and blood AA concentrations were not strongly correlated (-0.15 ≤ r ≤ 0.17) and the direction of the correlations depended on AA class: weak positive correlations were found for most essential AAs (isoleucine, leucine, lysine, methionine, threonine, tryptophan, and valine) and conditionally essential AAs (arginine and tyrosine), while negative associations were found for non-essential AAs. Similar results were found when using the 24-HDR. When conducting ANOVA tests for essential AAs, higher intake quintiles were linked to higher blood AA concentrations, except for histidine and phenylalanine. For non-essential AAs and glycine, an inverse relationship was observed. Conditionally-essential AAs showed mixed results. CONCLUSIONS: Weak positive correlations and dose responses were found between most essential and conditionally essential AA intakes, and blood concentrations, but not for the non-essential AAs. These results suggest that intake of dietary AA might b

Journal article

Robbins EC, Cross AJ, 2021, Guaiac fecal occult blood tests and mortality: a 30-year follow-up of two pooled trials, Clinical Gastroenterology and Hepatology, Vol: 19, Pages: 892-894, ISSN: 1542-3565

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., 2021, A prospective diet-wide association study for risk of colorectal cancer in EPIC, Clinical Gastroenterology and Hepatology, 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

Butt J, Jenab M, Werner J, Fedirko V, Weiderpass E, Dahm CC, Tjønneland A, Olsen A, Boutron-Ruault M-C, Rothwell JA, Severi G, Kaaks R, Turzanski-Fortner R, Aleksandrova K, Schulze M, Palli D, Pala V, Panico S, Tumino R, Sacerdote C, Bueno-de-Mesquita B, Van Gils CH, Gram IT, Lukic M, Sala N, Sánchez Pérez MJ, Ardanaz E, Chirlaque M-D, Palmquist R, Löwenmark T, Travis RC, Heath A, Cross AJ, Freisling H, Zouiouich S, Aglago E, Waterboer T, Hughes DJet al., 2021, Association of pre-diagnostic antibody responses to escherichia coli and bacteroides fragilis toxin proteins with colorectal cancer in a European cohort, Gut Microbes, Vol: 13, Pages: 1-14, ISSN: 1949-0976

Experimental evidence has implicated genotoxic Escherichia coli (E. coli) and enterotoxigenic Bacteroides fragilis (ETBF) in the development of colorectal cancer (CRC). However, evidence from epidemiological studies is sparse. We therefore assessed the association of serological markers of E. coli and ETBF exposure with odds of developing CRC in the European Prospective Investigation into Nutrition and Cancer (EPIC) study.Serum samples of incident CRC cases and matched controls (n = 442 pairs) were analyzed for immunoglobulin (Ig) A and G antibody responses to seven E. coli proteins and two isoforms of the ETBF toxin via multiplex serology. Multivariable-adjusted conditional logistic regression analyses were used to estimate odds ratios (ORs) and 95% confidence intervals (CIs) for the association of sero-positivity to E. coli and ETBF with CRC.The IgA-positivity of any of the tested E. coli antigens was associated with higher odds of developing CRC (OR: 1.42; 95% CI: 1.05–1.91). Dual-positivity for both IgA and IgG to E. coli and ETBF was associated with >1.7-fold higher odds of developing CRC, with a significant association only for IgG (OR: 1.75; 95% CI: 1.04, 2.94). This association was more pronounced when restricted to the proximal colon cancers (OR: 2.62; 95% CI: 1.09, 6.29) compared to those of the distal colon (OR: 1.24; 95% CI: 0.51, 3.00) (pheterogeneity = 0.095). Sero-positivity to E. coli and ETBF was associated with CRC development, suggesting that co-infection of these bacterial species may contribute to colorectal carcinogenesis. These findings warrant further exploration in larger prospective studies and within different population groups.

Journal article

Woodfield G, Belluomo I, Boshier PR, Waller A, Fayyad M, von Wagner C, Cross AJ, Hanna GBet al., 2021, Feasibility and acceptability of breath research in primary care: a prospective, cross-sectional, observational study, BMJ Open, Vol: 11, Pages: 1-10, ISSN: 2044-6055

Objectives To examine the feasibility and acceptability of breath research in primary care.Design Non-randomised, prospective, mixed-methods cross-sectional observational study.Setting Twenty-six urban primary care practices.Participants 1002 patients aged 18–90 years with gastrointestinal symptoms.Main outcome measures During the first 6 months of the study (phase 1), feasibility of patient enrolment using face-to-face, telephone or SMS-messaging (Short Message Service) enrolment strategies, as well as processes for breath testing at local primary care practices, were evaluated. A mixed-method iterative study design was adopted and outcomes evaluated using weekly Plan-Do-Study-Act cycles, focus groups and general practitioner (GP) questionnaires.During the second 6 months of the study (phase 2), patient and GP acceptability of the breath test and testing process was assessed using questionnaires. In addition a ‘single practice’ recruitment model was compared with a ‘hub and spoke’ centralised recruitment model with regards to enrolment ability and patient acceptability.Throughout the study feasibility of the collection of a large number of breath samples by clinical staff over multiple study sites was evaluated and quantified by the analysis of these samples using mass spectrometry.Results 1002 patients were recruited within 192 sampling days. Both ‘single practice’ and ‘hub and spoke’ recruitment models were effective with an average of 5.3 and 4.3 patients accrued per day, respectively. The ‘hub and spoke’ model with SMS messaging was the most efficient combined method of patient accrual. Acceptability of the test was high among both patients and GPs. The methodology for collection, handling and analysis of breath samples was effective, with 95% of samples meeting quality criteria.Conclusions Large-scale breath testing in primary care was feasible and acceptable. This study provides a practical fra

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

Cross A, Robbins E, Pack K, Stenson I, Patel B, Rutter M, Veitch A, Saunders B, Duffy S, Wooldrage Ket al., 2021, Colorectal cancer risk following polypectomy in a multicentre, retrospective, cohort study: an evaluation of the 2020 UK post-polypectomy surveillance guidelines, Gut, ISSN: 0017-5749

ObjectiveColonoscopy surveillance aims to reduce colorectal cancer (CRC) incidence post-polypectomy. The 2020 UK guidelines recommend surveillance at three years for ‘high-risk’ patients with ≥2 premalignant polyps (PMPs) of which ≥1 is ‘advanced’ (serrated polyp [or adenoma] ≥10mm or with [high-grade] dysplasia); ≥5 PMPs; or ≥1 non-pedunculated polyp ≥20mm; ‘low-risk’ patients without these findings are instead encouraged to participate in population-based CRC screening. We examined the appropriateness of these risk classification criteria and recommendations.DesignRetrospective analysis of patients who underwent colonoscopy and polypectomy mostly between 2000–2010 at 17 UK hospitals, followed-up through 2017. We examined CRC incidence by baseline characteristics, risk group, and number of surveillance visits using Cox regression, and compared incidence with that in the general population using standardised incidence ratios (SIRs).Results Among 21,318 patients, 368 CRCs occurred during follow-up (median: 10.1 years). Baseline CRC risk factors included age ≥55 years, ≥2 PMPs, adenomas with tubulovillous/villous/unknown histology or high-grade dysplasia, proximal polyps, and a baseline visit spanning 2–90 days. Compared with the general population, CRC incidence without surveillance was higher among those with adenomas with high-grade dysplasia (SIR:1.74, 95%CI:1.21–2.42) or ≥2 PMPs of which ≥1 was advanced (1.39, 1.09–1.75). For low-risk (71%) and high-risk (29%) patients, SIRs without surveillance were 0.75 (95%CI:0.63–0.88) and 1.30 (1.03–1.62), respectively; for high-risk patients after first surveillance, the SIR was 1.22 (0.91–1.60). ConclusionThese guidelines accurately classify post-polypectomy patients into those at high-risk, for whom one surveillance colonoscopy appears appropriate, and those at low-risk who can be managed by non-invasive screening.

Journal article

Pearson-Stuttard J, Bennett J, Vamos E, Cross A, Ezzati M, Gregg Eet al., 2021, Trends in predominant causes of death in individuals with and without diabetes in England from 2001 to 2018: an epidemiological analysis of linked primary care records, The Lancet Diabetes and Endocrinology, Vol: 9, Pages: 165-173, ISSN: 2213-8595

BackgroundThe prevalence of diabetes has increased in the UK and other high-income countries alongside a substantial decline in cardiovascular mortality. Yet data are scarce on how these trends have changed the causes of death in people with diabetes who have traditionally died primarily of vascular causes. We estimated how all-cause mortality and cause-specific mortality in people with diabetes have changed over time, how the composition of the mortality burden has changed, and how this composition compared with that of the non-diabetes population.MethodsIn this epidemiological analysis of primary care records, we identified 313 907 individuals with diabetes in the Clinical Practice Research Datalink, a well described primary care database, between 2001 to 2018, and linked these data to UK Office for National Statistics mortality data. We assembled serial cross sections with longitudinal follow-up to generate a mixed prevalence and incidence study population of patients with diabetes. We used discretised Poisson regression models to estimate annual death rates for deaths from all causes and 12 specific causes for men and women with diabetes. We also identified age-matched and sex matched (1:1) individuals without diabetes from the same dataset and estimated mortality rates in this group.FindingsBetween Jan 1, 2001, and Oct 31, 2018, total mortality declined by 32% in men and 31% in women with diagnosed diabetes. Death rates declined from 40·7 deaths per 1000 person-years to 27·8 deaths per 1000 person-years in men and from 42·7 deaths per 1000 person-years to 29·5 deaths per 1000 person-years in women with diagnosed diabetes. We found similar declines in individuals without diabetes, hence the gap in mortality between those with and without diabetes was maintained over the study period. Cause-specific death rates declined in ten of the 12 cause groups, with exceptions in dementia and liver disease, which increased in both populations. Th

Journal article

Pearson-Stuttard J, Bennett J, Cheng Y, Vamos E, Cross A, Ezzati M, Gregg Eet al., 2021, Trends in predominant causes of death in those with and without diabetes in England from 2001 to 2018, The Lancet Diabetes and Endocrinology, Vol: 9, Pages: 165-173, ISSN: 2213-8595

BackgroundThe prevalence of diabetes has increased in the UK and other high-income countries alongside a substantial decline in cardiovascular mortality. Yet data are scarce on how these trends have changed the causes of death in people with diabetes who have traditionally died primarily of vascular causes. We estimated how all-cause mortality and cause-specific mortality in people with diabetes have changed over time, how the composition of the mortality burden has changed, and how this composition compared with that of the non-diabetes population.MethodsIn this epidemiological analysis of primary care records, we identified 313 907 individuals with diabetes in the Clinical Practice Research Datalink, a well described primary care database, between 2001 to 2018, and linked these data to UK Office for National Statistics mortality data. We assembled serial cross sections with longitudinal follow-up to generate a mixed prevalence and incidence study population of patients with diabetes. We used discretised Poisson regression models to estimate annual death rates for deaths from all causes and 12 specific causes for men and women with diabetes. We also identified age-matched and sex matched (1:1) individuals without diabetes from the same dataset and estimated mortality rates in this group.FindingsBetween Jan 1, 2001, and Oct 31, 2018, total mortality declined by 32% in men and 31% in women with diagnosed diabetes. Death rates declined from 40·7 deaths per 1000 person-years to 27·8 deaths per 1000 person-years in men and from 42·7 deaths per 1000 person-years to 29·5 deaths per 1000 person-years in women with diagnosed diabetes. We found similar declines in individuals without diabetes, hence the gap in mortality between those with and without diabetes was maintained over the study period. Cause-specific death rates declined in ten of the 12 cause groups, with exceptions in dementia and liver disease, which increased in both populations. Th

Journal article

Brenner H, Cross AJ, 2021, Merits, challenges, and limitations of randomized trials on colorectal cancer screening effectiveness., Gastroenterology, Vol: 160, Pages: 1009-1011, ISSN: 0016-5085

Journal article

Cross AJ, Myles J, Greliak P, Hackshaw A, Halloran S, Benton SC, Addison C, Chapman C, Djedovic N, Smith S, Wagner CV, Duffy SW, Raine Ret al., 2021, Including a general practice endorsement letter with the testing kit in the Bowel Cancer Screening Programme: Results of a cluster randomised trial., Journal of Medical Screening, ISSN: 0969-1413

OBJECTIVES: To evaluate the effect of general practitioner endorsement accompanying the screening kit rather than with the invitation letter on participation in the NHS Bowel Cancer Screening Programme and on the socioeconomic gradient in participation in the Programme. METHODS: The NHS Bowel Cancer Screening Programme in England is delivered via five regional hubs. In early 2016, we carried out a cluster-randomised trial, with hub-day of invitation as the randomisation unit. We randomised 150 hub-days of invitation to the intervention group, GP endorsement on the letter accompanying the guaiac faecal occult blood testing kit (75 hub-days, 197,366 individuals) or control, usual letter (75 hub-days, 197,476 individuals). The endpoint was participation, defined as return of a valid kit within 18 weeks of initial invitation. Because of the cluster randomisation, data were analysed by a hierarchical logistic regression, allowing a random effect for date of invitation. Socioeconomic status was represented by the index of multiple deprivation. RESULTS: Participation was 59.4% in the intervention group and 58.7% in the control group, a significant difference (p = 0.04). There was no heterogeneity of the effect of intervention by index of multiple deprivation. We found that there was some confounding between date and screening episode order (first or subsequent screen). This in turn may have induced confounding with age and slightly diluted the result. CONCLUSIONS: General practitioner endorsement induces a modest increase in participation in bowel cancer screening, but does not affect the socioeconomic gradient. When considering cluster randomisation as a research method, careful scrutiny of potential confounding is indicated in advance if possible and in analysis otherwise.

Journal article

Jayasekara H, MacInnis RJ, Lujan-Barroso L, Mayen-Chacon A-L, Cross AJ, Wallner B, Palli D, Ricceri F, Pala V, Panico S, Tumino R, Kuehn T, Kaaks R, Tsilidis K, Sanchez M-J, Amiano P, Ardanaz E, Chirlaque Lopez MD, Merino S, Rothwell JA, Boutron-Ruault M-C, Severi G, Sternby H, Sonestedt E, Bueno-de-Mesquita B, Boeing H, Travis R, Sandanger TM, Trichopoulou A, Karakatsani A, Peppa E, Tjonneland A, Yang Y, Hodge AM, Mitchell H, Haydon A, Room R, Hopper JL, Weiderpass E, Gunter MJ, Riboli E, Giles GG, Milne RL, Agudo A, English DR, Ferrari Pet al., 2021, Lifetime alcohol intake, drinking patterns over time and risk of stomach cancer: A pooled analysis of data from two prospective cohort studies, International Journal of Cancer, Vol: 148, Pages: 2759-2773, ISSN: 0020-7136

Alcohol consumption is causally linked to several cancers but the evidence for stomach cancer is inconclusive. In our study, the association between long-term alcohol intake and risk of stomach cancer and its subtypes was evaluated. We performed a pooled analysis of data collected at baseline from 491 714 participants in the European Prospective Investigation into Cancer and Nutrition and the Melbourne Collaborative Cohort Study. Hazard ratios (HRs) and 95% confidence intervals (CIs) were estimated for incident stomach cancer in relation to lifetime alcohol intake and group-based life course intake trajectories, adjusted for potential confounders including Helicobacter pylori infection. In all, 1225 incident stomach cancers (78% noncardia) were diagnosed over 7 094 637 person-years; 984 in 382 957 study participants with lifetime alcohol intake data (5 455 507 person-years). Although lifetime alcohol intake was not associated with overall stomach cancer risk, we observed a weak positive association with noncardia cancer (HR = 1.03, 95% CI: 1.00-1.06 per 10 g/d increment), with a HR of 1.50 (95% CI: 1.08-2.09) for ≥60 g/d compared to 0.1 to 4.9 g/d. A weak inverse association with cardia cancer (HR = 0.93, 95% CI: 0.87-1.00) was also observed. HRs of 1.48 (95% CI: 1.10-1.99) for noncardia and 0.51 (95% CI: 0.26-1.03) for cardia cancer were observed for a life course trajectory characterized by heavy decreasing intake compared to light stable intake (Phomogeneity = .02). These associations did not differ appreciably by smoking or H pylori infection status. Limiting alcohol use during lifetime, particularly avoiding heavy use during early adulthood, might help prevent noncardia stomach cancer. Heterogeneous associations observed for cardia and noncardia cancers may indicate etiologic differences.

Journal article

Aleksandrova K, Reichmann R, Kaaks R, Jenab M, Bueno-de-Mesquita HB, Dahm CC, Eriksen AK, Tjønneland A, Artaud F, Boutron-Ruault M-C, Severi G, Hüsing A, Trichopoulou A, Karakatsani A, Peppa E, Panico S, Masala G, Grioni S, Sacerdote C, Tumino R, Elias SG, May AM, Borch KB, Sandanger TM, Skeie G, Sánchez M-J, Huerta JM, Sala N, Gurrea AB, Quirós JR, Amiano P, Berntsson J, Drake I, van Guelpen B, Harlid S, Key T, Weiderpass E, Aglago EK, Cross AJ, Tsilidis KK, Riboli E, Gunter MJet al., 2021, Development and validation of a lifestyle-based model for colorectal cancer risk prediction: the LiFeCRC score, BMC Medicine, Vol: 19, ISSN: 1741-7015

BACKGROUND: Nutrition and lifestyle have been long established as risk factors for colorectal cancer (CRC). Modifiable lifestyle behaviours bear potential to minimize long-term CRC risk; however, translation of lifestyle information into individualized CRC risk assessment has not been implemented. Lifestyle-based risk models may aid the identification of high-risk individuals, guide referral to screening and motivate behaviour change. We therefore developed and validated a lifestyle-based CRC risk prediction algorithm in an asymptomatic European population. METHODS: The model was based on data from 255,482 participants in the European Prospective Investigation into Cancer and Nutrition (EPIC) study aged 19 to 70 years who were free of cancer at study baseline (1992-2000) and were followed up to 31 September 2010. The model was validated in a sample comprising 74,403 participants selected among five EPIC centres. Over a median follow-up time of 15 years, there were 3645 and 981 colorectal cancer cases in the derivation and validation samples, respectively. Variable selection algorithms in Cox proportional hazard regression and random survival forest (RSF) were used to identify the best predictors among plausible predictor variables. Measures of discrimination and calibration were calculated in derivation and validation samples. To facilitate model communication, a nomogram and a web-based application were developed. RESULTS: The final selection model included age, waist circumference, height, smoking, alcohol consumption, physical activity, vegetables, dairy products, processed meat, and sugar and confectionary. The risk score demonstrated good discrimination overall and in sex-specific models. Harrell's C-index was 0.710 in the derivation cohort and 0.714 in the validation cohort. The model was well calibrated and showed strong agreement between predicted and observed risk. Random survival forest analysis suggested high model robustness. Beyond age, li

Journal article

Rothwell JA, Murphy N, Bešević J, Kliemann N, Jenab M, Ferrari P, Achaintre D, Gicquiau A, Vozar B, Scalbert A, Huybrechts I, Freisling H, Prehn C, Adamski J, Cross AJ, Pala VM, Boutron-Ruault M-C, Dahm CC, Overvad K, Gram IT, Sandanger TM, Skeie G, Jakszyn P, Tsilidis KK, Aleksandrova K, Schulze MB, Hughes DJ, van Guelpen B, Bodén S, Sánchez M-J, Schmidt JA, Katzke V, Kühn T, Colorado-Yohar S, Tumino R, Bueno-de-Mesquita B, Vineis P, Masala G, Panico S, Eriksen AK, Tjønneland A, Aune D, Weiderpass E, Severi G, Chajès V, Gunter MJet al., 2020, Metabolic Signatures of Healthy Lifestyle Patterns and Colorectal Cancer Risk in a European Cohort, Clinical Gastroenterology and Hepatology, ISSN: 1542-3565

Background & AimsColorectal cancer risk can be lowered by adherence to the World Cancer Research Fund/American Institute for Cancer Research (WCRF/AICR) guidelines. We derived metabolic signatures of adherence to these guidelines and tested their associations with colorectal cancer risk in the European Prospective Investigation into Cancer cohort.MethodsScores reflecting adherence to the WCRF/AICR recommendations (scale, 1–5) were calculated from participant data on weight maintenance, physical activity, diet, and alcohol among a discovery set of 5738 cancer-free European Prospective Investigation into Cancer participants with metabolomics data. Partial least-squares regression was used to derive fatty acid and endogenous metabolite signatures of the WCRF/AICR score in this group. In an independent set of 1608 colorectal cancer cases and matched controls, odds ratios (ORs) and 95% CIs were calculated for colorectal cancer risk per unit increase in WCRF/AICR score and per the corresponding change in metabolic signatures using multivariable conditional logistic regression.ResultsHigher WCRF/AICR scores were characterized by metabolic signatures of increased odd-chain fatty acids, serine, glycine, and specific phosphatidylcholines. Signatures were inversely associated more strongly with colorectal cancer risk (fatty acids: OR, 0.51 per unit increase; 95% CI, 0.29–0.90; endogenous metabolites: OR, 0.62 per unit change; 95% CI, 0.50–0.78) than the WCRF/AICR score (OR, 0.93 per unit change; 95% CI, 0.86–1.00) overall. Signature associations were stronger in male compared with female participants.ConclusionsMetabolite profiles reflecting adherence to WCRF/AICR guidelines and additional lifestyle or biological risk factors were associated with colorectal cancer. Measuring a specific panel of metabolites representative of a healthy or unhealthy lifestyle may identify strata of the population at higher risk of colorectal cancer.

Journal article

Bull CJ, Bell JA, Murphy N, Sanderson E, Davey Smith G, Timpson NJ, Banbury BL, Albanes D, Berndt SI, Bezieau S, Bishop DT, Brenner H, Buchanan DD, Burnett-Hartman A, Casey G, Castellvi-Bel S, Chan AT, Chang-Claude J, Cross AJ, de la Chapelle A, Figueiredo JC, Gallinger SJ, Gapstur SM, Giles GG, Gruber SB, Gsur A, Hampe J, Hampel H, Harrison TA, Hoffmeister M, Hsu L, Huang W-Y, Huyghe JR, Jenkins MA, Joshu CE, Keku TO, Kuhn T, Kweon S-S, Le Marchand L, Li CI, Li L, Lindblom A, Martin V, May AM, Milne RL, Moreno V, Newcomb PA, Offit K, Ogino S, Phipps AI, Platz EA, Potter JD, Qu C, Quiros JR, Rennert G, Riboli E, Sakoda LC, Schafmayer C, Schoen RE, Slattery ML, Tangen CM, Tsilidis KK, Ulrich CM, van Duijnhoven FJB, van Guelpen B, Visvanathan K, Vodicka P, Vodickova L, Wang H, White E, Wolk A, Woods MO, Wu AH, Campbell PT, Zheng W, Peters U, Vincent EE, Gunter MJet al., 2020, Adiposity, metabolites, and colorectal cancer risk: Mendelian randomization study, BMC Medicine, Vol: 18, ISSN: 1741-7015

BackgroundHigher adiposity increases the risk of colorectal cancer (CRC), but whether this relationship varies by anatomical sub-site or by sex is unclear. Further, the metabolic alterations mediating the effects of adiposity on CRC are not fully understood.MethodsWe examined sex- and site-specific associations of adiposity with CRC risk and whether adiposity-associated metabolites explain the associations of adiposity with CRC. Genetic variants from genome-wide association studies of body mass index (BMI) and waist-to-hip ratio (WHR, unadjusted for BMI; N = 806,810), and 123 metabolites from targeted nuclear magnetic resonance metabolomics (N = 24,925), were used as instruments. Sex-combined and sex-specific Mendelian randomization (MR) was conducted for BMI and WHR with CRC risk (58,221 cases and 67,694 controls in the Genetics and Epidemiology of Colorectal Cancer Consortium, Colorectal Cancer Transdisciplinary Study, and Colon Cancer Family Registry). Sex-combined MR was conducted for BMI and WHR with metabolites, for metabolites with CRC, and for BMI and WHR with CRC adjusted for metabolite classes in multivariable models.ResultsIn sex-specific MR analyses, higher BMI (per 4.2 kg/m2) was associated with 1.23 (95% confidence interval (CI) = 1.08, 1.38) times higher CRC odds among men (inverse-variance-weighted (IVW) model); among women, higher BMI (per 5.2 kg/m2) was associated with 1.09 (95% CI = 0.97, 1.22) times higher CRC odds. WHR (per 0.07 higher) was more strongly associated with CRC risk among women (IVW OR = 1.25, 95% CI = 1.08, 1.43) than men (IVW OR = 1.05, 95% CI = 0.81, 1.36). BMI or WHR was associated with 104/123 metabolites at false discovery rate-corrected P ≤ 0.05; several metabolites were associated with CRC, but not in directions that were consistent with the mediation of positive adiposity-CRC relatio

Journal article

Anderson AS, Renehan AG, Saxton JM, Bell J, Cade J, Cross AJ, King A, Riboli E, Sniehotta F, Treweek S, Martin RM, Beeken R, Mitrou Get al., 2020, Cancer prevention through weight control-where are we in 2020?, British Journal of Cancer, Vol: 124, Pages: 1049-1056, ISSN: 0007-0920

Growing data from epidemiological studies highlight the association between excess body fat and cancer incidence, but good indicative evidence demonstrates that intentional weight loss, as well as increasing physical activity, offers much promise as a cost-effective approach for reducing the cancer burden. However, clear gaps remain in our understanding of how changes in body fat or levels of physical activity are mechanistically linked to cancer, and the magnitude of their impact on cancer risk. It is important to investigate the causal link between programmes that successfully achieve short-term modest weight loss followed by weight-loss maintenance and cancer incidence. The longer-term impact of weight loss and duration of overweight and obesity on risk reduction also need to be fully considered in trial design. These gaps in knowledge need to be urgently addressed to expedite the development and implementation of future cancer-control strategies. Comprehensive approaches to trial design, Mendelian randomisation studies and data-linkage opportunities offer real possibilities to tackle current research gaps. In this paper, we set out the case for why non-pharmacological weight-management trials are urgently needed to support cancer-risk reduction and help control the growing global burden of cancer.

Journal article

Anderson AS, Martin RM, Renehan AG, Cade J, Copson ER, Cross AJ, Grimmett C, Keaver L, King A, Riboli E, Shaw C, Saxton JM, Beeken R, Mitrou Get al., 2020, Cancer survivorship, excess body fatness and weight-loss intervention-where are we in 2020?, British Journal of Cancer, Vol: 124, Pages: 1057-1065, ISSN: 0007-0920

Earlier diagnosis and more effective treatments mean that the estimated number of cancer survivors in the United Kingdom is expected to reach 4 million by 2030. However, there is an increasing realisation that excess body fatness (EBF) is likely to influence the quality of cancer survivorship and disease-free survival. For decades, the discussion of weight management in patients with cancer has been dominated by concerns about unintentional weight loss, low body weight and interventions to increase weight, often re-enforced by the existence of the obesity paradox, which indicates that high body weight is associated with survival benefits for some types of cancer. However, observational evidence provides strong grounds for testing the hypothesis that interventions for promoting intentional loss of body fat and maintaining skeletal muscle in overweight and obese cancer survivors would bring important health benefits in terms of survival outcomes and long-term impact on treatment-related side effects. In this paper, we outline the need for studies to improve our understanding of the health benefits of weight-loss interventions, such as hypocaloric healthy-eating plans combined with physical activity. In particular, complex intervention trials that are pragmatically designed are urgently needed to develop effective, clinically practical, evidence-based strategies for reducing EBF and optimising body composition in people living with and beyond common cancers.

Journal article

Robbins E, Wooldrage K, Stenson I, Pack K, Duffy S, Conell C, Wright S, Nickerson C, Martin J, Cross Aet al., 2020, Heterogeneity in colorectal cancer incidence among people recommended three-yearly surveillance post-polypectomy: a validation study, Endoscopy, Vol: 53, Pages: 402-410, ISSN: 0013-726X

BackgroundColonoscopy surveillance is recommended for patients at increased risk of colorectal cancer (CRC) following adenoma removal. Low-, intermediate-, and high-risk groups are defined by baseline adenoma characteristics. We previously evaluated surveillance in intermediate-risk patients using UK hospital data, identifying a higher-risk subgroup who benefitted from surveillance and a lower-risk subgroup who may not require surveillance. Here we explored whether these findings apply in individuals undergoing CRC screening. MethodsRetrospective study using data from the UK Flexible Sigmoidoscopy Screening Trial (UKFSST), English CRC screening pilot (ECP), and US Kaiser Permanente CRC prevention programme (KPCP). Screening participants aged 50–74 years and classed as intermediate-risk at baseline colonoscopy were included. CRC data were available through 2006 (KPCP) or 2014 (UKFSST, ECP). We classified participants into lower- and higher-risk subgroups using our previously identified baseline risk factors; higher-risk participants were those with incomplete colonoscopies, poor bowel preparation, adenomas ≥20mm or with high-grade dysplasia, or proximal polyps. We compared CRC incidence rates in these subgroups and in the presence versus absence of surveillance using Cox regression.ResultsOf 2291 intermediate-risk participants, 45% were classified as higher-risk. Median follow-up was 11.8 years. CRC incidence rates were significantly higher in the higher-risk than lower-risk subgroup (hazard ratio [HR]=2.08, 95%CI 1.07–4.06). Surveillance reduced CRC incidence rates in higher-risk participants (HR=0.35, 0.14–0.86), but not statistically significantly so in lower-risk participants (HR=0.41, 0.12–1.38).ConclusionAs previously demonstrated for hospital patients, screening participants classed as intermediate-risk comprise two risk subgroups. Surveillance clearly benefits the higher-risk subgroup.

Journal article

Aglago EK, Rinaldi S, Freisling H, Jiao L, Hughes DJ, Fedirko V, Schalkwijk CG, Weiderpass E, Dahm CC, Overvad K, Eriksen AK, Kyrø C, Boutron-Ruault M-C, Rothwell JA, Severi G, Katzke V, Kühn T, Schulze MB, Aleksandrova K, Masala G, Krogh V, Panico S, Tumino R, Naccarati A, Bueno-de-Mesquita B, van Gils CH, Sandanger TM, Gram IT, Skeie G, Quirós JR, Jakszyn P, Sánchez M-J, Amiano P, Huerta JM, Ardanaz E, Johansson I, Harlid S, Perez-Cornago A, Mayén A-L, Cordova R, Gunter MJ, Vineis P, Cross AJ, Riboli E, Jenab Met al., 2020, Soluble Receptor for Advanced Glycation End-products (sRAGE) and Colorectal Cancer Risk: A Case-Control Study Nested within a European Prospective Cohort, Cancer Epidemiology, Biomarkers and Prevention, Vol: 30, ISSN: 1055-9965

BACKGROUND: Overexpression of the receptor for advanced glycation end-product (RAGE) has been associated with chronic inflammation, which in turn has been associated with increased colorectal cancer risk. Soluble RAGE (sRAGE) competes with RAGE to bind its ligands, thus potentially preventing RAGE-induced inflammation. METHODS: To investigate whether sRAGE and related genetic variants are associated with colorectal cancer risk, we conducted a nested case-control study in the European Prospective Investigation into Cancer and Nutrition (EPIC). Plasma sRAGE concentrations were measured by ELISA in 1,361 colorectal cancer matched case-control sets. Twenty-four SNPs encoded in the genes associated with sRAGE concentrations were available for 1,985 colorectal cancer cases and 2,220 controls. Multivariable adjusted ORs and 95% confidence intervals (CIs) were computed using conditional and unconditional logistic regression for colorectal cancer risk and circulating sRAGE and SNPs, respectively. RESULTS: Higher sRAGE concentrations were inversely associated with colorectal cancer (ORQ5vs.Q1, 0.77; 95% CI, 0.59-1.00). Sex-specific analyses revealed that the observed inverse risk association was restricted to men (ORQ5vs.Q1, 0.63; 95% CI, 0.42-0.94), whereas no association was observed in women (ORQ5vs.Q1, 1.00; 95% CI, 0.68-1.48; Pheterogeneity for sex = 0.006). Participants carrying minor allele of rs653765 (promoter region of ADAM10) had lower colorectal cancer risk (C vs. T, OR, 0.90; 95% CI, 0.82-0.99). CONCLUSIONS: Prediagnostic sRAGE concentrations were inversely associated with colorectal cancer risk in men, but not in women. An SNP located within ADAM10 gene, pertaining to RAGE shedding, was associated with colorectal cancer risk. IMPACT: Further studies are needed to confirm our observed sex difference in the association and better explore the potential involvement of genetic variants of sRAGE in colorectal cancer development.

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