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1.  FGF receptor genes and breast cancer susceptibility: results from the Breast Cancer Association Consortium 
Agarwal, D | Pineda, S | Michailidou, K | Herranz, J | Pita, G | Moreno, L T | Alonso, M R | Dennis, J | Wang, Q | Bolla, M K | Meyer, K B | Menéndez-Rodríguez, P | Hardisson, D | Mendiola, M | González-Neira, A | Lindblom, A | Margolin, S | Swerdlow, A | Ashworth, A | Orr, N | Jones, M | Matsuo, K | Ito, H | Iwata, H | Kondo, N | Hartman, M | Hui, M | Lim, W Y | T-C Iau, P | Sawyer, E | Tomlinson, I | Kerin, M | Miller, N | Kang, D | Choi, J-Y | Park, S K | Noh, D-Y | Hopper, J L | Schmidt, D F | Makalic, E | Southey, M C | Teo, S H | Yip, C H | Sivanandan, K | Tay, W-T | Brauch, H | Brüning, T | Hamann, U | Dunning, A M | Shah, M | Andrulis, I L | Knight, J A | Glendon, G | Tchatchou, S | Schmidt, M K | Broeks, A | Rosenberg, E H | van't Veer, L J | Fasching, P A | Renner, S P | Ekici, A B | Beckmann, M W | Shen, C-Y | Hsiung, C-N | Yu, J-C | Hou, M-F | Blot, W | Cai, Q | Wu, A H | Tseng, C-C | Van Den Berg, D | Stram, D O | Cox, A | Brock, I W | Reed, M W R | Muir, K | Lophatananon, A | Stewart-Brown, S | Siriwanarangsan, P | Zheng, W | Deming-Halverson, S | Shrubsole, M J | Long, J | Shu, X-O | Lu, W | Gao, Y-T | Zhang, B | Radice, P | Peterlongo, P | Manoukian, S | Mariette, F | Sangrajrang, S | McKay, J | Couch, F J | Toland, A E | Yannoukakos, D | Fletcher, O | Johnson, N | Silva, I dos Santos | Peto, J | Marme, F | Burwinkel, B | Guénel, P | Truong, T | Sanchez, M | Mulot, C | Bojesen, S E | Nordestgaard, B G | Flyer, H | Brenner, H | Dieffenbach, A K | Arndt, V | Stegmaier, C | Mannermaa, A | Kataja, V | Kosma, V-M | Hartikainen, J M | Lambrechts, D | Yesilyurt, B T | Floris, G | Leunen, K | Chang-Claude, J | Rudolph, A | Seibold, P | Flesch-Janys, D | Wang, X | Olson, J E | Vachon, C | Purrington, K | Giles, G G | Severi, G | Baglietto, L | Haiman, C A | Henderson, B E | Schumacher, F | Le Marchand, L | Simard, J | Dumont, M | Goldberg, M S | Labrèche, F | Winqvist, R | Pylkäs, K | Jukkola-Vuorinen, A | Grip, M | Devilee, P | Tollenaar, R A E M | Seynaeve, C | García-Closas, M | Chanock, S J | Lissowska, J | Figueroa, J D | Czene, K | Eriksson, M | Humphreys, K | Darabi, H | Hooning, M J | Kriege, M | Collée, J M | Tilanus-Linthorst, M | Li, J | Jakubowska, A | Lubinski, J | Jaworska-Bieniek, K | Durda, K | Nevanlinna, H | Muranen, T A | Aittomäki, K | Blomqvist, C | Bogdanova, N | Dörk, T | Hall, P | Chenevix-Trench, G | Easton, D F | Pharoah, P D P | Arias-Perez, J I | Zamora, P | Benítez, J | Milne, R L
British Journal of Cancer  2014;110(4):1088-1100.
Background:
Breast cancer is one of the most common malignancies in women. Genome-wide association studies have identified FGFR2 as a breast cancer susceptibility gene. Common variation in other fibroblast growth factor (FGF) receptors might also modify risk. We tested this hypothesis by studying genotyped single-nucleotide polymorphisms (SNPs) and imputed SNPs in FGFR1, FGFR3, FGFR4 and FGFRL1 in the Breast Cancer Association Consortium.
Methods:
Data were combined from 49 studies, including 53 835 cases and 50 156 controls, of which 89 050 (46 450 cases and 42 600 controls) were of European ancestry, 12 893 (6269 cases and 6624 controls) of Asian and 2048 (1116 cases and 932 controls) of African ancestry. Associations with risk of breast cancer, overall and by disease sub-type, were assessed using unconditional logistic regression.
Results:
Little evidence of association with breast cancer risk was observed for SNPs in the FGF receptor genes. The strongest evidence in European women was for rs743682 in FGFR3; the estimated per-allele odds ratio was 1.05 (95% confidence interval=1.02–1.09, P=0.0020), which is substantially lower than that observed for SNPs in FGFR2.
Conclusion:
Our results suggest that common variants in the other FGF receptors are not associated with risk of breast cancer to the degree observed for FGFR2.
doi:10.1038/bjc.2013.769
PMCID: PMC3929867  PMID: 24548884
breast cancer; SNP; FGF receptors; susceptibility; disease subtypes
2.  Anthropometric measures and epithelial ovarian cancer risk among Chinese women: results from the Shanghai Women's Health Study 
British Journal of Cancer  2013;109(3):751-755.
Background:
Studies of anthropometric measures and ovarian cancer risk have predominantly included women of European descent with mixed findings.
Methods:
Data from the prospective Shanghai Women's Health Study (SWHS) were used to evaluate associations between anthropometric measures and risk of epithelial ovarian cancer (EOC). Hazard ratios (HRs) and 95% confidence intervals (CIs) were estimated by Cox proportional hazards regression.
Results:
A total of 152 EOC cases occurred among 70 258 women. Increasing quartiles of weight, hip circumference, and weight gain during adulthood were associated with significantly increased EOC risks. Body mass index (BMI) was also associated; overweight (25⩽BMI<29.99) and obese women (BMI⩾30.0) had significantly increased risks (HR: 1.49, 95% CI: 1.05, 2.13, and HR: 2.42, 95% CI: 1.37, 4.28, respectively). No significant associations were observed for height, waist circumference, waist-to-hip ratio (WHR), and waist-to-height ratio (WHER).
Conclusion:
Results from this large prospective study of Chinese women support the hypothesis that general adiposity contributes to the aetiology of ovarian cancer.
doi:10.1038/bjc.2013.384
PMCID: PMC3738128  PMID: 23860524
adiposity; obesity; body mass index; ovarian cancer; prospective cohort
3.  Cruciferous vegetables consumption and the risk of female lung cancer: a prospective study and a meta-analysis 
Annals of Oncology  2013;24(7):1918-1924.
Background
Epidemiological studies evaluating the association between cruciferous vegetables (CVs) intake and female lung cancer risk have produced inconsistent results.
Patients and methods
This study followed 74 914 Chinese women aged 40–70 years who participated in the Shanghai Women's Health Study. CV intake was assessed through a validated food-frequency questionnaire (FFQ) at baseline and reassessed during follow-up. Hazard ratios (HRs) and 95% confidence interval (CIs) were estimated by using Cox proportional hazards models. Furthermore, we carried out a meta-analysis of all observational studies until December 2011.
Results
After excluding the first 2 years of follow-up, 417 women developed lung cancer over a mean of 11.1 years of follow-up. An inverse association of borderline statistical significance was observed between CV consumption and female lung cancer risk, with HR for the highest compared with the lowest quartiles of 0.73 (95% CI 0.54–1.00, P trend = 0.1607). The association was strengthened in analyses restricting to never smokers, with the corresponding HR of 0.59 (95% CI 0.40–0.87, P trend = 0.0510). The finding of an inverse association between CV intake and lung cancer risk in women was supported by our meta-analysis of 10 included studies.
Conclusions
Our study suggests that CV consumption may reduce the risk of lung cancer in women, particularly among never smokers.
doi:10.1093/annonc/mdt119
PMCID: PMC3690909  PMID: 23553059
cruciferous vegetable; lung cancer; meta-analysis; prospective study; women
4.  Prospective evaluation of type 2 diabetes mellitus on the risk of primary liver cancer in Chinese men and women 
Annals of Oncology  2013;24(6):1679-1685.
Background
No prospective study has investigated the relationship between type 2 diabetes mellitus (T2DM) and the risk of primary liver cancer (PLC) in mainland China, and little is known about the effect of diabetes duration on PLC risk.
Design
Data from two population-based cohorts (the Shanghai Men's Health Study, SMHS, 2002–2006 and the Shanghai Women's Health Study, SWHS, 1996–2000) were thus used to assess the associations among T2DM, diabetes duration and PLC risk in Chinese population.
Results
During follow-up through 2009, 344 incident PLC cases were identified among 60 183 men and 73 105 women. T2DM is significantly associated with the increased risk of PLC in both men [hazard ratio (HR) = 1.63, 95% confidence interval (CI) 1.06–2.51] and women (HR = 1.64, 95% CI 1.03–2.61). The highest risk of incident liver cancer was observed in the first 5 years after diabetes diagnosis, and decreased substantially with the prolonged diabetes duration (Ptrend < 0.001). No synergistic interaction in the development of PLC was found between diabetes and other known risk factors.
Conclusions
T2DM is associated with the increased risk of subsequent liver cancer within 5 years after diagnosis in Chinese population, suggesting that hyperinsulinaemia rather than hyperglycaemia is more likely to be a primary mediator for this association.
doi:10.1093/annonc/mdt017
PMCID: PMC3660077  PMID: 23406734
China; cohort study; primary liver cancer; type 2 diabetes
5.  Evaluation of GWAS-identified genetic variants for age at menarche among Chinese women 
Human Reproduction (Oxford, England)  2013;28(4):1135-1143.
STUDY QUESTION
Do genetic polymorphisms which influence age at menarche in women of European ancestry also influence women of Chinese ancestry?
SUMMARY ANSWER
Many genetic variants influencing age at menarche in European populations appear to impact Chinese populations in a similar manner.
WHAT IS KNOWN AND WHAT THIS PAPER ADDS
Prior genome-wide association studies have uncovered 42 SNPs associated with age at menarche in European populations. This study is the first to demonstrate that many of the genetic determinants of age at menarche are shared between European and Chinese women.
PARTICIPANTS AND SETTING
We evaluated 37 of 42 SNPs identified as associated with age at menarche from a recent, large meta-analysis, consisting primarily of women of European ancestry, in a population of 6929 Chinese women from Shanghai, China. We also constructed weighted genetic risk scores (GRSs) combining the number of effect variants for all 37 SNPs, or only the SNPs associated with age at menarche among our study population, to evaluate their joint influence on age at menarche.
MAIN RESULTS
For 32 of the 37 evaluated variants, the direction of the allele associations were the same between women of European ancestry and women of Chinese ancestry (P = 3.71 × 10−6, binomial sign test); 9 of these were statistically significant. Subjects in the highest quintile of GRSs began menarche ∼5 months later than those in the lowest quintile.
BIAS, LIMITATIONS AND GENERALIZABILITY TO OTHER POPULATIONS
Age at menarche was obtained by self-report, which can be subject to recall errors. The current analysis was restricted to loci which met or approached GWAS significance thresholds and did not evaluate loci which may act predominantly or exclusively in the Chinese population. The smaller sample size for our meta-analysis compared with meta-analyses conducted in European populations reduced the power to detect significant results.
STUDY FUNDING/COMPETING INTERESTS
This study was supported, in part, by grants from US National Institutes of Health (grants R01CA124558, R01CA090899, R01CA070867; R01CA064277 and R01CA092585 and UL1 RR024975), Ingram professorship funds and Allen Foundation funds. There are no competing interests to declare.
doi:10.1093/humrep/det011
PMCID: PMC3600840  PMID: 23406970
menarche; genome-wide association study; genetics; reproductive endocrinology
6.  The etiology of uterine sarcomas: a pooled analysis of the epidemiology of endometrial cancer consortium 
British Journal of Cancer  2013;108(3):727-734.
Background:
Uterine sarcomas are characterised by early age at diagnosis, poor prognosis, and higher incidence among Black compared with White women, but their aetiology is poorly understood. Therefore, we performed a pooled analysis of data collected in the Epidemiology of Endometrial Cancer Consortium. We also examined risk factor associations for malignant mixed mullerian tumours (MMMTs) and endometrioid endometrial carcinomas (EECs) for comparison purposes.
Methods:
We pooled data on 229 uterine sarcomas, 244 MMMTs, 7623 EEC cases, and 28 829 controls. Odds ratios (ORs) and 95% confidence intervals (CIs) for risk factors associated with uterine sarcoma, MMMT, and EEC were estimated with polytomous logistic regression. We also examined associations between epidemiological factors and histological subtypes of uterine sarcoma.
Results:
Significant risk factors for uterine sarcoma included obesity (body mass index (BMI)⩾30 vs BMI<25 kg m−2 (OR: 1.73, 95% CI: 1.22–2.46), P-trend=0.008) and history of diabetes (OR: 2.33, 95% CI: 1.41–3.83). Older age at menarche was inversely associated with uterine sarcoma risk (⩾15 years vs <11 years (OR: 0.70, 95% CI: 0.34–1.44), P-trend: 0.04). BMI was significantly, but less strongly related to uterine sarcomas compared with EECs (OR: 3.03, 95% CI: 2.82–3.26) or MMMTs (OR: 2.25, 95% CI: 1.60–3.15, P-heterogeneity=0.01).
Conclusion:
In the largest aetiological study of uterine sarcomas, associations between menstrual, hormonal, and anthropometric risk factors and uterine sarcoma were similar to those identified for EEC. Further exploration of factors that might explain patterns of age- and race-specific incidence rates for uterine sarcoma are needed.
doi:10.1038/bjc.2013.2
PMCID: PMC3593566  PMID: 23348519
risk factors; uterine sarcoma; pooled analysis; obesity; diabetes
7.  Dietary glycemic load, glycemic index, and carbohydrates on the risk of primary liver cancer among Chinese women and men 
Annals of Oncology  2012;24(1):238-244.
Background
Dietary glycemic index (GI) and glycemic load (GL) typically have a positive relationship with obesity and diabetes, which are risk factors for liver cancer. However, studies on their association with liver cancer have yielded inconsistent results. Therefore, we assessed the association of GI, GL, and carbohydrates with liver cancer risk.
Patients and methods
A total of 72 966 women and 60 207 men from the Shanghai Women's Health Study (SWHS) and the Shanghai Men's Health Study (SMHS) were included for analysis. Food frequency questionnaire (FFQ) data were used to calculate daily dietary GI, GL, and carbohydrate intake. These values were energy adjusted and categorized into quintiles. The hazard ratios (HRs) and 95% confidence intervals (CI) were calculated with adjustment for potential confounders.
Results
After a median follow-up time of 11.2 years for the SWHS and 5.3 years for the SMHS, 139 and 208 incident liver cancer cases were identified in the SWHS and SMHS, respectively. In multivariable Cox regression models, no statistically significant trends by quintile of GI, GL, or carbohydrate intake were observed. Stratification by chronic liver disease/hepatitis, diabetes, or body mass index (BMI) did not alter the findings.
Conclusions
There is little evidence that dietary GI, GL, or carbohydrates affect the incidence of liver cancer in this Asian population.
doi:10.1093/annonc/mds287
PMCID: PMC3525137  PMID: 22898034
Chinese men and women; cohort study; diet; glycemic index; glycemic load; primary liver cancer
8.  Double Aneuploidy 48,XXY,+21 Associated with a Congenital Heart Defect in a Neonate 
A neonate with a double aneuploidy associated with congenital heart defect (CHD) suffered from cyanosis after birth. He had typical features of Down syndrome (DS) including hypertelorism, slightly lowset ears with protruding pinna. Doppler echocardiography indicated complex congenital heart disease with an ostium secundum atrial septal defect, enlarged right ventricle, and mild tricuspid valve regurgitation. Further chromosomal analysis showed a karyotype of 48,XXY,+21: a double aneuploidy of DS and Klinefelter syndrome (KS). Until now, only seven cases of double aneuploidy associated with CHD defect have been reported.
doi:10.2478/bjmg-2013-0038
PMCID: PMC4001422  PMID: 24778570
Double aneuploidy; Down syndrome (DS); Klinefelter syndrome (KS); 48,XXY,+21; Congenital heart defect (CHD)
9.  Body mass, tobacco smoking, alcohol drinking and risk of cancer of the small intestine—a pooled analysis of over 500 000 subjects in the Asia Cohort Consortium 
Annals of Oncology  2011;23(7):1894-1898.
Background
The evidence for a role of tobacco smoking, alcohol drinking, and body mass index (BMI) in the etiology of small intestine cancer is based mainly on case–control studies from Europe and United States.
Subjects and methods
We harmonized the data across 12 cohort studies from mainland China, Japan, Korea, Singapore, and Taiwan, comprising over 500 000 subjects followed for an average of 10.6 years. We calculated hazard ratios (HRs) for BMI and (only among men) tobacco smoking and alcohol drinking.
Results
A total of 134 incident cases were observed (49 adenocarcinoma, 11 carcinoid, 46 other histologic types, and 28 of unknown histology). There was a statistically non-significant trend toward increased HR in subjects with high BMI [HR for BMI >27.5 kg/m2, compared with 22.6–25.0, 1.50; 95% confidence interval (CI) 0.76–2.96]. No association was suggested for tobacco smoking; men drinking >400 g of ethanol per week had an HR of 1.57 (95% CI 0.66–3.70), compared with abstainers.
Conclusions
Our study supports the hypothesis that elevated BMI may be a risk factor for small intestine cancer. An etiologic role of alcohol drinking was suggested. Our results reinforce the existing evidence that the epidemiology of small intestine cancer resembles that of colorectal cancer.
doi:10.1093/annonc/mdr562
PMCID: PMC3493138  PMID: 22147734
alcohol drinking; body mass index; prospective studies; small intestine cancer; tobacco smoking
10.  Blood leukocyte Alu and LINE-1 methylation and gastric cancer risk in the Shanghai Women's Health Study 
British Journal of Cancer  2011;106(3):585-591.
Background:
Recent data suggest a link between blood leukocyte DNA methylation, and cancer risk. However, reports on DNA methylation from a prospective study are unavailable for gastric cancer.
Methods:
We explored the association between methylation in pre-diagnostic blood leukocyte DNA and gastric cancer risk in a case–control study nested in the prospective Shanghai Women's Health Study cohort. Incident gastric cancer cases (n=192) and matched controls (n=384) were included in the study. Methylation of Alu and long interspersed nucleotide elements (LINE)-1 were evaluated using bisulphite pyrosequencing. Odds ratios (ORs) and 95% confidence intervals (CI) were calculated from logistic regression adjusting for potential confounders.
Results:
Alu methylation was inversely associated with gastric cancer risk, mainly among cases diagnosed one or more years after blood collection. After excluding cases diagnosed during the first year of follow-up, the ORs for the third, second, and first quartiles of Alu methylation compared with the highest quartile were 2.43 (1.43–4.13), 1.47(0.85–2.57), and 2.22 (1.28–3.84), respectively. This association appeared to be modified by dietary intake, particularly isoflavone. In contrast, LINE-1 methylation levels were not associated with gastric cancer risk.
Conclusion:
Evidence from this prospective study is consistent with the hypothesis that DNA hypomethylation in blood leukocytes may be related to cancer risk, including risk of gastric cancer.
doi:10.1038/bjc.2011.562
PMCID: PMC3273339  PMID: 22173668
gastric cancer; DNA methylation; leukocyte
11.  Physical activity and breast cancer risk in Chinese women 
British Journal of Cancer  2011;105(9):1443-1450.
Background:
The influence of different types and intensities of physical activity on risk for breast cancer is unclear.
Methods:
In a prospective cohort of 73 049 Chinese women (40–70 years), who had worked outside the home, we studied breast cancer risk in relation to specific types of self-reported and work history-related physical activity, including adolescent and adult exercise and household activity and walking and cycling for transportation. Occupational sitting time and physical activity energy expenditure were assigned based on lifetime occupational histories.
Results:
In all, 717 incident breast cancer cases were diagnosed. Breast cancer risk was lower for women in the lowest quartile of average occupational sitting time and in the highest quartile of average occupational energy expenditure (adjusted hazard ratio (HR): 0.81 and 0.73, respectively, P⩽0.05). Adult exercise at or above the recommended level (8 metabolic equivalent (MET) h per week per year) was associated with lower risk (adjusted HR: 0.73, P<0.05) in post-menopausal women. Analysis of joint effects showed that having both an active job and exercise participation did not confer an additional benefit. Other common daily activities were not associated with lower risk.
Interpretation:
These findings suggest that both exercise and occupational activity are associated with lower breast cancer risk, which supports current health promotion campaigns promoting exercise.
doi:10.1038/bjc.2011.370
PMCID: PMC3241547  PMID: 21934685
breast cancer; physical activity; exercise; occupational; critical period
12.  A novel isoform of the 8p22 tumor suppressor gene DLC1 suppresses tumor growth and is frequently silenced in multiple common tumors 
Oncogene  2011;30(16):1923-1935.
The critical 8p22 tumor suppressor deleted in liver cancer 1 (DLC1) is frequently inactivated by aberrant CpG methylation and/or genetic deletion and implicated in tumorigeneses of multiple tumor types. Here, we report the identification and characterization of its new isoform, DLC1 isoform 4 (DLC1-i4). This novel isoform encodes an 1125-aa (amino acid) protein with distinct N-terminus as compared with other known DLC1 isoforms. Similar to other isoforms, DLC1-i4 is expressed ubiquitously in normal tissues and immortalized normal epithelial cells, suggesting a role as a major DLC1 transcript. However, differential expression of the four DLC1 isoforms is found in tumor cell lines: Isoform 1 (longest) and 3 (short thus probably nonfunctional) share a promoter and are silenced in almost all cancer and immortalized cell lines, whereas isoform 2 and 4 utilize different promoters and are frequently downregulated. DLC1-i4 is significantly down-regulated in multiple carcinoma cell lines, including 2/4 nasopharyngeal, 8/16 (50%) esophageal, 4/16 (25%) gastric, 6/9 (67%) breast, 3/4 colorectal, 4/4 cervical and 2/8(25%) lung carcinoma cell lines. The functional DLC1-i4 promoter is within a CpG island and is activated by wild-type p53. CpG methylation of the DLC1-i4 promoter is associated with its silencing in tumor cells and was detected in 38–100% of multiple primary tumors. Treatment with 5-aza-2′-deoxycytidine or genetic double knockout of DNMT1 and DNMT3B led to demethylation of the promoter and reactivation of its expression, indicating a predominantly epigenetic mechanism of silencing. Ectopic expression of DLC1-i4 in silenced tumor cells strongly inhibited their growth and colony formation. Thus, we identified a new isoform of DLC1 with tumor suppressive function. The differential expression of various DLC1 isoforms suggests interplay in modulating the complex activities of DLC1 during carcinogenesis.
doi:10.1038/onc.2010.576
PMCID: PMC3385516  PMID: 21217778
DLC1; RhoGAP; methylation; tumor suppressor gene; carcinoma; p53
14.  Plasma pepsinogens, antibodies against Helicobacter pylori, and risk of gastric cancer in the Shanghai Women's Health Study Cohort 
British Journal of Cancer  2011;104(9):1511-1516.
Background:
Circulating pepsinogens can indicate atrophic gastritis, a precursor of gastric cancer. We tested the association between gastric cancer and plasma pepsinogens and antibodies against Helicobacter pylori in a case–control study nested in a prospective cohort.
Methods:
We selected 141 gastric cancer cases and 282 incidence-density sampled controls. Plasma concentrations of pepsinogens 1 and 2 were measured using ELISA kits, and anti-H. pylori antibodies were measured using a kit specific to Chinese strains. Associations were estimated using conditional logistic regression models adjusted for potential confounders.
Results:
Gastric cancer subjects were more likely to be anti-H. pylori positive than controls, 97 vs 92%. A plasma pepsinogen 1 (PG1) concentration <50 ng ml–1 (15% of cases) was associated with a significantly increased risk of gastric cancer (OR 4.23; (95% CI: 1.86–9.63), whereas a plasma pepsinogen 2 (PG2) concentration >6.6 ng ml–1 (75% of cases) was also associated with a significantly increased risk of gastric cancer (OR 3.62; (95% CI: 1.85–7.09). We also found that the PG1 : 2 ratio had a nearly linear association with gastric cancer risk.
Conclusion:
Lower plasma PG1 : 2 ratios are associated with a higher risk of gastric cancer. Furthermore, it appears that circulating pepsinogens 1 and 2 may be independently associated with the risk of gastric cancer.
doi:10.1038/bjc.2011.77
PMCID: PMC3101941  PMID: 21407214
gastric cancer; pepsinogens; Helicobacter pylori; cohort; China
15.  Association of genetic variation in FTO with risk of obesity and type 2 diabetes with data from 96,551 East and South Asians 
Diabetologia  2011;55(4):981-995.
Aims/hypothesis
FTO harbours the strongest known obesity-susceptibility locus in Europeans. While there is growing evidence for a role for FTO in obesity risk in Asians, its association with type 2 diabetes, independently of BMI, remains inconsistent. To test whether there is an association of the FTO locus with obesity and type 2 diabetes, we conducted a meta-analysis of 32 populations including 96,551 East and South Asians.
Methods
All studies published on the association between FTO-rs9939609 (or proxy [r2 > 0.98]) and BMI, obesity or type 2 diabetes in East or South Asians were invited. Each study group analysed their data according to a standardised analysis plan. Association with type 2 diabetes was also adjusted for BMI. Random-effects meta-analyses were performed to pool all effect sizes.
Results
The FTO-rs9939609 minor allele increased risk of obesity by 1.25-fold/allele (p = 9.0 × 10−19), overweight by 1.13-fold/allele (p = 1.0 × 10−11) and type 2 diabetes by 1.15-fold/allele (p = 5.5 × 10−8). The association with type 2 diabetes was attenuated after adjustment for BMI (OR 1.10-fold/allele, p = 6.6 × 10−5). The FTO-rs9939609 minor allele increased BMI by 0.26 kg/m2 per allele (p = 2.8 × 10−17), WHR by 0.003/allele (p = 1.2 × 10−6), and body fat percentage by 0.31%/allele (p = 0.0005). Associations were similar using dominant models. While the minor allele is less common in East Asians (12–20%) than South Asians (30–33%), the effect of FTO variation on obesity-related traits and type 2 diabetes was similar in the two populations.
Conclusions/interpretation
FTO is associated with increased risk of obesity and type 2 diabetes, with effect sizes similar in East and South Asians and similar to those observed in Europeans. Furthermore, FTO is also associated with type 2 diabetes independently of BMI.
Electronic supplementary material
The online version of this article (doi:10.1007/s00125-011-2370-7) contains peer-reviewed but unedited supplementary material, which is available to authorised users.
doi:10.1007/s00125-011-2370-7
PMCID: PMC3296006  PMID: 22109280
Asians; FTO; Meta-analysis; Obesity; Type 2 diabetes
16.  Cancer risk in patients hospitalised for Graves' disease: a population-based cohort study in Sweden 
British Journal of Cancer  2010;102(9):1397-1399.
Background:
The possibility of an association of Graves' disease (GD) with subsequent cancers raised by certain studies.
Methods:
Using a database on 18 156 hospitalised GD patients, subsequent cancers were ascertained.
Results:
Increased risks of thyroid and parathyroid tumours were limited to the early follow-up period, which is probably a surveillance bias. Cancer sites with observed excess included the mouth and breast, in contrast to decreased risks of colon cancer, melanoma and non-Hodgkin's lymphoma.
Conclusion:
Increased subsequent cancers in GD patients appeared to be balanced by decreased risks at other sites; chance cannot be excluded.
doi:10.1038/sj.bjc.6605624
PMCID: PMC2865750  PMID: 20354521
subsequent cancer; hyperthyroidism; Hospital Discharge Registry
17.  Paediatric germ cell tumours and congenital abnormalities: a Children's Oncology Group study 
British Journal of Cancer  2009;101(3):518-521.
Methods:
Maternally reported congenital abnormalities (CAs) were examined in a case–control study of 278 cases of paediatric germ cell tumours (GCTs) and 423 controls.
Results and conclusions
Germ cell tumours were significantly associated with cryptorchidism in males (OR=10.8, 95% CI: 2.1–55.1), but not with any other specific CA in either sex.
doi:10.1038/sj.bjc.6605169
PMCID: PMC2720246  PMID: 19603020
germ cell tumours; paediatrics; congenital abnormalities
18.  Cancer risk in hospitalised psoriasis patients: a follow-up study in Sweden 
British Journal of Cancer  2009;100(9):1499-1502.
We examined overall and specific cancer risks among Swedish subjects who had been hospitalised one or more times for psoriasis. A database was created by identifying such patients from the Swedish Hospital Discharge Register and linking them with the Cancer Registry. Follow-up of patients was carried out from the last hospitalisation through 2004. A total of 15 858 patients were hospitalised for psoriasis during 1965–2004, of whom 1408 developed cancer, giving an overall standardised incidence ratios (SIRs) of 1.33. A significant excess was noted for squamous cell skin cancer, and for cancers of the upper aerodigestive tract, oesophagus, stomach, liver, pancreas, lung, kidney and bladder as well as non-Hodgkin lymphoma. Many of these may reflect the effects of alcohol drinking and tobacco smoking. Patients with multiple hospitalisations showed high risk, particularly for oesophageal (SIR 6.97) and skin (SIR 4.76) cancers.
doi:10.1038/sj.bjc.6605027
PMCID: PMC2694437  PMID: 19352386
psoriasis; national databases
19.  Cancer risk in hospitalised asthma patients 
British Journal of Cancer  2009;100(5):829-833.
Asthma is an increasingly common disorder, affecting 5–10% of the population. It involves a dysregulated immune function, which may predispose to subsequent cancer. We examined cancer risk among Swedish subjects who had hospital admission once or multiple times for asthma. An asthma research database was created by identifying asthma patients from the Swedish Hospital Discharge Register and by linking them with the Cancer Registry. A total of 140 425 patients were hospitalised for asthma during 1965–2004, of whom 7421 patients developed cancer, giving an overall standardised incidence ratio (SIR) of 1.36. A significant increase was noted for most sites, with the exception of breast and ovarian cancers and non-Hodgkin's lymphoma and myeloma. Patients with multiple hospital admissions showed a high risk, particularly for stomach (SIR 1.70) and colon (SIR 1.99) cancers. A significant decrease was noted for endometrial cancer and skin melanoma. Oesophageal and lung cancers showed high risks throughout the study period, whereas stomach cancer increased towards the end of the period. The relatively stable temporal trends suggest that the asthmatic condition rather than its medication is responsible for the observed associations.
doi:10.1038/sj.bjc.6604890
PMCID: PMC2653753  PMID: 19174822
asthma; cancer risk; national databases
20.  Serum Response Factor Micro-Managing Cardiogenesis 
Current opinion in cell biology  2007;19(6):618-627.
Serum response factor (SRF), a cardiac enriched transcription factor, is required for the appearance of beating sarcomeres in the heart. SRF may also direct the expression of microRNAs (miRs) that inhibit the expression of cardiac regulatory factors. The recent knockout of miR-1-2, an SRF gene target, showed defective heart development, caused in part by the induction of GATA6, Irx4/5, and Hand2, that may alter cardiac morphogenesis, channel activity and cell cycling. SRF and co-factors play an obligatory role in cardiogenesis, as major determinants of myocyte differentiation not only by regulating the biogenesis of muscle contractile proteins but also by driving the expression of silencer miRNA.
doi:10.1016/j.ceb.2007.09.013
PMCID: PMC2735128  PMID: 18023168
21.  Duration of breast-feeding and the incidence of type 2 diabetes mellitus in the Shanghai Women’s Health Study 
Diabetologia  2007;51(2):258-266.
Aims/hypothesis
The aim of this study was to examine the association between lifetime breast-feeding and the incidence of type 2 diabetes mellitus in a large population-based cohort study of middle-aged women.
Methods
This was a prospective study of 62,095 middle-aged parous women in Shanghai, China, who had no prior history of type 2 diabetes mellitus, cancer or cardiovascular disease at study recruitment. Breast-feeding history, dietary intake, physical activity and anthropometric measurements were assessed by in-person interviews. The Cox regression model was employed to evaluate the association between breast-feeding and the risk of type 2 diabetes mellitus.
Results
After 4.6 years of follow-up, 1,561 women were diagnosed with type 2 diabetes mellitus. Women who had breastfed their children tended to have a lower risk of diabetes mellitus than those who had never breastfed [relative risk (RR) = 0.88; 95% CI, 0.76–1.02; p = 0.08]. Increasing duration of breast-feeding was associated with a reduced risk of type 2 diabetes mellitus. The fully adjusted RRs for lifetime breast-feeding duration were 1.00, 0.88, 0.89, 0.88, 0.75 and 0.68 (p trend = 0.01) for 0, >0 to 0.99, >0.99 to 1.99, >1.99 to 2.99, >2.99 to 3.99 and ≥4 years in analyses adjusted for age, daily energy intake, BMI, WHR, smoking, alcohol intake, physical activity, occupation, income level, education level, number of live births and presence of hypertension at baseline.
Conclusions/interpretation
Breast-feeding may protect parous women from developing type 2 diabetes mellitus later in life.
doi:10.1007/s00125-007-0885-8
PMCID: PMC2170456  PMID: 18040660
Lifelong breast-feeding; Middle-aged women; Parous women; Type 2 diabetes mellitus
22.  Animal food intake and cooking methods in relation to endometrial cancer risk in Shanghai 
British Journal of Cancer  2006;95(11):1586-1592.
We evaluated animal food intake and cooking methods in relation to endometrial cancer risk in a population-based case–control study in Shanghai, China. A validated food frequency questionnaire was used to collect the usual dietary habits of 1204 cases and 1212 controls aged 30–69 years between 1997 and 2003. Statistical analyses were based on an unconditional logistic regression model adjusting for potential confounders. High intake of meat and fish was associated with an increased risk of endometrial cancer, with adjusted odds ratios for the highest vs the lowest quartile groups being 1.7 (95% confidence interval: 1.3–2.2) and 2.4 (1.8–3.1), respectively. The elevated risk was observed for all types of meat and fish intake. Intake of eggs and milk was not related to risk. Cooking methods and doneness levels for meat and fish were not associated with risk, nor did they modify the association with meat and fish consumption. Our study suggests that animal food consumption may play an important role in the aetiology of endometrial cancer, but cooking methods have minimal influence on risk among Chinese women.
doi:10.1038/sj.bjc.6603458
PMCID: PMC2360744  PMID: 17060930
endometrial cancer; dietary factor; case–control study
23.  A case–control study in Shanghai of fruit and vegetable intake and endometrial cancer 
British Journal of Cancer  2005;92(11):2059-2064.
In a population-based case–control study of 832 incident endometrial cancer cases and 846 frequency-matched controls among Chinese women in Shanghai, using a validated food-frequency questionnaire, dietary habits were estimated by in-person interviews. Total vegetable consumption was inversely associated with endometrial cancer risk (highest quartile vs lowest: OR=0.69, 95% CI 0.50–0.96). The risk was reduced with increasing intake of dark green/dark yellow vegetables (trend test, P=0.02), fresh legumes (trend test, P<0.01), and allium vegetables (trend test, P=0.04). Fruit consumption was unrelated to risk. These results suggest that high consumption of certain vegetables may reduce the risk of endometrial cancer.
doi:10.1038/sj.bjc.6602609
PMCID: PMC2361791  PMID: 15886701
vegetables; fruit; endometrial cancer
24.  Reply 1: An assessment of the preconceptional mitochondrial hypothesis 
British Journal of Cancer  2003;88(11):1819-1820.
doi:10.1038/sj.bjc.6600980
PMCID: PMC2377149
25.  Weight at birth and adolescence and premenopausal breast cancer risk in a low-risk population 
British Journal of Cancer  2002;86(1):84-88.
We assessed breast cancer risk in relation to weight at birth and adolescence. In-person interviews were completed with the biological mothers of women aged 45 years and younger who participated in the Shanghai Breast Cancer Study in 1996–98 (288 cases, 350 controls). After adjustment for confounding, women who were 4000 g or more at birth were not at increased risk of breast cancer (odds ratio=0.7; 95% confidence interval 0.4–1.4) relative to women whose birth weight was 2500–2999 g. Compared with women of average perceived weight at age 15 years, no relation was apparent for heavier than average weight based on maternal report (odds ratio=0.7; 95% confidence interval 0.5–1.2) or self-report (odds ratio=1.0; 95% confidence interval 0.7–1.6). Perceived adolescent weight and height did not modify the association of birth weight with breast cancer risk. These results suggest that weight early in life is not related to premenopausal breast cancer risk in this low-risk population.
British Journal of Cancer (2002) 86, 84–88. DOI: 10.1038/sj/bjc/6600009 www.bjcancer.com
© 2002 The Cancer Research Campaign
doi:10.1038/sj.bjc.6600009
PMCID: PMC2746545  PMID: 11857016
breast cancer; birth weight; adolescent weight; adult body size

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