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Exposure to exogenous (oral contraceptives, postmenopausal hormone therapy) and endogenous (number of ovulatory cycles, adiposity) steroid hormones is associated with breast cancer risk. Breast cancer risk associated with these exposures could hypothetically be modified by genes in the steroid hormone synthesis, metabolism and signaling pathways. Estrogen receptors are the first step along the path of signaling cell growth and development upon stimulation with estrogens. The National Cancer Institute Breast and Prostate Cancer Cohort Consortium has systematically selected haplotype tagging SNPs in genes along the steroid hormone synthesis, metabolism and binding pathways, including the estrogen receptor beta (ESR2) gene. Four htSNPs tag the 6 major (>5% frequency) haplotypes of the ESR2 gene. These polymorphisms have been genotyped in 5,789 breast cancer cases and 7,761 controls nested within the American Cancer Society Cancer Prevention Study II, European Prospective Investigation into Cancer and Nutrition, Multiethnic Cohort, Nurses' Health Study and Women's Health Study cohorts. None of the SNPs were independently associated with breast cancer risk. One haplotype of the ESR2 gene was associated with breast cancer risk before correction for multiple testing (OR 1.17, 95% CI 1.07-1.28, p = 0.0007). This haplotype remained associated with breast cancer risk after adjustment for multiple testing using a permutation procedure. There was no statistically significant heterogeneity in SNP or haplotype odds ratios across cohorts. These data suggest that inherited variants in ESR2 (while possibly conferring a small increased risk of breast cancer) are not associated with appreciable (OR > 1.2) changes in breast cancer risk among Caucasian women.

The presence of multiple (5-100) colorectal adenomas suggests an inherited predisposition, but the genetic aetiology of this phenotype is undetermined if patients test negative for Mendelian polyposis syndromes such as familial adenomatous polyposis (FAP) and MUTYH-associated polyposis (MAP). We investigated whether 18 common colorectal cancer (CRC) predisposition single-nucleotide polymorphisms (SNPs) could help to explain some cases with multiple adenomas who phenocopied FAP or MAP, but had no pathogenic APC or MUTYH variant. No multiple adenoma case had an outlying number of CRC SNP risk alleles, but multiple adenoma patients did have a significantly higher number of risk alleles than population controls (P = 5.7 × 10-7). The association was stronger in those with ≥ 10 adenomas. The CRC SNPs accounted for 4.3% of the variation in multiple adenoma risk, with three SNPs (rs6983267, rs10795668, rs3802842) explaining 3.0% of the variation. In FAP patients, the CRC risk score did not differ significantly from the controls, as we expected given the overwhelming effect of pathogenic germline APC variants on the phenotype of these cases. More unexpectedly, we found no evidence that the CRC SNPs act as modifier genes for the number of colorectal adenomas in FAP patients. In conclusion, common colorectal tumour risk alleles contribute to the development of multiple adenomas in patients without pathogenic germline APC or MUTYH variants. This phenotype may have 'polygenic' or monogenic origins. The risk of CRC in relatives of multiple adenoma cases is probably much lower for cases with polygenic disease, and this should be taken into account when counselling such patients. © 2015 Macmillan Publishers Limited All rights reserved.

Background: Gastric cancer poses a significant global health burden. It is the second most common cause of cancer death worldwide and the ninth leading cause of cancer mortality in Zambia, at a rate of 3.8/100,000; comparable to USA (2/100,000) and UK (3.4/100,000). Survival data on gastric malignancy in Zambia is not known.Objectives: To provide preliminary survival rates of patients with histologically proven gastric adenocarcinoma in Zambia.Study Design: Using our prospective gastric cancer research database, we conducted a retrospective audit of patients diagnosed with gastric cancer at the University Teaching Hospital, Zambia, from June 2010 until January 2012. We contacted patients or their relatives using phone numbers provided at time of enrollment.Main Outcomes: We reviewed age, sex, demographic data (income, education), body mass index, symptoms, duration of symptoms, treatment (surgery, chemotherapy, radiotherapy or combination) and survival outcome. Analysis was performed using Kaplan-Meier models and log rank test.Results: Fifty one patients were diagnosed with gastric adenocarcinoma during the study period, but follow-up data were available for 50. Median survival was 142 days. Age, sex, income, education, BMI, tumor location, and treatment modality were not significantly associated with overall survival. In Cox regression models, covariates associated with survival were a history of regular alcohol intake (HR 0.49, 95%CI 0.26,0.92; P=0.025) and intestinal type cancer histology (HR 0.40, 95%CI 0.19,0.83; P=0.01).Conclusion: Prognosis of newly diagnosed gastric cancer in Zambia is poor with significant mortality within 1 yearof diagnosis, particularly among patients with weight loss and dysphagia.

COLLABORATORS (in alphabetical order of institution, study name, or location) Aichi Cancer Research Institute, Nagoya, Japan: N Hamajima, K Hirose, K Tajima; Albert Einstein College of Medicine, NY, USA: T Rohan; American Cancer Society, GA, USA: EE Calle, CW Jr Heath; Atlanta, Emory University, GA, USA: RJ Coates, JM Liff; Aviano Cancer Center, Pordenone, Italy: R Talamini; Mahidol University, Bangkok, Thailand: N Chantarakul, S Koetsawang, D Rachawat; Breast Tumor Collaborative Study, Johns Hopkins University, MD, USA: A Morabia, L Schuman, W Stewart, M Szklo; University of Queensland, Brisbane, Australia: C Bain, F Schofield, V Siskind; British Columbia Cancer Agency, BC, Canada: P Band, AJ Coldman, RP Gallagher, TG Hislop, P Yang; Cancer Research Center, University of Hawaii, Hawaii, USA: LM Kolonel, AMY Nomura; Canadian Cancer Registries Epidemiology Research Group, Canada: J Hu, KC Johnson, Y Mao; Catalán Institut of Oncology, Barcelona, Spain: S De Sanjosé; Centers for Disease Control & Prevention, GA, USA: N Lee, P Marchbanks, HW Ory, HB Peterson, HG Wilson, PA Wingo; Central Institute of Cancer Research, Berlin, Germany: K Ebeling, D Kunde, P Nishan; Centre for Genetic Epidemiology, University of Melbourne, Melbourne, Australia: JL Hopper; Channing Laboratory, Brigham and Women's Hospital, Harvard Medical School, MA, USA: G Colditz for Nurses' Health Study Research Group; Chennai Cancer Institute, Madras, India: V Gajalakshmi; Chiang Mai University, Chiang Mai, Thailand: N Martin, T Pardthaisong, S Silpisornkosol, C Theetranont; Chulalongkorn University, Bangkok, Thailand: B Boosiri, S Chutivongse, P Jimakorn, P Virutamasen, C Wongsrichanalai; Danish Cancer Society, Aalborg, Denmark: M Ewertz; Department of Medical Epidemiology, Karolinska Institute, Stockholm, Sweden: HO Adami, L Bergkvist, C Magnusson, I Persson; Deutsches Krebsforschungszentrum, Heidelberg, Germany: J Chang-Claude; University of Otago, Dunedin, New Zealand: C Paul, DCG Skegg, GFS Spears; European Institute of Oncology, Milan, Italy: P Boyle, T Evstifeeva; Fred Hutchinson Cancer Research Center, WA, USA: JR Daling, WB Hutchinson, K Malone, EA Noonan, JL Stanford, DB Thomas, NS Weiss, E White; French Multicentre Breast Study, INSERM, Villejuif, France: N Andrieu, A Brêmond, F Clavel, B Gairard, J Lansac, L Piana, R Renaud; Girona Cancer Registry, Girona, Spain: A Izquierdo, P Viladiu; Hospital General de Mexico, Mexico City, Mexico: HR Cuevas, P Ontiveros, A Palet, SB Salazar; Hospital Universitario, Cali, Colombia: N Aristizabal, A Cuadros; Icelandic Cancer Society, Reykjavik, Iceland: L Tryggvadottir, H Tulinius; INSERM, Institut Gustave-Roussey, Villejuif, France: A Bachelot, MG Lê; Institute of Cancer Research, Sutton and London School of Hygiene and Tropical Medicine, UK: J Peto; International Agency for Research in Cancer, Lyon, France: S Franceschi; Israel Chaim Sheba Medical Centre, Tel-Hashomer, Israel: F Lubin, B Modan, E Ron, Y Wax; Kaiser Permanente, CA, USA: GD Friedman, RA Hiatt; Institut universitaire de medecine sociale et preventive, Lausanne, Switzerland: F Levi; Cancer Research UK Genetic Epidemiology Laboratory, Leeds, UK: T Bishop; Institute of Oncology, Ljubljana, Slovenia: K Kosmelj, M Primic-Zakelj, B Ravnihar, J Stare; Loma Linda University, CA, USA: WL Beeson, G Fraser; Cancer Research UK Department of Mathematics, Statistics & Epidemiology, London: RD Bulbrook, J Cuzick, SW Duffy, IS Fentiman, JL Hayward, DY Wang; London School of Hygiene & Tropical Medicine, London, UK: AJ McMichael, K McPherson; Long Island Breast Cancer Study, NY, USA: RL Hanson, MC Leske, MC Mahoney, PC Nasca, AO Varma, AL Weinstein; University Hospital, Lund, Sweden: TR Moller, H Olsson, J Ranstam; Maastricht University, Maastricht, The Netherlands: RA Goldbohm, PA van den Brandt; University of Philippines, Manila, Philippines: RA Apelo, J Baens, JR de la Cruz, B Javier, LB Lacaya, CA Ngelangel; Istituto ‘Mario Negri', Milan, Italy: C La Vecchia, E Negri; Istituto Nazionale Tumori, Divisione di Statistica Medica e Biometria, Milan, Italy: E Marubini; Istituto di Statistica Medica e Biometria, Milan, Italy: M Ferraroni; Montpellier Cancer Centre & INSERM, Montpellier, France: M Gerber, S Richardson, C Segala; Nairobi Centre for Research in Reproduction, Nairobi, Kenya: D Gatei, P Kenya, A Kungu, JG Mati; National Cancer Institute, MD, USA: LA Brinton, R Hoover, C Schairer; National Institute of Child Health & Human Development, MD, USA: R Spirtas; National University of Singapore, Singapore: HP Lee; The Netherlands Cancer Institute, Amsterdam, The Netherlands: MA Rookus, FE van Leeuwen for the Netherlands Oral Contraceptives and Breast Cancer Study Group; New Jersey State Department of Health, NJ, USA: JA Schoenberg; New South Wales Cancer Council, Sydney, Australia: M McCredie; Columbia University School of Public Health, NY, USA: MD Gammon; Ontario Cancer Treatment & Research Foundation, Ontario, Canada: EA Clarke; Department of Public Health & Primary Care, Oxford, UK: L Jones, A Neil, M Vessey, D Yeates; Cancer Research UK Epidemiology Unit, Oxford, UK (Secretariat): P Appleby, E Banks, V Beral, D Bull, B Crossley, A Goodill, J Green, C Hermon, T Key, N Langston, C Lewis, G Reeves; Cancer Research UK/MRC/BHF Clinical Trial Service Unit & Epidemiological Studies Unit, Oxford, UK: R Collins, R Doll, R Peto; Radiation Effects Research Foundation, Hiroshima, Japan: K Mabuchi, D Preston; Royal College of General Practitioners Oral Contraception Study, London, UK: P Hannaford, C Kay; University of Costa Rica, San Jose, Costa Rica: L Rosero-Bixby; Shanghai Cancer Institute, Shanghai, China: YT Gao, F Jin, J-M Yuan; Shanghai Institute of Planned Parenthood Research, Shanghai, China: HY Wei, T Yun, C Zhiheng; Department of Public Health, Sydney, Australia: G Berry, J Cooper Booth, T Jelihovsky, R MacLennan, R Shearman; Tianjin Cancer Institute, Tianjin, China: Q-S Wang; Department of Public Health Sciences, Toronto, Canada: CJ Baines, AB Miller, C Wall; Tromso University, Tromso, Norway: E Lund, H Stalsberg; Vanderbilt University, TN, USA: XO Shu, W Zheng; University of Athens Medical School, Athens, Greece: K Katsouyanni, A Trichopoulou, D Trichopoulos; University of Chile, Santiago, Chile: A Dabancens, L Martinez, R Molina, O Salas; University of Edinburgh, Edinburgh, UK: FE Alexander; University of Minnesota School of Public Health, MN, USA: K Anderson, AR Folsom on behalf of the Iowa Women's Health Study; University of North Carolina at Chapel Hill, School of Public Health, NC, USA: BS Hulka; University of Nottingham, Nottingham, UK: CED Chilvers; University of Southern California, LA, USA: L Bernstein, S Enger, RW Haile, A Paganini-Hill, MC Pike, RK Ross, G Ursin, MC Yu; University of Wisconsin Comprehensive Cancer Center, WI, USA: MP Longnecker, P Newcomb for the 4 State Study; Vasteras, Sweden: L Bergkvist; World Health Organisation, Geneva, Switzerland: A Kalache; World Health Organisation, UNDP/UNFPA/WHO/World Bank Special Programme of Research, Development and Research Training in Human Reproduction, Geneva, Switzerland: TMM Farley, S Holck, O Meirik. Analysis and writing committee: Beral V, Bull D, Doll R, Peto R, Reeves G Steering committee: Skegg D (Chairman), Colditz G, Hulka B, La Vecchia C, Magnusson C, Muller A, Peterson B, Pike M, Thomas D, Van Leeuven M.; International audience; Alcohol and tobacco consumption are closely correlated and published results on their association with breast cancer have not always allowed adequately for confounding between these exposures. Over 80% of the relevant information worldwide on alcohol and tobacco consumption and breast cancer were collated, checked and analysed centrally. Analyses included 58,515 women with invasive breast cancer and 95,067 controls from 53 studies. Relative risks of breast cancer were estimated, after stratifying by study, age, parity and, where appropriate, women's age when their first child was born and consumption of alcohol and tobacco. The average consumption of alcohol reported by controls from developed countries was 6.0 g per day, i.e. about half a unit/drink of alcohol per day, and was greater in ever-smokers than never-smokers, (8.4 g per day and 5.0 g per day, respectively). Compared with women who reported drinking no alcohol, the relative risk of breast cancer was 1.32 (1.19-1.45, P/=45 g per day alcohol. The relative risk of breast cancer increased by 7.1% (95% CI 5.5-8.7%; P

Choline and betaine are involved in methyl-group metabolism as methyl-group donors; thus, like folate, another methyl-group donor, they may be associated with a reduced risk of colorectal adenomas. No epidemiologic study has examined the association of intake of these nutrients and colorectal adenoma risk.

The Collaborative Group on Hormonal Factors in Breast Cancer has brought together and reanalysed the worldwide epidemiological evidence on breast cancer risk and use oi hormonal contraceptives. Original data from 54 studies, representing about 90% of the information available on the topic, were collected, checked and analysed centrally. The 54 studies were performed in 26 countries and include a total of 53,297 women with breast cancer and 100,239 women without breast cancer. The studies were varied in their design, setting and timing. Most information came from case-control studies with controls chosen from the general population; most women resided in Europe or North America and most cancers were diagnosed during the 1980s. Overall 41% of the women with breast cancer and 40% of the women without breast cancer had used oral contraceptives at some time: the median age at first use was 26 years, the median duration of use was 3 years, the median year of first use was 1968, the median time since first use was 16 years, and the median time since last use was 9 years. The main findings, summarised elsewhere,I are that there is a small increase in the risk of having breast cancer diagnosed in current users of combined oral contraceptives and in women who had stopped use in the past 10 years but that there is no evidence of an increase in the risk more than 10 years after stopping use. In addition, the cancers diagnosed in women who had used oral contraceptives tended to be less advanced clinically than the cancers diagnosed in women who had not used them. Despite the large number of possibilities investigated, few factors appeared to modify the main findings either in recent or in past users. For recent users who began use before age 20 the relative risks are higher than for recent users who began at older ages. For women whose use of oral contraceptives ceased more than 10 years before there was some suggestion of a reduction in breast cancer risk in certain subgroups, with a deficit of tumors that had spread beyond the breast, especially among women who had used preparations containing the highest doses of oestrogen and progestogen. These findings are unexpected and need to be confirmed. Although these data represent most of the epidemiologi cal evidence on the topic to date, there is still insufficient information to comment reliably about the effects of specific types of oestrogen or of progestogen. What evidence there is suggests, however, no major differences in the effects for specific types of oestrogen or of progestogen and that the pattern of risk associated with use of hormonal contraceptives containing progestogens alone may be similar to that observed for preparations containing both oestrogens and progestogens. On the basis of these results, there is little difference between women who have and have not used combined oral contraceptives in terms of the estimated cumulative number of breast cancers diagnosed during the period from starting use up to 20 rears after stopping. The cancers diagnosed in women who have used oral contraceptives are, however, less advanced clinically than the cancers diag nosed in never users. Further research is needed to establish whether the associations described here are due to earlier diagnosis of breast cancer in women who have used oral contraceptives, to the biological effects of the hormonal contraceptives or to a combination of both. Little information is as yet available about the effects on breast cancer risk of oral contraceptive use that ceased more than 20 years before and as such data accumulate it will be necessary to reexamine the worldwide evidence. RI Ranstam, Jonas/A-4386-2009; Colditz, Graham/A-3963-2009

The 17 beta-hydroxysteroid dehydrogenase 1 gene (HSD17B1) encodes 17HSD1, which catalyzes the final step of estradiol biosynthesis. Despite the important role of HSD17B1 in hormone metabolism, few epidemiologic studies of HSD17B1 and breast cancer have been conducted. This study includes 5,370 breast cancer cases and 7,480 matched controls from five large cohorts in the Breast and Prostate Cancer Cohort Consortium. We characterized variation in HSD17B1 by resequencing and dense genotyping a multiethnic sample and identified haplotype-tagging single nucleotide polymorphisms (htSNP) that capture common variation within a 33.3-kb region around HSD17B1. Four htSNPs, including the previously studied SNP rs605059 (S312G), were genotyped to tag five common haplotypes in all cases and controls. Conditional logistic regression was used to estimate odds ratios (OR) for disease. We found no evidence of association between common HSD17B1 haplotypes or htSNPs and overall risk of breast cancer. The OR for each haplotype relative to the most common haplotype ranged from 0.98 to 1.07 (omnibus test for association: X-2 = 3.77, P = 0.58, 5 degrees of freedom). When cases were subdivided by estrogen receptor (ER) status, two common haplotypes were associated with ER-negative tumors (test for trend, Ps = 0.0009 and 0.0076; n = 353 cases). HSD17B1 variants that are common in Caucasians are not associated with overall risk of breast cancer; however, there was an association among the subset of ER-negative tumors. Although the probability that these ER-negative findings are false-positive results is high, these findings were consistent across each cohort examined and warrant further study.