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

 

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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240 results found

Cross A, Robbins E, Saunders B, Duffy SW, Wooldrage Ket al., 2020, Higher adenoma detection rates at screening associated with lower long-term colorectal cancer incidence and mortality, Clinical Gastroenterology and Hepatology, ISSN: 1542-3565

Journal article

Bueno-de-Mesquita B, Cross A, Aune D, Tsilidis Ket al., 2020, Circulating bilirubin levels and risk of colorectal cancer: serological and Mendelian randomization analyses, BMC Medicine, Vol: 18, Pages: 1-15, ISSN: 1741-7015

BACKGROUND: Bilirubin, a byproduct of hemoglobin breakdown and purported antioxidant, is thought to be cancer preventive. We conducted complementary serological and Mendelian randomization (MR) analyses to investigate whether alterations in circulating levels of bilirubin are associated with risk of colorectal cancer (CRC). We decided a priori to perform analyses separately in men and women based on suggestive evidence that associations may differ by sex.METHODS: In a case-control study nested in the European Prospective Investigation into Cancer and Nutrition (EPIC), pre-diagnostic unconjugated bilirubin (UCB, main component of total bilirubin) concentrations were measured by high-performance liquid chromatography in plasma samples of 1386 CRC cases and their individually matched controls. Additionally, 115 single-nucleotide polymorphisms (SNPs) robustly associated (P < 5x10-8) with circulating total bilirubin were instrumented in a 2-sample MR to test for a potential causal effect of bilirubin on CRC risk in 52,775 CRC cases and 45,940 matched controls in the Genetics and Epidemiology of Colorectal Cancer Consortium (GECCO), the Colon Cancer Family Registry (CCFR), and the Colorectal Transdisciplinary (CORECT) study.RESULTS: The associations between circulating UCB levels and CRC risk differed by sex (Pheterogeneity=0.008). Among men, higher levels of UCB were positively associated with CRC risk (odds ratio [OR] = 1.19, 95% confidence interval [CI] = 1.04-1.36; per 1-SD increment of log-UCB). In women, an inverse association was observed (OR = 0.86 (0.76-0.97)). In the MR analysis of the main UGT1A1 SNP (rs6431625), genetically predicted higher levels of total bilirubin, were associated with a 7% increase in CRC risk in men (OR = 1.07 (1.02-1.12); P=0.006; per 1-SD increment of total bilirubin), while there was no association in women (OR = 1.01 (0.96-1.06); P=0.73). Raised bilirubin levels, predicted by instrumental variables excluding rs6431625, were

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, 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

Jakszyn P, Cayssials V, Buckland G, Perez-Cornago A, Weiderpass E, Boeing H, Bergmann MM, Vulcan A, Ohlsson B, Masala G, Cross AJ, Riboli E, Ricceri F, Dahm C, Nyvang D, Katzke VA, Kühns T, Kyrø C, Tjønneland A, Ward HA, Tsilidis KK, Skeie G, Sieri S, Sanchez MJ, Huerta JM, Amiano P, Lasheras C, Ardanaz E, Mahamat-Saleh Y, Boutron-Ruault MC, Carbonnel F, Panico S, Peppa E, Trichopoulou A, Karakatsani A, Tumino R, Vermeulen R, Jenab M, Gunter M, Agudo Aet al., 2020, Inflammatory potential of the diet and risk of colorectal cancer in the European Prospective Investigation into Cancer and Nutrition (EPIC) study, International Journal of Cancer, Vol: 147, Pages: 1027-1039, ISSN: 0020-7136

Pro-inflammatory diets are associated with risk of developing colorectal cancer (CRC), however inconsistencies exist in subsite- and sex-specific associations. The relationship between CRC and combined lifestyle-related factors that contribute towards a low-grade inflammatory profile has not yet been explored. We examined the association between the dietary inflammatory potential and an inflammatory profile and CRC risk in the European Prospective Investigation into Cancer and Nutrition (EPIC) study. This cohort included 476,160 participants followed-up of 14 years and 5,991 incident CRC cases (3,897 colon and 2,094 rectal tumours). Dietary inflammatory potential was estimated using an Inflammatory Score of the Diet (ISD). An Inflammatory Profile Score (IPS) was constructed, incorporating the ISD, physical activity level and abdominal obesity. The associations between the ISD and CRC and IPS and CRC were assessed using multivariable regression models. More pro- inflammatory diets were related to a higher CRC risk, particularly for colon cancer; Hazar Ratio (HR) for highest versus lowest ISD quartile was 1.15 (95% confidence interval (CI) 1.04-1.27) for CRC, 1.24 (95% CI 1.09-1.41) for colon cancer and 0.99 (95% CI 0.83-1.17) for rectal cancer. Associations were more pronounced in men and not significant in women. The IPS was associated with CRC risk, particularly colon cancer among men; HRs for the highest versus lowest IPS were 1.62 (95% CI 1.31- 2.01) for colon cancer overall and 2.11 (95% CI 1.50-2.97) for colon cancer in men. This study shows that more pro-inflammatory diets and a more inflammatory profile are associated with higher risk of CRC, principally colon cancer and in men. This article is protected by copyright. All rights reserved.

Journal article

Robbins EC, Cross AJ, 2020, Guaiac Fecal Occult Blood Tests and Mortality: A 30-Year Follow-Up of Two Pooled Trials., Clin Gastroenterol Hepatol

Journal article

Cross A, Robbins E, Pack K, Stenson I, Kirby P, Patel B, Rutter MD, Veitch AM, Saunders B, Duffy SW, Wooldrage Ket al., 2020, Long-term colorectal cancer incidence after adenoma removal and the effects of surveillance on incidence: a multicentre, retrospective, cohort study, Gut, Vol: 69, Pages: 1645-1658, ISSN: 0017-5749

Objective Post-polypectomy colonoscopy surveillance aims to prevent colorectal cancer (CRC). The 2002 UK surveillance guidelines define low-, intermediate-, and high-risk groups, recommending different strategies for each. Evidence supporting the guidelines is limited. We examined CRC incidence and effects of surveillance on incidence among each risk group. Design Retrospective study of 33,011 patients who underwent colonoscopy with adenoma removal at 17 UK hospitals, mostly (87%) from 2000–2010. Patients were followed-up through 2016. Cox regression with time-varying covariates was used to estimate effects of surveillance on CRC incidence adjusted for patient, procedural, and polyp characteristics. Standardised incidence ratios (SIRs) compared incidence with that in the general population. Results After exclusions, 28,972 patients were available for analysis; 14,401 (50%) were classed as low-risk, 11,852 (41%) as intermediate-risk, and 2719 (9%) as high-risk. Median follow-up was 9.3 13years. In the low-, intermediate-, and high-risk groups, CRC incidence per 100,000 person-years was 14140 (95%CI 122–162), 221 (195–251), and 366 (295–453), respectively. CRC incidence was 40–50% lower with a single surveillance visit than with none: hazard ratios were 0.56 (0.39–0.80), 0.59 (0.43–0.81), and 0.49 (0.29–0.82) in the low-, intermediate-, and high-risk groups, respectively. Compared with the general population, CRC incidence without surveillance was similar among low-risk (SIR 0.86, 0.73–1.02) and intermediate-risk (1.16, 0.97–1.37) patients, but higher among high-risk patients (1.91, 1.39–2.56).20Conclusion Post-polypectomy surveillance reduces CRC risk. However, even without surveillance, CRC risk in some low-risk and intermediate-risk patients is no higher than in the general population. These patients could be managed by screening rather than surveillance.

Journal article

Lujan-Barroso L, Botteri E, Caini S, Ljungberg B, Roswall N, Tjønneland A, Bueno-de-Mesquita B, Gram IT, Tumino R, Kiemeney LA, Liedberg F, Stocks T, Gunter MJ, Murphy N, Cervenka I, Fournier A, Kvaskoff M, Häggström C, Overvad K, Lund E, Waaseth M, Fortner RT, Kühn T, Menéndez V, Sánchez M-J, Santiuste C, Perez-Cornago A, Zamora-Ros R, Cross AJ, Trichopoulou A, Karakatsani A, Peppa E, Palli D, Krogh V, Sciannameo V, Mattiello A, Panico S, van Gils CH, Onland-Moret NC, Barricarte A, Amiano P, Khaw K-T, Boeing H, Weiderpass E, Duell EJet al., 2020, Menstrual factors, reproductive history, hormone use, and urothelial carcinoma risk: a prospective study in the EPIC cohort, Cancer Epidemiology, Biomarkers and Prevention, Vol: 29, Pages: 1654-1664, ISSN: 1055-9965

BACKGROUND: Urothelial carcinoma is the predominant (95%) bladder cancer subtype in industrialized nations. Animal and epidemiologic human studies suggest that hormonal factors may influence urothelial carcinoma risk. METHODS: We used an analytic cohort of 333,919 women from the European Prospective Investigation into Cancer and Nutrition Cohort. Associations between hormonal factors and incident urothelial carcinoma (overall and by tumor grade, tumor aggressiveness, and non-muscle-invasive urothelial carcinoma) risk were evaluated using Cox proportional hazards models. RESULTS: During a mean of 15 years of follow-up, 529 women developed urothelial carcinoma. In a model including number of full-term pregnancies (FTP), menopausal status, and menopausal hormone therapy (MHT), number of FTP was inversely associated with urothelial carcinoma risk (HR≥5vs1 = 0.48; 0.25-0.90; Ptrend in parous women = 0.010) and MHT use (compared with nonuse) was positively associated with urothelial carcinoma risk (HR = 1.27; 1.03-1.57), but no dose response by years of MHT use was observed. No modification of HRs by smoking status was observed. Finally, sensitivity analyses in never smokers showed similar HR patterns for the number of FTP, while no association between MHT use and urothelial carcinoma risk was observed. Association between MHT use and urothelial carcinoma risk remained significant only in current smokers. No heterogeneity of the risk estimations in the final model was observed by tumor aggressiveness or by tumor grade. A positive association between MTH use and non-muscle-invasive urothelial carcinoma risk was observed. CONCLUSIONS: Our results support that increasing the number of FTP may reduce urothelial carcinoma risk. IMPACT: More detailed studies on parity are needed to understand the possible effects of perinatal hormone changes in urothelial cells.

Journal article

Wedekind R, Kiss A, Keski-Rahkonen P, Viallon V, Rothwell JA, Cross AJ, Rostgaard-Hansen AL, Sandanger TM, Jakszyn P, Schmidt JA, Pala V, Vermeulen R, Schulze MB, Kühn T, Johnson T, Trichopoulou A, Peppa E, La Vechia C, Masala G, Tumino R, Sacerdote C, Wittenbecher C, de Magistris MS, Dahm CC, Severi G, Mancini FR, Weiderpass E, Gunter MJ, Huybrechts I, Scalbert Aet al., 2020, A metabolomic study of red and processed meat intake and acylcarnitine concentrations in human urine and blood, American Journal of Clinical Nutrition, Vol: 112, Pages: 381-388, ISSN: 0002-9165

BACKGROUND: Acylcarnitines (ACs) play a major role in fatty acid metabolism and are potential markers of metabolic dysfunction with higher blood concentrations reported in obese and diabetic individuals. Diet, and in particular red and processed meat intake, has been shown to influence AC concentrations but data on the effect of meat consumption on AC concentrations is limited. OBJECTIVES: To investigate the effect of red and processed meat intake on AC concentrations in plasma and urine using a randomized controlled trial with replication in an observational cohort. METHODS: In the randomized crossover trial, 12 volunteers successively consumed 2 different diets containing either pork or tofu for 3 d each. A panel of 44 ACs including several oxidized ACs was analyzed by LC-MS in plasma and urine samples collected after the 3-d period. ACs that were associated with pork intake were then measured in urine (n = 474) and serum samples (n = 451) from the European Prospective Investigation into Cancer and nutrition (EPIC) study and tested for associations with habitual red and processed meat intake derived from dietary questionnaires. RESULTS: In urine samples from the intervention study, pork intake was positively associated with concentrations of 18 short- and medium-chain ACs. Eleven of these were also positively associated with habitual red and processed meat intake in the EPIC cross-sectional study. In blood, C18:0 was positively associated with red meat intake in both the intervention study (q = 0.004, Student's t-test) and the cross-sectional study (q = 0.033, linear regression). CONCLUSIONS: AC concentrations in urine and blood were associated with red meat intake in both a highly controlled intervention study and in subjects of a cross-sectional study. Our data on the role of meat intake on this important pathway of fatty acid and energy metabolism may help understanding the role of red meat consumption in the etiology of

Journal article

Butt J, Jenab M, Pawlita M, Tjonneland A, Kyrø C, Boutron-Ruault M-C, Carbonnel F, Dong C, Kaaks R, Kühn T, Boeing H, Schulze MB, Trichopoulou A, Karakatsani A, La Vecchia C, Palli D, Agnoli C, Tumino R, Sacerdote C, Panico S, Bueno-de-Mesquita B, Vermeulen R, Gram IT, Weiderpass E, Benjaminsen Borch K, Quirós JR, Agudo A, Rodríguez-Barranco M, Santiuste C, Ardanaz E, Van Guelpen B, Harlid S, Imaz L, Perez-Cornago A, Gunter MJ, Zouiouich S, Park JY, Riboli E, Cross AJ, Heath AK, Waterboer T, Hughes DJet al., 2020, Antibody responses to Helicobacter pylori and risk of developing colorectal cancer in a European cohort, Cancer Epidemiology, Biomarkers and Prevention, Vol: 29, Pages: 1475-1481, ISSN: 1055-9965

BACKGROUND: While Helicobacter pylori (H. pylori) is the major cause of gastric cancer, it has also been suggested to be involved in colorectal cancer (CRC) development. However, prospective studies addressing H. pylori and CRC are sparse and inconclusive. We assessed the association of antibody responses to H. pylori proteins with CRC in the European Prospective Investigation into Cancer and Nutrition (EPIC) cohort. METHODS: We applied H. pylori multiplex serology to measure antibody responses to 13 H. pylori proteins in pre-diagnostic serum samples from 485 CRC cases and 485 matched controls nested within the EPIC study. Odds ratios (OR) and 95% confidence intervals (CI) were calculated using multivariable conditional logistic regression to estimate the association of H. pylori overall and protein-specific sero-positivity with odds of developing CRC. RESULTS: Fifty-one percent of CRC cases were H. pylori sero-positive compared to 44% of controls resulting in an OR of 1.36 (95% CI: 1.00-1.85). Among the 13 individual H. pylori proteins, the association was driven mostly by sero-positivity to Helicobacter cysteine-rich protein C (HcpC) (OR: 1.66, 95% CI: 1.19-2.30) and Vacuolating cytotoxin A (VacA) (OR: 1.34, 95% CI: 0.99-1.82), the latter being non-statistically significant only in the fully adjusted model. CONCLUSION: In this prospective multi-center European study, antibody responses to H. pylori proteins, specifically HcpC and VacA, were associated with an increased risk of developing CRC. IMPACT: Biological mechanisms for a potential causal role of H. pylori in colorectal carcinogenesis need to be elucidated, and subsequently whether H. pylori eradication may decrease CRC incidence.

Journal article

Robbins EC, Wooldrage K, Cross AJ, 2020, Is surveillance colonoscopy necessary for all patients with bowel polyps?, BMJ, Vol: 369, Pages: 1-5, ISSN: 1759-2151

Journal article

Rutter MD, Bretthauer M, Hassan C, Jover R, Adami H-O, Corley DA, Cubiella J, Cross AJ, Evelien Dekker PD, Gupta S, Kalager M, Løberg M, Matsuda T, Moss A, Pellisé M, Rabeneck L, Rex DK, Schoen R, Senore C, Whyte DSet al., 2020, Principles for evaluation of surveillance after removal of colorectal polyps: recommendations from the world endoscopy organization, Gastroenterology, Vol: 158, Pages: 1529-1533.e4, ISSN: 0016-5085

Journal article

Murphy N, Carreras-Torres R, Song M, Chan AT, Martin RM, Papadimitriou N, Dimou N, Tsilidis KK, Banbury B, Bradbury KE, Besevic J, Rinaldi S, Riboli E, Cross AJ, Travis RC, Agnoli C, Albanes D, Berndt SI, Bézieau S, Bishop DT, Brenner H, Buchanan DD, Onland-Moret NC, Burnett-Hartman A, Campbell PT, Casey G, Castellví-Bel S, Chang-Claude J, Chirlaque M-D, Chapelle ADL, English D, Figueiredo JC, Gallinger SJ, Giles GG, Gruber SB, Gsur A, Hampe J, Hampel H, Harrison TA, Hoffmeister M, Hsu L, Huang W-Y, Huyghe JR, Jenkins MA, Keku TO, Kühn T, Kweon S-S, Le Marchand L, Li CI, Li L, Lindblom A, Martín V, Milne RL, Moreno V, Newcomb PA, Offit K, Ogino S, Ose J, Perduca V, Phipps AI, Platz EA, Potter JD, Qu C, Rennert G, Sakoda LC, Schafmayer C, Schoen RE, Slattery ML, Tangen CM, Ulrich CM, van Duijnhoven FJ, Van Guelpen B, Visvanathan K, Vodicka P, Vodickova L, Vymetalkova V, Wang H, White E, Wolk A, Woods MO, Wu AH, Zheng W, Peters U, Gunter MJet al., 2020, Circulating levels of insulin-like growth factor 1 and insulin-like growth factor binding protein 3 associate with risk of colorectal cancer based on serologic and mendelian randomization analyses, Gastroenterology, Vol: 158, Pages: 1300-1312.e20, ISSN: 0016-5085

BACKGROUND AIMS: Human studies examining associations between circulating levels of insulin-like growth factor 1 (IGF1) and insulin-like growth factor binding protein 3 (IGFBP3) and colorectal cancer risk have reported inconsistent results. We conducted complementary serologic and Mendelian randomization (MR) analyses to determine whether alterations in circulating levels of IGF1 or IGFBP3 are associated with colorectal cancer development. METHODS: Serum levels of IGF1 and other proteins were measured in blood samples collected from 397,380 participants from the UK Biobank, from 2006 through 2010. Incident cancer cases and cancer cases recorded first in death certificates were identified through linkage to national cancer and death registries. Complete follow up was available through March 31, 2016. For the MR analyses, we identified genetic variants associated with circulating levels of IGF1 and IGFBP3. The association of these genetic variants with colorectal cancer was examined with 2-sample MR methods using genome-wide association study consortia data (52,865 cases with colorectal cancer and 46,287 individuals without [controls]) RESULTS: After a median follow-up period of 7.1 years, 2665 cases of colorectal cancer were recorded. In a multivariable-adjusted model, circulating level of IGF1 level associated with colorectal cancer risk (hazard ratio per 1 standard deviation increment of IGF1, 1.11; 95% CI, 1.05-1.17). Similar associations were found by sex, follow-up time, and tumor subsite. In the MR analyses, a 1 standard deviation increment in IGF1 level, predicted based on genetic factors, was associated with a higher risk of colorectal cancer risk (odds ratio, 1.08; 95% CI, 1.03-1.12; P=3.3 x 10-4). Level of IGFBP3, predicted based on genetic factors, was associated with colorectal cancer risk (odds ratio per 1 standard deviation increment, 1.12; 95% CI, 1.06-1.18; P =4.2 x 10-5). Colorectal cancer risk was associated with only 1 variant in IGFBP3 (rs11977526

Journal article

Archambault AN, Su Y-R, Jeon J, Thomas M, Lin Y, Conti DV, Win AK, Sakoda LC, Lansdorp-Vogelaar I, Peterse EF, Zauber AG, Duggan D, Holowatyj AN, Huyghe JR, Brenner H, Cotterchio M, Bézieau S, Schmit SL, Edlund CK, Southey MC, MacInnis RJ, Campbell PT, Chang-Claude J, Slattery ML, Chan AT, Joshi AD, Song M, Cao Y, Woods MO, White E, Weinstein SJ, Ulrich CM, Hoffmeister M, Bien SA, Harrison TA, Hampe J, Li CI, Schafmayer C, Offit K, Pharoah PD, Moreno V, Lindblom A, Wolk A, Wu AH, Li L, Gunter MJ, Gsur A, Keku TO, Pearlman R, Bishop DT, Castellví-Bel S, Moreira L, Vodicka P, Kampman E, Giles GG, Albanes D, Baron JA, Berndt SI, Brezina S, Buch S, Buchanan DD, Trichopoulou A, Severi G, Chirlaque M-D, Sánchez M-J, Palli D, Kühn T, Murphy N, Cross AJ, Burnett-Hartman AN, Chanock SJ, Chapelle ADL, Easton DF, Elliott F, English DR, Feskens EJ, FitzGerald LM, Goodman PJ, Hopper JL, Hudson TJ, Hunter DJ, Jacobs EJ, Joshu CE, Küry S, Markowitz SD, Milne RL, Platz EA, Rennert G, Rennert HS, Schumacher FR, Sandler RS, Seminara D, Tangen CM, Thibodeau SN, Toland AE, van Duijnhoven FJ, Visvanathan K, Vodickova L, Potter JD, Männistö S, Weigl K, Figueiredo J, Martín V, Larsson SC, Parfrey PS, Huang W-Y, Lenz H-J, Castelao JE, Gago-Dominguez M, Muñoz-Garzón V, Mancao C, Haiman CA, Wilkens LR, Siegel E, Barry E, Younghusband B, Van Guelpen B, Harlid S, Zeleniuch-Jacquotte A, Liang PS, Du M, Casey G, Lindor NM, Le Marchand L, Gallinger SJ, Jenkins MA, Newcomb PA, Gruber SB, Schoen RE, Hampel H, Corley DA, Hsu L, Peters U, Hayes RBet al., 2020, Cumulative burden of colorectal cancer-associated genetic variants is more strongly associated with early-onset vs late-onset cancer, Gastroenterology, Vol: 158, Pages: 1274-1286.e12, ISSN: 0016-5085

BACKGROUND & AIMS: Early-onset colorectal cancer (CRC, in persons younger than 50 years old) is increasing in incidence; yet, in the absence of a family history of CRC, this population lacks harmonized recommendations for prevention. We aimed to determine whether a polygenic risk score (PRS) developed from 95 CRC-associated common genetic risk variants was associated with risk for early-onset CRC. METHODS: We studied risk for CRC associated with a weighted PRS in 12,197 participants younger than 50 years old vs 95,865 participants 50 years or older. PRS was calculated based on single-nucleotide polymorphisms associated with CRC in a large-scale genome-wide association study as of January 2019. Participants were pooled from 3 large consortia that provided clinical and genotyping data: the Colon Cancer Family Registry, the Colorectal Transdisciplinary study, and the Genetics and Epidemiology of Colorectal Cancer Consortium and were all of genetically defined European descent. Findings were replicated in an independent cohort of 72,573 participants. RESULTS: Overall associations with CRC per standard deviation of PRS were significant for early-onset cancer, and were stronger compared with late-onset cancer (P for interaction=.01); when we compared the highest PRS quartile with the lowest, risk increased 3.7-fold for early-onset CRC (95% CI, 3.28-4.24) vs 2.9-fold for late-onset CRC (95% CI, 2.80-3.04). This association was strongest for participants without a first-degree family history of CRC (P for interaction=5.61x10-5). When we compared the highest with the lowest quartiles in this group, risk increased 4.3-fold for early-onset CRC (95% CI, 3.61-5.01) vs 2.9-fold for late-onset CRC (95% CI, 2.70-3.00). Sensitivity analyses were consistent with these findings. CONCLUSIONS: In an analysis of associations with CRC per standard deviation of PRS, we found the cumulative burden of CRC-associated common genetic variants to associate with early-onset cancer, and to be

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., 2020, 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, Vol: 18, Pages: 654-666.e6, 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

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

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

Journal article

Rutter MD, East J, Rees CJ, Cripps N, Docherty J, Dolwani S, Kaye PV, Monahan KJ, Novelli MR, Plumb A, Saunders BP, Thomas-Gibson S, Tolan DJM, Whyte S, Bonnington S, Scope A, Wong R, Hibbert B, Marsh J, Moores B, Cross A, Sharp Let al., 2020, British Society of Gastroenterology/Association of Coloproctology of Great Britain and Ireland/Public Health England post-polypectomy and post-colorectal cancer resection surveillance guidelines, Gut, Vol: 69, Pages: 201-223, ISSN: 0017-5749

These consensus guidelines were jointly commissioned by the British Society of Gastroenterology (BSG), the Association of Coloproctology of Great Britain and Ireland (ACPGBI) and Public Health England (PHE). They provide an evidence-based framework for the use of surveillance colonoscopy and non-colonoscopic colorectal imaging in people aged 18 years and over. They are the first guidelines that take into account the introduction of national bowel cancer screening. For the first time, they also incorporate surveillance of patients following resection of either adenomatous or serrated polyps and also post-colorectal cancer resection. They are primarily aimed at healthcare professionals, and aim to address:Which patients should commence surveillance post-polypectomy and post-cancer resection?What is the appropriate surveillance interval?When can surveillance be stopped? two or more premalignant polyps including at least one advanced colorectal polyp (defined as a serrated polyp of at least 10 mm in size or containing any grade of dysplasia, or an adenoma of at least 10 mm in size or containing high-grade dysplasia); or five or more premalignant polyps The Appraisal of Guidelines for Research and Evaluation (AGREE II) instrument provided a methodological framework for the guidelines. The BSG's guideline development process was used, which is National Institute for Health and Care Excellence (NICE) compliant.two or more premalignant polyps including at least one advanced colorectal polyp (defined as a serrated polyp of at least 10 mm in size or containing any grade of dysplasia, or an adenoma of at least 10 mm in size or containing high-grade dysplasia); or five or more premalignant polyps The key recommendations are that the high-risk criteria for future colorectal cancer (CRC) following polypectomy comprise either:two or more premalignant polyps including at least one advanced colorectal polyp (defined as a serrated polyp of at least 10&thin

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, Vol: 145, Pages: 1510-1516, 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

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, Journal of the National Cancer Institute, Vol: 112, Pages: 516-524, ISSN: 0027-8874

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

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, and Eggs and Risk of Ischemic Heart Disease:A Prospective Study of 7198 Incident Cases Among 409885 Participants in the Pan-European EPIC Cohort, Circulation, Vol: 139, Pages: 2835-2845, 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

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

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, Vol: 30, Pages: 510-519, 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

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., 2019, 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, Vol: 68, Pages: 672-683, 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

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

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

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

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