Imperial College London

Dr Amanda Cross

Faculty of MedicineSchool of Public Health

Professor of Cancer Epidemilogy
 
 
 
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Contact

 

+44 (0)20 7594 3338amanda.cross

 
 
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Assistant

 

Mrs Elizabeth Coles +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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227 results found

Cross A, Wooldrage K, Robbins E, Kralj-Hans I, MacRae E, Piggott C, Stenson I, Prendergast A, Patel B, Pack K, Howe R, Swart N, Snowball J, Duffy SW, Morris S, von Wagner C, Halloran S, Atkin Wet al., 2019, Faecal immunochemical tests (FIT) versus colonoscopy for surveillance after screening and polypectomy: a diagnostic accuracy and cost-effectiveness study, Gut, Vol: 68, Pages: 1642-1652, ISSN: 0017-5749

Objective The English Bowel Cancer Screening Programme (BCSP) recommends 3 yearly colonoscopy surveillance for patients at intermediate risk of colorectal cancer (CRC) postpolypectomy (those with three to four small adenomas or one ≥10 mm). We investigated whether faecal immunochemical tests (FITs) could reduce surveillance burden on patients and endoscopy services.Design Intermediate-risk patients (60–72 years) recommended 3 yearly surveillance were recruited within the BCSP (January 2012–December 2013). FITs were offered at 1, 2 and 3 years postpolypectomy. Invitees consenting and returning a year 1 FIT were included. Participants testing positive (haemoglobin ≥40 µg/g) at years one or two were offered colonoscopy early; all others were offered colonoscopy at 3 years. Diagnostic accuracy for CRC and advanced adenomas (AAs) was estimated considering multiple tests and thresholds. We calculated incremental costs per additional AA and CRC detected by colonoscopy versus FIT surveillance.Results 74% (5938/8009) of invitees were included in our study having participated at year 1. Of these, 97% returned FITs at years 2 and 3. Three-year cumulative positivity was 13% at the 40 µg/g haemoglobin threshold and 29% at 10 µg/g. 29 participants were diagnosed with CRC and 446 with AAs. Three-year programme sensitivities for CRC and AAs were, respectively, 59% and 33% at 40 µg/g, and 72% and 57% at 10 µg/g. Incremental costs per additional AA and CRC detected by colonoscopy versus FIT (40 µg/g) surveillance were £7354 and £180 778, respectively.Conclusions Replacing 3 yearly colonoscopy surveillance in intermediate-risk patients with annual FIT could reduce colonoscopies by 71%, significantly cut costs but could miss 30%–40% of CRCs and 40%–70% of AAs.

Journal article

Kühn T, Stepien M, López-Nogueroles M, Machado AD, Sookthai D, Johnson T, Roca M, Hüsing A, Maldonado SG, Cross AJ, Murphy N, Freisling H, Rinaldi S, Scalbert A, Fedirco V, Severi G, Boutron-Ruault M-C, Mancini FR, Sowah SA, Boeing H, Jakszyn P, Sánchez M-J, Merino S, Colorado-Yohar S, Barricarte A, Khaw KT, Schmidt JA, Perez-Cornago A, Trichopoulou A, Karakatsani A, Thriskos P, Palli D, Agnoli C, Tumino R, Sacerdote C, Panico S, Bueno-de-Mesquita B, van Gils CH, Heath A, Gunter MJ, Riboli E, Lahoz A, Jenab M, Kaaks Ret al., 2019, Pre-diagnostic plasma bile acid levels and colon cancer risk: A prospective study., J Natl Cancer Inst

BACKGROUND: Bile acids have been proposed to promote colon carcinogenesis. However, there are limited prospective data on circulating bile acid levels and colon cancer risk in humans. METHODS: Associations between pre-diagnostic plasma levels of 17 primary, secondary and tertiary bile acid metabolites (conjugated and unconjugated) and colon cancer risk were evaluated in a nested case-control study within the European Prospective Investigation into Cancer and Nutrition (EPIC) cohort. Bile acid levels were quantified by tandem mass spectrometry in samples from 569 incident colon cancer cases and 569 matched controls. Multivariable logistic regression analyses were used to estimate odds ratios (ORs) for colon cancer risk across quartiles of bile acid concentrations. RESULTS: Positive associations were observed between colon cancer risk and plasma levels of 7 conjugated bile acid metabolites, i.e. primary bile acids glycocholic acid (ORQuartile 4 vs. Quartile 1=2.22,95 % confidence interval[CI]=1.52, 3.26), taurocholic acid (OR = 1.78, 95%CI=1.23, 2.58), glycochenodeoxycholic acid (OR = 1.68, 95%CI=1.13, 2.48), taurochenodeoxycholic acid (OR = 1.62, 95%CI=1.11-2.36), and glycohyocholic acid (OR = 1.65, 95%CI=1.13, 2.40) as well as the secondary bile acids glycodeoxycholic acid (OR = 1.68, 95%CI=1.12, 2.54) and taurodeoxycholic acid (OR = 1.54, 95%CI=1.02, 2.31). By contrast, unconjugated bile acids and tertiary bile acids were not associated with risk. CONCLUSIONS: This prospective study showed that pre-diagnostic levels of certain conjugated primary and secondary bile acids were positively associated with risk of colon cancer. Our findings support experimental data to suggest that a high bile acid load is colon cancer promotive.

Journal article

Ward HA, Whitman J, Muller DC, Johansson M, Jakszyn P, Weiderpass E, Palli D, Fanidi A, Vermeulen R, Tjønneland A, Hansen L, Dahm CC, Overvad K, Severi G, Boutron-Ruault M-C, Affret A, Kaaks R, Fortner R, Boeing H, Trichopoulou A, La Vecchia C, Kotanidou A, Berrino F, Krogh V, Tumino R, Ricceri F, Panico S, Bueno-de-Mesquita HB, Peeters PH, Nøst TH, Sandanger TM, Quirós JR, Agudo A, Rodríguez-Barranco M, Larrañaga N, Huerta JM, Ardanaz E, Drake I, Brunnström H, Johansson M, Grankvist K, Travis RC, Freisling H, Stepien M, Merritt MA, Riboli E, Cross AJet al., 2019, Haem iron intake and risk of lung cancer in the European Prospective Investigation into Cancer and Nutrition (EPIC) cohort, European Journal of Clinical Nutrition, Vol: 73, Pages: 1122-1132, ISSN: 1476-5640

BACKGROUND: Epidemiological studies suggest that haem iron, which is found predominantly in red meat and increases endogenous formation of carcinogenic N-nitroso compounds, may be positively associated with lung cancer. The objective was to examine the relationship between haem iron intake and lung cancer risk using detailed smoking history data and serum cotinine to control for potential confounding. METHODS: In the European Prospective Investigation into Cancer and Nutrition (EPIC), 416,746 individuals from 10 countries completed demographic and dietary questionnaires at recruitment. Cox proportional hazards models were used to estimate hazard ratios (HRs) and 95% confidence intervals (CIs) for incident lung cancer (n = 3731) risk relative to haem iron, non-haem iron, and total dietary iron intake. A corresponding analysis was conducted among a nested subset of 800 lung cancer cases and 1489 matched controls for whom serum cotinine was available. RESULTS: Haem iron was associated with lung cancer risk, including after adjustment for details of smoking history (time since quitting, number of cigarettes per day): as a continuous variable (HR per 0.3 mg/1000 kcal 1.03, 95% CI 1.00-1.07), and in the highest versus lowest quintile (HR 1.16, 95% CI 1.02-1.32; trend across quintiles: P = 0.035). In contrast, non-haem iron intake was related inversely with lung cancer risk; however, this association attenuated after adjustment for smoking history. Additional adjustment for serum cotinine did not considerably alter the associations detected in the nested case-control subset. CONCLUSIONS: Greater haem iron intake may be modestly associated with lung cancer risk.

Journal article

Aglago EK, Huybrechts I, Murphy N, Casagrande C, Nicolas G, Pischon T, Fedirko V, Severi G, Boutron-Ruault M-C, Fournier A, Katzke V, Kühn T, Olsen A, Tjønneland A, Dahm CC, Overvad K, Lasheras C, Agudo A, Sánchez M-J, Amiano P, Huerta JM, Ardanaz E, Perez-Cornago A, Trichopoulou A, Karakatsani A, Martimianaki G, Palli D, Pala V, Tumino R, Naccarati A, Panico S, Bueno-de-Mesquita B, May A, Derksen JWG, Hellstrand S, Ohlsson B, Wennberg M, Van Guelpen B, Skeie G, Brustad M, Weiderpass E, Cross AJ, Ward H, Riboli E, Norat T, Chajes V, Gunter MJet al., 2019, Consumption of fish and long-chain n-3 polyunsaturated fatty acids is associated with reduced risk of colorectal cancer in a large European cohort, Clinical Gastroenterology and Hepatology, ISSN: 1542-3565

BACKGROUND & AIMS: There is an unclear association between intake of fish and long-chain n-3 polyunsaturated fatty acids (n-3 LC-PUFAs) and colorectal cancer (CRC). We examined the association between fish consumption, dietary and circulating levels of n-3 LC-PUFAs, and ratio of n-6:n-3 LC-PUFA with CRC using data from the European Prospective Investigation into Cancer and Nutrition (EPIC) cohort. METHODS: Dietary intake of fish (total, fatty/oily, lean/white) and n-3 LC-PUFA were estimated by food frequency questionnaires given to 521,324 participants in the EPIC study; among these, 6291 individuals developed CRC (median follow up, 14.9 years). Levels of phospholipid LC-PUFA were measured by gas chromatography in plasma samples from a sub-group of 461 CRC cases and 461 matched individuals without CRC (controls). Multivariable Cox proportional hazards and conditional logistic regression models were used to calculate hazard ratios (HRs) and odds ratios (ORs), respectively, with 95% CIs. RESULTS: Total intake of fish (HR for quintile 5 vs 1, 0.88; 95% CI, 0.80-0.96; Ptrend=.005), fatty fish (HR for quintile 5 vs 1, 0.90; 95% CI, 0.82-0.98; Ptrend=.009), and lean fish (HR for quintile 5 vs 1, 0.91; 95% CI, 0.83-1.00; Ptrend=.016) were inversely associated with CRC incidence. Intake of total n-3 LC-PUFA (HR for quintile 5 vs 1, 0.86; 95% CI, 0.78-0.95; Ptrend=.010) was also associated with reduced risk of CRC, whereas dietary ratio of n-6:n-3 LC-PUFA was associated with increased risk of CRC (HR for quintile 5 vs 1, 1.31; 95% CI, 1.18-1.45; Ptrend<.001). Plasma levels of phospholipid n-3 LC-PUFA was not associated with overall CRC risk, but an inverse trend was observed for proximal compared with distal colon cancer (Pheterogeneity=.026). CONCLUSIONS: In an analysis of dietary patterns of participants in the EPIC study, we found regular consumption of fish, at recommended levels, to be associated with a lower risk of CRC, possibly through exposure to n-3 LC-PUFA.

Journal article

Murphy N, Ward HA, Jenab M, Rothwell JA, Boutron-Ruault M-C, Carbonnel F, Kvaskoff M, Kaaks R, Kuhn T, Boeing H, Aleksandrova K, Weiderpass E, Skeie G, Borch KB, Tjønneland A, Kyrø C, Overvad K, Dahm CC, Jakszyn P, Sanchez M-JS, Gil L, Huerta JM, Barricarte A, Quiros JR, Khaw K-T, Wareham N, Bradbury KE, Trichopoulou A, La Vecchia C, Karakatsani A, Palli D, Grioni S, Tumino R, Fasanelli F, Panico S, Bueno-de-Mesquita B, Peeters PH, Gylling B, Myte R, Jirstrom K, Berntsson J, Xue X, Riboli E, Cross AJ, Gunter MJet al., 2019, Heterogeneity of colorectal cancer risk factors by anatomical subsite in 10 European countries: a multinational cohort study, Clinical Gastroenterology and Hepatology, Vol: 17, Pages: 1323-1331.e6, ISSN: 1542-3565

Background and AimsColorectal cancer located at different anatomical subsites may have distinct etiologies and risk factors. Previous studies that have examined this hypothesis have yielded inconsistent results, possibly because most have been of insufficient size to identify heterogeneous associations with precision.MethodsIn the European Prospective Investigation into Cancer and Nutrition study, we used multivariable joint Cox proportional hazards models, which accounted for tumors at different anatomical sites (proximal colon, distal colon, and rectum) as competing risks, to examine the relationships between 14 established/suspected lifestyle, anthropometric, and reproductive/menstrual risk factors with colorectal cancer risk. Heterogeneity across sites was tested using Wald tests.ResultsAfter 14.9 years (median) follow-up of 521,330 men and women, 6,291 colorectal cancer cases occurred. Physical activity was inversely related to proximal colon and distal colon cancer, but not to rectal cancer (P-heterogeneity=0.03). Height was positively associated with proximal and distal colon cancer only, but not rectal cancer (P-heterogeneity=0.0001). For men, but not women, heterogeneous relationships were observed for body mass index (P-heterogeneity=0.008) and waist circumference (P-heterogeneity=0.03), with weaker positive associations found for rectal cancer, compared to proximal and distal colon cancer. Current smoking was associated with a greater risk of rectal and proximal colon cancer, but not distal colon cancer (P-heterogeneity=0.05). No heterogeneity by anatomical site was found for alcohol consumption, diabetes, nonsteroidal anti-inflammatory drug use, and reproductive/menstrual factors.ConclusionsThe physical activity, anthropometry, and smoking relationships with colorectal cancer risk differed by subsite, supporting the hypothesis that tumors in different anatomical regions may have distinct etiologies.

Journal article

Cook MB, Barnett MJ, Bock CH, Cross AJ, Goodman PJ, Goodman GE, Haiman CA, Khaw K-T, McCullough ML, Newton CC, Boutron-Ruault M-C, Lund E, Rutegård M, Thornquist MD, Spriggs M, Giffen C, Freedman ND, Kemp T, Kroenke CH, Le Marchand L, Park JY, Simon M, Wilkens LR, Pinto L, Hildesheim A, Campbell PTet al., 2019, Prediagnostic circulating markers of inflammation and risk of oesophageal adenocarcinoma: a study within the National Cancer Institute Cohort Consortium, Gut, Vol: 68, Pages: 960-968, ISSN: 0017-5749

OBJECTIVE: Cross-sectional data indicate that systemic inflammation is important in oesophageal adenocarcinoma. We conducted a prospective study to assess whether prediagnostic circulating markers of inflammation were associated with oesophageal adenocarcinoma and to what extent they mediated associations of obesity and cigarette smoking with cancer risk. DESIGN: This nested case-control study included 296 oesophageal adenocarcinoma cases and 296 incidence density matched controls from seven prospective cohort studies. We quantitated 69 circulating inflammation markers using Luminex-based multiplex assays. Conditional logistic regression models estimated associations between inflammation markers and oesophageal adenocarcinoma, as well as direct and indirect effects of obesity and smoking on risk of malignancy. RESULTS: Soluble tumour necrosis factor receptor 2 (sTNFR2) (ORsquartile 4 vs 1=2.67, 95% CI 1.52 to 4.68) was significantly associated with oesophageal adenocarcinoma. Additional markers close to the adjusted significance threshold included C reactive protein, serum amyloid A, lipocalin-2, resistin, interleukin (IL) 3, IL17A, soluble IL-6 receptor and soluble vascular endothelial growth factor receptor 3. Adjustment for body mass index, waist circumference or smoking status slightly attenuated biomarker-cancer associations. Mediation analysis indicated that sTNFR2 may account for 33% (p=0.005) of the effect of waist circumference on oesophageal adenocarcinoma risk. Resistin, plasminogen activator inhibitor 1, C reactive protein and serum amyloid A were also identified as potential mediators of obesity-oesophageal adenocarcinoma associations. For smoking status, only plasminogen activator inhibitor 1 was a nominally statistically significant (p<0.05) mediator of cancer risk. CONCLUSION: This prospective study provides evidence of a link between systemic inflammation and oesophageal adenocarcinoma risk. In addition, this study provides the first evidence tha

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., 2019, 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, 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

Key TJ, Appleby PN, Bradbury KE, Sweeting M, Wood A, Johansson I, Kühn T, Steur M, Weiderpass E, Wennberg M, Würtz AML, Agudo A, Andersson J, Arriola L, Boeing H, Boer JMA, Bonnet F, Boutron-Ruault M-C, Cross AJ, Ericson U, Fagherazzi G, Ferrari P, Gunter M, Huerta JM, Katzke V, Khaw K-T, Krogh V, La Vecchia C, Matullo G, Moreno-Iribas C, Naska A, Nilsson LM, Olsen A, Overvad K, Palli D, Panico S, Molina-Portillo E, Quirós JR, Skeie G, Sluijs I, Sonestedt E, Stepien M, Tjønneland A, Trichopoulou A, Tumino R, Tzoulaki I, van der Schouw YT, Verschuren WMM, Di Angelantonio E, Langenberg C, Forouhi N, Wareham N, Butterworth A, Riboli E, Danesh Jet al., 2019, Consumption of meat, fish, dairy products, eggs and risk of ischemic heart disease: A prospective study of 7198 incident cases among 409,885 participants in the pan-European EPIC cohort, Circulation, ISSN: 0009-7322

BACKGROUND: There is uncertainty about the relevance of animal foods to the etiology of ischemic heart disease (IHD). We examined meat, fish, dairy products and eggs and risk for IHD in the pan-European EPIC cohort. METHODS: A prospective study of 409,885 men and women in nine European countries. Diet was assessed using validated questionnaires, calibrated using 24-hour recalls. Lipids and blood pressure were measured in a subsample. During 12.6 years mean follow up, 7198 participants had a myocardial infarction or died from IHD. The relationships of animal foods with risk were examined using Cox regression with adjustment for other animal foods and relevant covariates. RESULTS: The hazard ratio (HR) for IHD was 1.19 (95% CI 1.06-1.33) for a 100 g/d increment in intake of red and processed meat, and this remained significant after excluding the first 4 years of follow-up (HR 1.25 [1.09-1.42]). Risk was inversely associated with intakes of yogurt (HR 0.93 [0.89-0.98] per 100 g/d increment), cheese (HR 0.92 [0.86-0.98] per 30 g/d increment) and eggs (HR 0.93 [0.88-0.99] per 20 g/d increment); the associations with yogurt and eggs were attenuated and non-significant after excluding the first 4 years of follow-up. Risk was not significantly associated with intakes of poultry, fish or milk. In analyses modelling dietary substitutions, replacement of 100 kcal/d from red and processed meat with 100 kcal/d from fatty fish, yogurt, cheese or eggs was associated with approximately 20% lower risk of IHD. Consumption of red and processed meat was positively associated with serum non-HDL cholesterol concentration and systolic blood pressure, and consumption of cheese was inversely associated with serum non-HDL cholesterol. CONCLUSIONS: Risk for IHD was positively associated with consumption of red and processed meat, and inversely associated with consumption of yogurt, cheese and eggs, although the associations with yogurt and eggs may be influenced by reverse causation bias. It

Journal article

Brown JP, Wooldrage K, Kralj-Hans I, Wright S, Cross A, Atkin Wet al., 2019, Effect of once-only flexible sigmoidoscopy screening on the outcomes of subsequent faecal occult blood test screening, Journal of Medical Screening, Vol: 26, Pages: 11-18, ISSN: 0969-1413

Objectives:To investigate the outcomes of biennial guaiac faecal occult blood test (gFOBT) screening after once-only flexible sigmoidoscopy (FS) screening. Methods:Between 1994 and 1999, as part of the UK FS Screening Trial (UKFSST), adults aged 55-64 years were randomly allocated to an intervention group (offered FS screening) or a control group (not contacted). From 2006, a subset of UKFSST participants (20,895/44,041 intervention group; 41,497/87,149 control group) were invited to biennial gFOBT screening by the English Bowel Cancer Screening Programme. We analysed gFOBT uptake, test positivity, yield of colorectal cancer (CRC), and positive predictive value (PPV) for CRC, advanced adenomas (AA), and advanced colorectal neoplasia (ACN: AA/CRC). Results:Uptake of gFOBT at first invite was 1.9% lower (65.7% vs. 67.6%, p<0.01) among intervention versus control group participants; positivity was 0.4% lower (2.0% vs. 2.4%, p<0.01); and CRC yield was 0.08% lower (0.19% vs. 0.27%, p=0.14). PPVs were also lower in the intervention versus control group at 10.3% vs. 12.3% (p=0.44) for CRC, 22.7% vs. 31.4% (p<0.01) for AA, and 33.0% vs. 43.7% (p<0.01) for ACN. Among those who refused FS (n=5,532), gFOBT uptake at first invite was 47.7%, CRC yield was 0.25%, and PPV for ACN was 46.2%; among FS attenders (n=15,363), uptake was 72.2%, CRC yield was 0.18%, and PPV for ACN was 27.9%. Conclusions:Uptake, positivity and PPV of gFOBT screening were reduced following prior offer of FS screening. However, a quarter of FS screened participants receiving a diagnostic examination after positive gFOBT were diagnosed with ACN.

Journal article

Gunter MJ, Alhomoud S, Arnold M, Brenner H, Burn J, Casey G, Chan AT, Cross AJ, Giovannucci E, Hoover R, Houlston R, Jenkins M, Laurent-Puig P, Peters U, Ransohoff D, Riboli E, Sinha R, Stadler ZK, Brennan P, Chanock SJet al., 2019, Meeting Report from the joint IARC-NCI international cancer seminar series: a focus on colorectal cancer, Annals of Oncology, ISSN: 0923-7534

Despite significant progress in our understanding of the etiology, biology and genetics of colorectal cancer, as well as important clinical advances, it remains the third most frequently diagnosed cancer worldwide and is the second leading cause of cancer death. Based on demographic projections, the global burden of colorectal cancer would be expected to rise by 72% from 1.8 million new cases in 2018 to over 3 million in 2040 with substantial increases anticipated in low and middle income countries. In this meeting report, we summarize the content of a joint workshop led by the National Cancer Institute (NCI) and the International Agency for Research on Cancer (IARC) which was held to summarize the important achievements that have been made in our understanding of colorectal cancer etiology, genetics, early detection and treatment and to identify key research questions that remain to be addressed.

Journal article

Cross A, Wooldrage K, Robbins E, Pack K, Brown JP, Hamilton W, Thompson MR, Flashman KG, Halligan S, Thomas-Gibson S, Vance M, Saunders BP, Atkin Wet al., 2019, Whole colon investigation versus flexible sigmoidoscopy for suspected colorectal cancer based on presenting symptoms and signs: a multicentre cohort study, British Journal of Cancer, Vol: 120, Pages: 154-164, ISSN: 0007-0920

BackgroundPatients with suspected colorectal cancer (CRC) usually undergo colonoscopy. Flexible sigmoidoscopy (FS) may be preferred if proximal cancer risk is low. We investigated which patients could undergo FS alone.MethodsCohort study of 7375 patients (≥55 years) referred with suspected CRC to 21 English hospitals (2004–2007), followed using hospital records and cancer registries. We calculated yields and number of needed whole-colon examinations (NNE) to diagnose one cancer by symptoms/signs and subsite. We considered narrow (haemoglobin <11 g/dL men; <10 g/dL women) and broad (<13 g/dL men; <12 g/dL women) anaemia definitions and iron-deficiency anaemia (IDA).ResultsOne hundred and twenty-seven proximal and 429 distal CRCs were diagnosed. A broad anaemia definition identified 80% of proximal cancers; a narrow definition with IDA identified 39%. In patients with broad definition anaemia and/or abdominal mass, proximal cancer yield and NNE were 4.8% (97/2022) and 21. In patients without broad definition anaemia and/or abdominal mass, with rectal bleeding or increased stool frequency (41% of cohort), proximal cancer yield and NNE were 0.4% (13/3031) and 234.ConclusionMost proximal cancers are accompanied by broad definition anaemia. In patients without broad definition anaemia and/or abdominal mass, with rectal bleeding or increased stool frequency, proximal cancer is rare and FS should suffice.

Journal article

Gunter MJ, Alhomoud S, Arnold M, Brenner H, Burn J, Casey G, Chain AT, Cross AJ, Giovannucci E, Hoover R, Houlston R, Jenkins M, Laurent-Puig P, Peters U, Ransohoff D, Riboli E, Sinha R, Stadler ZK, Brennan P, Chanock SJet al., International cancer seminars:a focus on colorectal cancer, Annals of Oncology, ISSN: 0923-7534

Despite significant progress in our understanding of the etiology, biology and genetics of colorectal cancer, as well as important clinical advances, it remains the third most frequently diagnosed cancer worldwide and is the second leading cause of cancer death. Based on demographic projections, the global burden of colorectal cancer would be expected to rise by 72% from 1.8 million new cases in 2018 to over 3 million in 2040 with substantial increases anticipated in low and middle income countries. In this meeting report, we summarize the content of a joint workshop led by the National Cancer Institute (NCI) and the International Agency for Research on Cancer (IARC) which was held to summarize the important achievements that have been made in our understanding of colorectal cancer etiology, genetics, early detection and treatment and to identify key research questions that remain to be addressed.

Journal article

Sen A, Papadimitriou N, Lagiou P, Perez-Cornago A, Travis RC, Key TJ, Murphy N, Gunter M, Freisling H, Tzoulaki I, Muller DC, Cross AJ, Lopez DS, Bergmann M, Boeing H, Bamia C, Kotanidou A, Karakatsani A, Tjønneland A, Kyrø C, Outzen M, Redondo M-L, Cayssials V, Chirlaque M-D, Barricarte A, Sánchez M-J, Larrañaga N, Tumino R, Grioni S, Palli D, Caini S, Sacerdote C, Bueno-de-Mesquita B, Kühn T, Kaaks R, Nilsson LM, Landberg R, Wallström P, Drake I, Bech BH, Overvad K, Aune D, Khaw K-T, Riboli E, Trichopoulos D, Trichopoulou A, Tsilidis KKet al., 2019, Coffee and tea consumption and risk of prostate cancer in the European Prospective Investigation into Cancer and Nutrition, International Journal of Cancer, Vol: 144, Pages: 240-250, ISSN: 0020-7136

The epidemiological evidence regarding the association of coffee and tea consumption with prostate cancer risk is inconclusive, and few cohort studies have assessed these associations by disease stage and grade. We examined the associations of coffee (total, caffeinated and decaffeinated) and tea intake with prostate cancer risk in the European Prospective Investigation into Cancer and Nutrition. Among 142,196 men, 7,036 incident prostate cancer cases were diagnosed over 14 years of follow-up. Data on coffee and tea consumption were collected through validated country-specific food questionnaires at baseline. We used Cox proportional hazards regression models to compute hazard ratios (HRs) and 95% confidence intervals (CI). Models were stratified by center and age, and adjusted for anthropometric, lifestyle and dietary factors. Median coffee and tea intake were 375 mL/day and 106 mL/day, respectively, but large variations existed by country. Comparing the highest (median of 855 mL/day) versus lowest (median of 103 mL/day) consumers of coffee and tea (450 mL/day versus 12 mL/day) the HRs were 1.02 (95% CI, 0.94-1.09) and 0.98 (95% CI, 0.90-1.07) for risk of total prostate cancer, and 0.97 (95% CI, 0.79-1.21) and 0.89 (95% CI, 0.70-1.13) for risk of fatal disease, respectively. No evidence of association was seen for consumption of total, caffeinated or decaffeinated coffee or tea and risk of total prostate cancer or cancer by stage, grade or fatality in this large cohort. Further investigations are needed to clarify whether an association exists by different preparations or by concentrations and constituents of these beverages. This article is protected by copyright. All rights reserved.

Journal article

Ward HA, Murphy N, Weiderpass E, Leitzmann MF, Aglago E, Gunter MJ, Freisling H, Jenab M, Boutron-Ruault M-C, Severi G, Carbonnel F, Kühn T, Kaaks R, Boeing H, Tjønneland A, Olsen A, Overvad K, Merino S, Zamora-Ros R, Rodríguez-Barranco M, Dorronsoro M, Chirlaque M-D, Barricarte A, Perez-Cornago A, Trichopoulou A, Bamia C, Lagiou P, Masala G, Grioni S, Tumino R, Sacerdote C, Mattiello A, Bueno-de-Mesquita B, Vermeulen R, Van Gils C, Nyström H, Rutegård M, Aune D, Riboli E, Cross AJet al., 2019, Gallstones and incident colorectal cancer in a large pan-European cohort study, International Journal of Cancer, ISSN: 0020-7136

Gallstones, a common gastrointestinal condition, can lead to several digestive complications and can result in inflammation. Risk factors for gallstones include obesity, diabetes, smoking and physical inactivity, all of which are known risk factors for colorectal cancer (CRC), as is inflammation. However, it is unclear whether gallstones are a risk factor for CRC. We examined the association between history of gallstones and CRC in the European Prospective Investigation into Cancer and Nutrition (EPIC) study, a prospective cohort of over half a million participants from ten European countries. History of gallstones was assessed at baseline using a self-reported questionnaire. The analytic cohort included 334,986 participants; a history of gallstones was reported by 3,917 men and 19,836 women, and incident CRC was diagnosed among 1,832 men and 2,178 women (mean follow-up: 13.6 years). Hazard ratios (HR) and 95% confidence intervals (CI) for the association between gallstones and CRC were estimated using Cox proportional hazards regression models, stratified by sex, study centre and age at recruitment. The models were adjusted for body mass index, diabetes, alcohol intake and physical activity. A positive, marginally significant association was detected between gallstones and CRC among women in multivariable analyses (HR = 1.14, 95%CI 0.99-1.31, p = 0.077). The relationship between gallstones and CRC among men was inverse but not significant (HR = 0.81, 95%CI 0.63-1.04, p = 0.10). Additional adjustment for details of reproductive history or waist circumference yielded minimal changes to the observed associations. Further research is required to confirm the nature of the association between gallstones and CRC by sex.

Journal article

Huyghe JR, Bien SA, Harrison TA, Kang HM, Chen S, Schmit SL, Conti DV, Qu C, Jeon J, Edlund CK, Greenside P, Wainberg M, Schumacher FR, Smith JD, Levine DM, Nelson SC, Sinnott-Armstrong NA, Albanes D, Alonso MH, Anderson K, Arnau-Collell C, Arndt V, Bamia C, Banbury BL, Baron JA, Berndt SI, Bezieau S, Bishop DT, Boehm J, Boeing H, Brenner H, Brezina S, Buch S, Buchanan DD, Burnett-Hartman A, Butterbach K, Caan BJ, Campbell PT, Carlson CS, Castellvi-Bel S, Chan AT, Chang-Claude J, Chanock SJ, Chirlaque M-D, Cho SH, Connolly CM, Cross AJ, Cuk K, Curtis KR, de la Chapelle A, Doheny KF, Duggan D, Easton DF, Elias SG, Elliott F, English DR, Feskens EJM, Figueiredo JC, Fischer R, FitzGerald LM, Forman D, Gala M, Gallinger S, Gauderman WJ, Giles GG, Gillanders E, Gong J, Goodman PJ, Grady WM, Grove JS, Gsur A, Gunter MJ, Haile RW, Hampe J, Hampel H, Harlid S, Hayes RB, Hofer P, Hoffmeister M, Hopper JL, Hsu W-L, Huang W-Y, Hudson TJ, Hunter DJ, Ibanez-Sanz G, Idos GE, Ingersoll R, Jackson RD, Jacobs EJ, Jenkins MA, Joshi AD, Joshu CE, Keku TO, Key TJ, Kim HR, Kobayashi E, Kolonel LN, Kooperberg C, Kuehn T, Kury S, Kweon S-S, Larsson SC, Laurie CA, Le Marchand L, Leal SM, Lee SC, Lejbkowicz F, Lemire M, Li CI, Li L, Lieb W, Lin Y, Lindblom A, Lindor NM, Ling H, Louie TL, Mannisto S, Markowitz SD, Martin V, Masala G, McNeil CE, Melas M, Milne RL, Moreno L, Murphy N, Myte R, Naccarati A, Newcomb PA, Offit K, Ogino S, Onland-Moret NC, Pardini B, Parfrey PS, Pearlman R, Perduca V, Pharoah PDP, Pinchev M, Platz EA, Prentice RL, Pugh E, Raskin L, Rennert G, Rennert HS, Riboli E, Rodriguez-Barranco M, Romm J, Sakoda LC, Schafmayer C, Schoen RE, Seminara D, Shah M, Shelford T, Shin M-H, Shulman K, Sieri S, Slattery ML, Southey MC, Stadler ZK, Stegmaier C, Su Y-R, Tangen CM, Thibodeau SN, Thomas DC, Thomas SS, Toland AE, Trichopoulou A, Ulrich CM, Van den Berg DJ, van Duijnhoven FJB, Van Guelpen B, van Kranen H, Vijai J, Visvanathan K, Vodicka P, Vodickova L, Vymetalkova V, Weigl Ket al., 2019, Discovery of common and rare genetic risk variants for colorectal cancer, Nature Genetics, Vol: 51, Pages: 76-87, ISSN: 1061-4036

To further dissect the genetic architecture of colorectal cancer (CRC), we performed whole-genome sequencing of 1,439 cases and 720 controls, imputed discovered sequence variants and Haplotype Reference Consortium panel variants into genome-wide association study data, and tested for association in 34,869 cases and 29,051 controls. Findings were followed up in an additional 23,262 cases and 38,296 controls. We discovered a strongly protective 0.3% frequency variant signal at CHD1. In a combined meta-analysis of 125,478 individuals, we identified 40 new independent signals at P < 5 × 10−8, bringing the number of known independent signals for CRC to ~100. New signals implicate lower-frequency variants, Krüppel-like factors, Hedgehog signaling, Hippo-YAP signaling, long noncoding RNAs and somatic drivers, and support a role for immune function. Heritability analyses suggest that CRC risk is highly polygenic, and larger, more comprehensive studies enabling rare variant analysis will improve understanding of biology underlying this risk and influence personalized screening strategies and drug development.

Journal article

Scelo G, Muller DC, Riboli E, Johansson M, Cross A, Vineis P, Tsilidis K, Brennan P, Boeing H, Peeters P, Vermeulen R, Overvad K, Bueno-de-Mesquita HB, Severi G, Perduca V, Kvaskoff M, Trichopoulou A, La Vecchia C, Karakatsani A, Palli D, Sieri S, Panico S, Weiderpass E, Sandanger T, Nost T, Agudo A, Quiros JR, Rodriguez-Barranco M, Chirlaque M-D, Key T, Khanna P, Bonventre J, Sabbisetti V, Bhatt Ret al., 2018, KIM-1 as a blood-based marker for early detection of kidney cancer: a prospective nested case-control study, Clinical Cancer Research, Vol: 24, ISSN: 1078-0432

Purpose: Renal cell carcinoma (RCC) has the potential for cure with surgery when diagnosed at an early stage. Kidney injury molecule-1 (KIM-1) has been shown to be elevated in the plasma of RCC patients. We aimed to test whether plasma KIM-1 could represent a means of detecting RCC prior to clinical diagnosis. Experimental Design: KIM-1 concentrations were measured in pre-diagnostic plasma from 190 RCC cases and 190 controls nested within a population-based prospective cohort study. Cases had entered the cohort up to five years before diagnosis, and controls were matched on cases for date of birth, date at blood donation, sex, and country. We applied conditional logistic regression and flexible parametric survival models to evaluate the association between plasma KIM-1 concentrations and RCC risk and survival. Results: The incidence rate ratio (IRR) of RCC for a doubling in KIM-1 concentration was 1.71 (95% confidence interval [CI]: 1.44-2.03, p-value = 4.1x10-23), corresponding to an IRR of 63.3 (95% CI: 16.2-246.9) comparing the 80th to the 20th percentile of the KIM-1 distribution in this sample. Compared with a risk model including known risk factors of RCC (age, sex, country, body mass index and tobacco smoking status), a risk model additionally including KIM-1 substantially improved discrimination between cases and controls (area under the receiver operating characteristic curve of 0.8 compared to 0.7). High plasma KIM-1 concentrations were also associated with poorer survival (p=0.0053). Conclusions: Plasma KIM-1 concentrations could predict RCC incidence up to 5 years prior to diagnosis and were associated with poorer survival.

Journal article

Zamora-Ros R, Cayssials V, Jenab M, Rothwell JA, Fedirko V, Aleksandrova K, Tjønneland A, Kyrø C, Overvad K, Boutron-Ruault M-C, Carbonnel F, Mahamat-Saleh Y, Kaaks R, Kühn T, Boeing H, Trichopoulou A, Valanou E, Vasilopoulou E, Masala G, Pala V, Panico S, Tumino R, Ricceri F, Weiderpass E, Lukic M, Sandanger TM, Lasheras C, Agudo A, Sánchez M-J, Amiano P, Navarro C, Ardanaz E, Sonestedt E, Ohlsson B, Nilsson LM, Rutegård M, Bueno-de-Mesquita B, Peeters PH, Khaw K-T, Wareham NJ, Bradbury K, Freisling H, Romieu I, Cross AJ, Vineis P, Scalbert Aet al., 2018, Dietary intake of total polyphenol and polyphenol classes and the risk of colorectal cancer in the European Prospective Investigation into Cancer and Nutrition (EPIC) cohort, European Journal of Epidemiology, Vol: 33, Pages: 1063-1075, ISSN: 0393-2990

Polyphenols may play a chemopreventive role in colorectal cancer (CRC); however, epidemiological evidence supporting a role for intake of individual polyphenol classes, other than flavonoids is insufficient. We evaluated the association between dietary intakes of total and individual classes and subclasses of polyphenols and CRC risk and its main subsites, colon and rectum, within the European Prospective Investigation into Cancer and Nutrition (EPIC) study. The cohort included 476,160 men and women from 10 European countries. During a mean follow-up of 14 years, there were 5991 incident CRC cases, of which 3897 were in the colon and 2094 were in the rectum. Polyphenol intake was estimated using validated centre/country specific dietary questionnaires and the Phenol-Explorer database. In multivariable-adjusted Cox regression models, a doubling in total dietary polyphenol intake was not associated with CRC risk in women (HRlog2 = 1.06, 95% CI 0.99-1.14) or in men (HRlog2 = 0.97, 95% CI 0.90-1.05), respectively. Phenolic acid intake, highly correlated with coffee consumption, was inversely associated with colon cancer in men (HRlog2 = 0.91, 95% CI 0.85-0.97) and positively associated with rectal cancer in women (HRlog2 = 1.10, 95% CI 1.02-1.19); although associations did not exceed the Bonferroni threshold for significance. Intake of other polyphenol classes was not related to colorectal, colon or rectal cancer risks. Our study suggests a possible inverse association between phenolic acid intake and colon cancer risk in men and positive with rectal cancer risk in women.

Journal article

Murphy N, Achaintre D, Zamora-Ros R, Jenab M, Boutron-Ruault M-C, Carbonnel F, Savoye I, Kaaks R, Kühn T, Boeing H, Aleksandrova K, Tjønneland A, Kyrø C, Overvad K, Quirós JR, Sánchez M-J, Altzibar JM, María Huerta J, Barricarte A, Khaw K-T, Bradbury KE, Perez-Cornago A, Trichopoulou A, Karakatsani A, Peppa E, Palli D, Grioni S, Tumino R, Sacerdote C, Panico S, Bueno-de-Mesquita B, Peeters PH, Rutegård M, Johansson I, Freisling H, Noh H, Cross AJ, Vineis P, Tsilidis K, Gunter MJ, Scalbert Aet al., 2018, A prospective evaluation of plasma polyphenol levels and colon cancer risk, International Journal of Cancer, Vol: 143, Pages: 1620-1631, ISSN: 0020-7136

Polyphenols have been shown to exert biological activity in experimental models of colon cancer; however, human data linking specific polyphenols to colon cancer is limited. We assessed the relationship between pre-diagnostic plasma polyphenols and colon cancer risk in a case-control study nested within the European Prospective Investigation into Cancer and Nutrition study. Using high pressure liquid chromatography coupled to tandem mass spectrometry, we measured concentrations of 35 polyphenols in plasma from 809 incident colon cancer cases and 809 matched controls. We used multivariable adjusted conditional logistic regression models that included established colon cancer risk factors. The false discovery rate (qvalues ) was computed to control for multiple comparisons. All statistical tests were two-sided. After false discovery rate correction and in continuous log2 -transformed multivariable models, equol (odds ratio [OR] per log2 -value, 0.86, 95% confidence interval [95%CI]=0.79-0.93; qvalue =0.01) and homovanillic acid (OR per log2 -value, 1.46, 95%CI=1.16-1.84; qvalue =0.02) were associated with colon cancer risk. Comparing extreme fifths, equol concentrations were inversely associated with colon cancer risk (OR=0.61, 95%CI=0.41-0.91, ptrend =0.003), while homovanillic acid concentrations were positively associated with colon cancer development (OR=1.72, 95%CI=1.17-2.53, ptrend <0.0001). No heterogeneity for these associations was observed by sex and across other colon cancer risk factors. The remaining polyphenols were not associated with colon cancer risk. Higher equol concentrations were associated with lower risk, and higher homovanillic acid concentrations were associated with greater risk, of colon cancer. These findings support a potential role for specific polyphenols in colon tumorigenesis. This article is protected by copyright. All rights reserved.

Journal article

Freisling H, Noh H, Slimani N, Chajès V, May AM, Peeters PH, Weiderpass E, Cross AJ, Skeie G, Jenab M, Mancini FR, Boutron-Ruault M-C, Fagherazzi G, Katzke VA, Kühn T, Steffen A, Boeing H, Tjønneland A, Kyrø C, Hansen CP, Overvad K, Duell EJ, Redondo-Sánchez D, Amiano P, Navarro C, Barricarte A, Perez-Cornago A, Tsilidis KK, Aune D, Ward H, Trichopoulou A, Naska A, Orfanos P, Masala G, Agnoli C, Berrino F, Tumino R, Sacerdote C, Mattiello A, Bueno-de-Mesquita HB, Ericson U, Sonestedt E, Winkvist A, Braaten T, Romieu I, Sabaté Jet al., 2018, Nut intake and 5-year changes in body weight and obesity risk in adults: results from the EPIC-PANACEA study, European Journal of Nutrition, Vol: 57, Pages: 2399-2408, ISSN: 0044-264X

PURPOSE: There is inconsistent evidence regarding the relationship between higher intake of nuts, being an energy-dense food, and weight gain. We investigated the relationship between nut intake and changes in weight over 5 years. METHODS: This study includes 373,293 men and women, 25-70 years old, recruited between 1992 and 2000 from 10 European countries in the European Prospective Investigation into Cancer and Nutrition (EPIC) study. Habitual intake of nuts including peanuts, together defined as nut intake, was estimated from country-specific validated dietary questionnaires. Body weight was measured at recruitment and self-reported 5 years later. The association between nut intake and body weight change was estimated using multilevel mixed linear regression models with center/country as random effect and nut intake and relevant confounders as fixed effects. The relative risk (RR) of becoming overweight or obese after 5 years was investigated using multivariate Poisson regressions stratified according to baseline body mass index (BMI). RESULTS: On average, study participants gained 2.1 kg (SD 5.0 kg) over 5 years. Compared to non-consumers, subjects in the highest quartile of nut intake had less weight gain over 5 years (-0.07 kg; 95% CI -0.12 to -0.02) (P trend = 0.025) and had 5% lower risk of becoming overweight (RR 0.95; 95% CI 0.92-0.98) or obese (RR 0.95; 95% CI 0.90-0.99) (both P trend <0.008). CONCLUSIONS: Higher intake of nuts is associated with reduced weight gain and a lower risk of becoming overweight or obese.

Journal article

Pinsky PF, Loberg M, Senore C, Wooldrage K, Atkin W, Bretthauer M, Cross AJ, Hoff G, Holme O, Kalager M, Segnan N, Schoen REet al., 2018, Number of adenomas removed and colorectal cancers prevented in randomized trials of flexible sigmoidoscopy screening, Gastroenterology, Vol: 155, Pages: 1059-1068.e2, ISSN: 0016-5085

Background & AimsScreening for colorectal cancer (CRC) with sigmoidoscopy reduces CRC incidence by detecting and removing adenomas. The number needed to screen is a measure of screening efficiency, but is not directly associated with adenoma removal. We propose 2 new metrics for quantifying the relationship between adenoma removal and CRC prevented: number of adenomas needed to remove (NNR) and adenoma dwell time avoided (DTA).MethodsWe collected data from 4 randomized trials of sigmoidoscopy screening (in the United States and 3 in Europe) to assess NNR and DTA. For each trial, NNR was computed as the number of adenomas removed from subjects in the intervention group divided by the number of CRCs prevented. DTA was computed similarly but taking into account the timing of adenoma removal. Combined results across trials were assessed using standard meta-analytic techniques.ResultsThe estimated NNR for the PLCO trial was 74 (95% CI, 56–110), for the NORCCAP trial was 71 (95% CI, 44–174), for the SCORE trial was 27 (95% CI, 14–135), and for the UKFSST trial was 36 (95% CI, 28–52). The combined estimate (meta-analysis) of NNR was 52 (95% CI, 36–93) assuming heterogeneity (P for heterogeneity=.014). DTA estimates among trials ranged from 278 to 730 years, with a combined estimate of 500 years (95% CI, 344–833 years) assuming heterogeneity (P for heterogeneity=.035), or 2 CRC cases prevented per 1000 adenoma dwell years avoided. The combined estimates of NNR and DTA restricted to advanced adenomas were 13 (95% CI, 9–22) and 122 years (95% CI, 90–190), respectively.ConclusionsWe collected data from 4 randomized trials of sigmoidoscopy screening for CRC to develop metrics endoscopic efficiency, NNR and DTA, that are directly linked to adenoma detection and removal. They can be used to compare screening among endoscopic modalities and to more precisely measure adenoma to carcinoma transition rates.

Journal article

Murphy G, Cross AJ, Dawsey SM, Stanczyk FZ, Kamangar F, Weinstein SJ, Taylor PR, Männistö S, Albanes D, Abnet CC, Freedman NDet al., 2018, Serum ghrelin is associated with risk of colorectal adenocarcinomas in the ATBC study, Gut, Vol: 67, Pages: 1646-1641, ISSN: 0017-5749

BACKGROUND: Colorectal cancers are the third most common cancers in women and men in the USA. While dietary and lifestyle factors such as Western diet, physical inactivity and obesity have been linked to an increased risk of this malignancy, the mechanisms for these associations are unclear. GI hormones, including ghrelin, are involved in energy balance by mediating appetite and metabolism; however, the association between ghrelin and colorectal cancer has not been studied. METHODS: We conducted a case-control study nested within the all-male Alpha-Tocopherol, Beta-Carotene Cancer Prevention Study of Finnish smokers (aged 50-69 years) to examine serum ghrelin concentration and colorectal cancer risk. Data from 284 colon and 239 rectal cancers and 523 controls (matched on age, date of blood draw and serum availability) were analysed. ORs and 95% CIs were calculated using multivariable (conditional) logistic regression. RESULTS: Overall, low-serum ghrelin was significantly associated with increased risk of colorectal cancer (Q1 vs Q4: OR:1.57, 95% CI 1.05 to 2.34). For individuals developing tumours within 10 years of blood draw, those in the lowest quartile of serum ghrelin concentrations were statistically significantly more likely to develop colorectal cancers than those with higher serum ghrelin concentrations (OR: 10.86, 95% CI 5.01 to 23.55). However, for individuals with tumours developing more than 20 years after blood draw, low-serum ghrelin concentrations were associated with a decreased risk of colorectal cancer relative to those with the highest serum ghrelin concentrations (OR: 0.26, 95% CI 0.11 to 0.64). CONCLUSION: Low-serum ghrelin was associated with an increased colorectal cancer risk within 10 years of blood draw with a decreased risk for developing colorectal cancer more than 20 years after blood draw. These results suggest that ghrelin concentrations may vary across the carcinogenic process.

Journal article

Lin C, Travis RC, Appleby PN, Tipper S, Weiderpass E, Chang-Claude J, Gram IT, Kaaks R, Kiemeney LA, Ljungberg B, Tumino R, Tjønneland A, Roswall N, Overvad K, Boutron-Ruault M-C, Manciniveri FR, Severi G, Trichopoulou A, Masala G, Sacerdote C, Agnoli C, Panico S, Bueno-de-Mesquita B, Peeters PH, Salamanca-Fernández E, Chirlaque M-D, Ardanaz E, Dorronsoro M, Menéndez V, Luján-Barroso L, Liedberg F, Freisling H, Gunter M, Aune D, Cross AJ, Riboli E, Key TJ, Perez-Cornago Aet al., 2018, Pre-diagnostic circulating insulin-like growth factor-I and bladder cancer risk in the European prospective investigation into cancer and nutrition, International Journal of Cancer, Vol: 143, Pages: 2351-2358, ISSN: 0020-7136

Previous in vitro and case-control studies have found an association between the insulin-like growth factor (IGF)-axis and bladder cancer risk. Circulating concentrations of IGF-I have also been found to be associated with an increased risk of several cancer types; however, the relationship between pre-diagnostic circulating IGF-I concentrations and bladder cancer has never been studied prospectively. We investigated the association of pre-diagnostic plasma concentrations of IGF-I with risk of overall bladder cancer and urothelial cell carcinoma (UCC) in a case-control study nested within the European Prospective Investigation into Cancer and Nutrition (EPIC) cohort. A total of 843 men and women diagnosed with bladder cancer between 1992 and 2005 were matched with 843 controls by recruitment centre, sex, age at recruitment, date of blood collection, duration of follow-up, time of day and fasting status at blood collection using an incidence density sampling protocol. Odds ratios (ORs) and 95% confidence intervals (CIs) were calculated using conditional logistic regression with adjustment for smoking status. No association was found between pre-diagnostic circulating IGF-I concentration and overall bladder cancer risk (adjusted OR for highest versus lowest fourth: 0.91, 95% CI: 0.66-1.24, Ptrend =0.40) or UCC (n of cases=776; 0.91, 0.65-1.26, Ptrend =0.40). There was no significant evidence of heterogeneity in the association of IGF-I with bladder cancer risk by tumour aggressiveness, sex, smoking status, or by time between blood collection and diagnosis (Pheterogeneity >0.05 for all). This first prospective study indicates no evidence of an association between plasma IGF-I concentrations and bladder cancer risk. This article is protected by copyright. All rights reserved.

Journal article

Ward HA, Gayle A, Jakszyn P, Merritt M, Melin B, Freisling H, Weiderpass E, Tjonneland A, Olsen A, Dahm CC, Overvad K, Katzke V, Kühn T, Boeing H, Trichopoulou A, Lagiou P, Kyrozis A, Palli D, Krogh V, Tumino R, Ricceri F, Mattiello A, Bueno-de-Mesquita B, Peeters PH, Quirós JR, Agudo A, Rodriguez-Barranco M, Larrañaga N, Huerta JM, Barricarte A, Sonestedt E, Drake I, Sandström M, Travis RC, Ferrari P, Riboli E, Cross AJet al., 2018, Meat and haem iron intake in relation to glioma in the European Prospective Investigation into Cancer and Nutrition study, European Journal of Cancer Prevention, Vol: 27, Pages: 379-383, ISSN: 1473-5709

Diets high in red or processed meat have been associated positively with some cancers, and several possible underlying mechanisms have been proposed, including iron-related pathways. However, the role of meat intake in adult glioma risk has yielded conflicting findings because of small sample sizes and heterogeneous tumour classifications. The aim of this study was to examine red meat, processed meat and iron intake in relation to glioma risk in the European Prospective Investigation into Cancer and Nutrition study. In this prospective cohort study, 408 751 individuals from nine European countries completed demographic and dietary questionnaires at recruitment. Multivariable Cox proportional hazards models were used to examine intake of red meat, processed meat, total dietary iron and haem iron in relation to incident glioma. During an average follow-up of 14.1 years, 688 incident glioma cases were diagnosed. There was no evidence that any of the meat variables (red, processed meat or subtypes of meat) or iron (total or haem) were associated with glioma; results were unchanged when the first 2 years of follow-up were excluded. This study suggests that there is no association between meat or iron intake and adult glioma. This is the largest prospective analysis of meat and iron in relation to glioma and as such provides a substantial contribution to a limited and inconsistent literature.

Journal article

Jacobs ET, Gupta S, Baron JA, Cross AJ, Lieberman DA, Murphy G, Martinez MEet al., 2018, Family history of colorectal cancer in first-degree relatives and metachronous colorectal adenoma, American Journal of Gastroenterology, Vol: 113, Pages: 899-905, ISSN: 1572-0241

OBJECTIVESLittle is known about the relationship between having a first-degree relative (FDR) with colorectal cancer (CRC) and risk for metachronous colorectal adenoma (CRA) following polypectomy.METHODSWe pooled data from seven prospective studies of 7697 patients with previously resected CRAs to quantify the relationship between having a FDR with CRC and risk for metachronous adenoma.RESULTSCompared with having no family history of CRC, a positive family history in any FDR was significantly associated with increased odds of developing any metachronous CRA (OR = 1.14; 95% CI = 1.01–1.29). Higher odds of CRA were observed among individuals with an affected mother (OR = 1.27; 95% CI = 1.05–1.53) or sibling (OR = 1.34; 95% CI = 1.11–1.62) as compared with those without, whereas no association was shown for individuals with an affected father. Odds of having a metachronous CRA increased with number of affected FDRs, with ORs (95% CIs) of 1.07 (0.93–1.23) for one relative and 1.39 (1.02–1.91) for two or more. Younger age of diagnosis of a sibling was associated with higher odds of metachronous CRA, with ORs (95% CIs) of 1.66 (1.08–2.56) for diagnosis at <54 years; 1.34 (0.89–2.03) for 55–64 years; and 1.10 (0.70–1.72) for >65 years (p-trend = 0.008). Although limited by sample size, results for advanced metachronous CRA were similar to those for any metachronous CRA.CONCLUSIONSA family history of CRC is related to a modestly increased odds of metachronous CRA. Future research should explore whether having a FDR with CRC, particularly at a young age, should have a role in risk stratification for surveillance colonoscopy.

Journal article

Morris JS, Bradbury KE, Cross AJ, Gunter MJ, Murphy Net al., 2018, Physical activity, sedentary behaviour and colorectal cancer risk in the UK Biobank, British Journal of Cancer, Vol: 118, Pages: 920-929, ISSN: 0007-0920

BACKGROUND: Observational studies have shown that physical activity levels are inversely, and sedentary behaviours are positively, associated with colorectal cancer risk; however, whether these relationships are consistent across anatomical subsites is uncertain. METHODS: We investigated the associations between colorectal cancer and physical activity (metabolic equivalents (METs)-hours per week), and indicators of sedentary behaviour (television watching time and time spent using computers) among 430 584 men and women enroled in the UK Biobank. Multivariable hazard ratios (HRs) and 95% confidence intervals (CI) were estimated using Cox proportional hazards models. RESULTS: After a median follow-up time of 5.6 years, 2391 incident colorectal cancer cases were recorded. High (⩾60-MET-hours per week) vs low (<10-MET-hours per week) total physical activity was associated with a lower colon cancer risk (HR=0.84, 95% CI: 0.72-0.98; p-trend=0.04), with comparable relationships observed for proximal and distal colon tumours, but no association for rectal cancer. Higher levels of television watching time were associated with greater colon cancer risk (HR for ⩾5 h per day vs ⩽1 h per day=1.32, 95% CI: 1.04-1.68; p-trend=0.007). Time spent using computers was not associated with colorectal cancer risk. CONCLUSIONS: Higher levels of physical activity were associated with lower colon cancer risk, with no heterogeneity by colonic subsite. Sedentary behaviour (television watching) was associated with elevated colon cancer risk.British Journal of Cancer advance online publication, 8 March 2018; doi:10.1038/bjc.2017.496 www.bjcancer.com.

Journal article

Brown JP, Wooldrage K, Wright S, Nickerson C, Cross AJ, Atkin WSet al., 2018, High test positivity and low positive predictive value for colorectal cancer of continued faecal occult blood test screening after negative colonoscopy, Journal of Medical Screening, Vol: 25, Pages: 70-75, ISSN: 1475-5793

ObjectivesThe English Bowel Cancer Screening Programme (BCSP) offers biennial screening with a guaiac faecal occult blood test (gFOBT) to 60-74 year olds. Participants with a positive gFOBT are referred for follow-up, but many do not have significant findings. These individuals are reinvited for gFOBT screening provided they remain in the eligible age range. We evaluated the performance of repeat screening in this group. MethodsWe analysed data on BCSP participants reinvited to gFOBT screening, either after previous negative gFOBT (n=327,542), or after a positive gFOBT followed by a diagnostic investigation negative for colorectal cancer (CRC) or adenomas requiring surveillance (n=42,280). Outcomes calculated were uptake, test positivity, yield of CRC, and positive predictive value (PPV) of gFOBT for CRC. ResultsAfter a positive gFOBT and a negative diagnostic investigation, gFOBT uptake in the repeat screening round was 82.6%, positivity was 11.3%, CRC yield was 0.172% of participants adequately screened, and the PPV of gFOBT for CRC was 1.7%. For participants with a previous negative gFOBT, in the subsequent screening round uptake was 87.5%, positivity was 1.3%, yield of CRC was 0.112% of those adequately screened, and the PPV of gFOBT for CRC was 9.1%.Conclusion With high positivity and low PPV for CRC, the suitability of routine repeat gFOBT screening in two years among individuals with a previous positive test and a negative diagnostic exam needs to be carefully considered.

Journal article

Robbins E, Wooldrage K, MacRae E, Stenson I, Patel B, Pack K, Piggott C, Pearson S, Snowball J, Duffy S, Halloran S, Atkin W, Cross Aet al., 2018, OTU-029 Faecal immunochemical tests (FIT) for surveillance after screening and polypectomy: an accuracy and efficiency study, British Society of Gastroenterology Annual Conference, Publisher: BMJ Publishing Group, Pages: A222-A222, ISSN: 0017-5749

Conference paper

Lennon H, Kelly S, Sperrin M, Buchan I, Cross AJ, Leitzmann M, Cook MB, Renehan AGet al., 2018, Framework to construct and interpret latent class trajectory modelling, BMJ Open, Vol: 8, ISSN: 2044-6055

OBJECTIVES: Latent class trajectory modelling (LCTM) is a relatively new methodology in epidemiology to describe life-course exposures, which simplifies heterogeneous populations into homogeneous patterns or classes. However, for a given dataset, it is possible to derive scores of different models based on number of classes, model structure and trajectory property. Here, we rationalise a systematic framework to derive a 'core' favoured model. METHODS: We developed an eight-step framework: step 1: a scoping model; step 2: refining the number of classes; step 3: refining model structure (from fixed-effects through to a flexible random-effect specification); step 4: model adequacy assessment; step 5: graphical presentations; step 6: use of additional discrimination tools ('degree of separation'; Elsensohn's envelope of residual plots); step 7: clinical characterisation and plausibility; and step 8: sensitivity analysis. We illustrated these steps using data from the NIH-AARP cohort of repeated determinations of body mass index (BMI) at baseline (mean age: 62.5 years), and BMI derived by weight recall at ages 18, 35 and 50 years. RESULTS: From 288 993 participants, we derived a five-class model for each gender (men: 177 455; women: 111 538). From seven model structures, the favoured model was a proportional random quadratic structure (model F). Favourable properties were also noted for the unrestricted random quadratic structure (model G). However, class proportions varied considerably by model structure-concordance between models F and G were moderate (Cohen κ: men, 0.57; women, 0.65) but poor with other models. Model adequacy assessments, evaluations using discrimination tools, clinical plausibility and sensitivity analyses supported our model selection. CONCLUSION: We propose a framework to construct and select a 'core' LCTM, which will facilitate generalisability of results in future studies.

Journal article

Smith T, Muller D, Moons K, Cross A, Johansson M, Ferrari P, Fagherazzi G, Peeters P, Severi G, Husing A, Kaaks R, Tjonneland A, Olsen A, Overvad K, Bonet C, Rodriguez-Barranco M, Huerta JM, Barricarte Gurrea A, Bradbury K, Trichopoulou A, Bamia C, Orfanos P, Palli D, Pala V, Vineis P, Bueno-de-Mesquita B, Ohlsson B, Harlid S, Van Guelpen B, Skeie G, Weiderpass E, Jenab M, Murphy N, Riboli E, Gunter M, Aleksandrova K, Tzoulaki Iet al., Comparison of prognostic models to predict the occurrence of colorectal cancer in asymptomatic individuals: A systematic literature review and external validation in the EPIC and UK Biobank prospective cohort studies, Gut, ISSN: 0017-5749

ObjectiveTo systematically identify and validate published colorectal cancer risk prediction models that do not require invasive testing in two large population-based prospective cohorts.DesignModels were identified through an update of a published systematic review and validated in the European Prospective Investigation into Cancer and Nutrition (EPIC) and the UK Biobank. The performance of the models to predict the occurrence of colorectal cancer within 5 or 10 years after study enrolment was assessed by discrimination (C-statistic) and calibration (plots of observed versus predicted probability).ResultsThe systematic review and its update identified 16 models from 8 publications (8 colorectal, 5 colon and 3 rectal). The number of participants included in each model validation ranged from 41,587 to 396,515, and the number of cases from 115 to 1,781. Eligible and ineligible participants across the models were largely comparable. Calibration of the models, where assessable, was very good and further improved by recalibration. The C-statistics of the models were largely similar between validation cohorts with the highest values achieved being 0.70 (95%CI 0.68-0.72) in the UK Biobank and 0.71 (0.67-0.74) in EPIC. ConclusionSeveral of these non-invasive models exhibited good calibration and discrimination within both external validation populations and are therefore potentially suitable candidates for the facilitation of risk stratification in population-based colorectal screening programmes. Future work should both evaluate this potential, through modelling and impact studies, and ascertain if further enhancement in their performance can be obtained.

Journal article

Agudo A, Cayssials V, Bonet C, Tjonneland 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, Nost TH, Lasheras C, Rodriguez-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., 2018, Inflammatory potential of the diet and risk of gastric cancer in the European Prospective Investigation into Cancer and Nutrition (EPIC) study, AMERICAN JOURNAL OF CLINICAL NUTRITION, Vol: 107, Pages: 607-616, ISSN: 0002-9165

BackgroundChronic inflammation plays a critical role in the pathogenesis of the 2 major types of gastric cancer. Several foods, nutrients, and nonnutrient food components seem to be involved in the regulation of chronic inflammation.ObjectiveWe assessed the association between the inflammatory potential of the diet and the risk of gastric carcinoma, overall and for the 2 major subsites: cardia cancers and noncardia cancers.DesignA total of 476,160 subjects (30% men, 70% women) from the European Investigation into Cancer and Nutrition (EPIC) study were followed for 14 y, during which 913 incident cases of gastric carcinoma were identified, including 236 located in the cardia, 341 in the distal part of the stomach (noncardia), and 336 with overlapping or unknown tumor site. The dietary inflammatory potential was assessed by means of an inflammatory score of the diet (ISD), calculated with the use of 28 dietary components and their corresponding inflammatory scores. The association between the ISD and gastric cancer risk was estimated by HRs and 95% CIs calculated by multivariate Cox regression models adjusted for confounders.ResultsThe inflammatory potential of the diet was associated with an increased risk of gastric cancer. The HR (95% CI) for each increase in 1 SD of the ISD were 1.25 (1.12, 1.39) for all gastric cancers, 1.30 (1.06, 1.59) for cardia cancers, and 1.07 (0.89, 1.28) for noncardia cancers. The corresponding values for the highest compared with the lowest quartiles of the ISD were 1.66 (1.26, 2.20), 1.94 (1.14, 3.30), and 1.07 (0.70, 1.70), respectively.ConclusionsOur results suggest that low-grade chronic inflammation induced by the diet may be associated with gastric cancer risk. This pattern seems to be more consistent for gastric carcinomas located in the cardia than for those located in the distal stomach.

Journal article

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