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1.  Dairy products and pancreatic cancer risk: a pooled analysis of 14 cohort studies 
Annals of Oncology  2014;25(6):1106-1115.
Associations between dairy product consumption and pancreatic cancer risk have been inconsistent in prior studies. In a pooled analysis of 14 prospective cohorts, intakes of dairy products, calcium, and vitamin D during adulthood were not significantly associated with pancreatic cancer risk. These results were consistent within strata defined by gender, smoking status, and body mass index.
Pancreatic cancer has few early symptoms, is usually diagnosed at late stages, and has a high case-fatality rate. Identifying modifiable risk factors is crucial to reducing pancreatic cancer morbidity and mortality. Prior studies have suggested that specific foods and nutrients, such as dairy products and constituents, may play a role in pancreatic carcinogenesis. In this pooled analysis of the primary data from 14 prospective cohort studies, 2212 incident pancreatic cancer cases were identified during follow-up among 862 680 individuals. Adjusting for smoking habits, personal history of diabetes, alcohol intake, body mass index (BMI), and energy intake, multivariable study-specific hazard ratios (MVHR) and 95% confidence intervals (CIs) were calculated using the Cox proportional hazards models and then pooled using a random effects model. There was no association between total milk intake and pancreatic cancer risk (MVHR = 0.98, 95% CI = 0.82–1.18 comparing ≥500 with 1–69.9 g/day). Similarly, intakes of low-fat milk, whole milk, cheese, cottage cheese, yogurt, and ice-cream were not associated with pancreatic cancer risk. No statistically significant association was observed between dietary (MVHR = 0.96, 95% CI = 0.77–1.19) and total calcium (MVHR = 0.89, 95% CI = 0.71–1.12) intake and pancreatic cancer risk overall when comparing intakes ≥1300 with <500 mg/day. In addition, null associations were observed for dietary and total vitamin D intake and pancreatic cancer risk. Findings were consistent within sex, smoking status, and BMI strata or when the case definition was limited to pancreatic adenocarcinoma. Overall, these findings do not support the hypothesis that consumption of dairy foods, calcium, or vitamin D during adulthood is associated with pancreatic cancer risk.
doi:10.1093/annonc/mdu019
PMCID: PMC4037857  PMID: 24631943
pancreatic cancer; dairy products; calcium intake; pooled analysis
2.  Reproductive risk factors and oestrogen/progesterone receptor-negative breast cancer in the Breast Cancer Family Registry 
British Journal of Cancer  2014;110(5):1367-1377.
Background:
Oestrogen receptor (ER)- and progesterone receptor (PR)-negative (ER−PR−) breast cancer is associated with poorer prognosis compared with other breast cancer subtypes. High parity has been associated with an increased risk of ER−PR− cancer, but emerging evidence suggests that breastfeeding may reduce this risk. Whether this potential breastfeeding benefit extends to women at high risk of breast cancer remains critical to understand for prevention.
Methods:
Using population-based ascertained cases (n=4011) and controls (2997) from the Breast Cancer Family Registry, we examined reproductive risk factors in relation to ER and PR status.
Results:
High parity (⩾3 live births) without breastfeeding was positively associated only with ER−PR− tumours (odds ratio (OR)=1.57, 95% confidence interval (CI), 1.10–2.24); there was no association with parity in women who breastfed (OR=0.93, 95% CI 0.71–1.22). Across all race/ethnicities, associations for ER−PR− cancer were higher among women who did not breastfeed than among women who did. Oral contraceptive (OC) use before 1975 was associated with an increased risk of ER−PR− cancer only (OR=1.32, 95% CI 1.04–1.67). For women who began OC use in 1975 or later there was no increased risk.
Conclusions:
Our findings support that there are modifiable factors for ER−PR− breast cancer and that breastfeeding in particular may mitigate the increased risk of ER−PR− cancers seen from multiparity.
doi:10.1038/bjc.2013.807
PMCID: PMC3950851  PMID: 24548865
breast cancer; epidemiology; breastfeeding; oral contraceptives
3.  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
4.  Prospective validation of the breast cancer risk prediction model BOADICEA and a batch-mode version BOADICEACentre 
British Journal of Cancer  2013;109(5):1296-1301.
Background:
Breast and Ovarian Analysis of Disease Incidence and Carrier Estimation Algorithm (BOADICEA) is a risk prediction algorithm that can be used to compute estimates of age-specific risk of breast cancer. It is uncertain whether BOADICEA performs adequately for populations outside the United Kingdom.
Methods:
Using a batch mode version of BOADICEA that we developed (BOADICEACentre), we calculated the cumulative 10-year invasive breast cancer risk for 4176 Australian women of European ancestry unaffected at baseline from 1601 case and control families in the Australian Breast Cancer Family Registry. Based on 115 incident breast cancers, we investigated calibration, discrimination (using receiver-operating characteristic (ROC) curves) and accuracy at the individual level.
Results:
The ratio of expected to observed number of breast cancers was 0.92 (95% confidence interval (CI) 0.76–1.10). The E/O ratios by subgroups of the participant's relationship to the index case and by the reported number of affected relatives ranged between 0.83 and 0.98 and all 95% CIs included 1.00. The area under the ROC curve was 0.70 (95% CI 0.66–0.75) and there was no evidence of systematic under- or over-dispersion (P=0.2).
Conclusion:
BOADICEA is well calibrated for Australian women, and had good discrimination and accuracy at the individual level.
doi:10.1038/bjc.2013.382
PMCID: PMC3778274  PMID: 23942072
breast cancer incidence; validation; risk prediction model
5.  Tumour morphology predicts PALB2 germline mutation status 
British Journal of Cancer  2013;109(1):154-163.
Background:
Population-based studies of breast cancer have estimated that at least some PALB2 mutations are associated with high breast cancer risk. For women carrying PALB2 mutations, knowing their carrier status could be useful in directing them towards effective cancer risk management and therapeutic strategies. We sought to determine whether morphological features of breast tumours can predict PALB2 germline mutation status.
Methods:
Systematic pathology review was conducted on breast tumours from 28 female carriers of PALB2 mutations (non-carriers of other known high-risk mutations, recruited through various resources with varying ascertainment) and on breast tumours from a population-based sample of 828 Australian women diagnosed before the age of 60 years (which included 40 BRCA1 and 18 BRCA2 mutation carriers). Tumour morphological features of the 28 PALB2 mutation carriers were compared with those of 770 women without high-risk mutations.
Results:
Tumours arising in PALB2 mutation carriers were associated with minimal sclerosis (odds ratio (OR)=19.7; 95% confidence interval (CI)=6.0–64.6; P=5 × 10−7). Minimal sclerosis was also a feature that distinguished PALB2 mutation carriers from BRCA1 (P=0.05) and BRCA2 (P=0.04) mutation carriers.
Conclusion:
This study identified minimal sclerosis to be a predictor of germline PALB2 mutation status. Morphological review can therefore facilitate the identification of women most likely to carry mutations in PALB2.
doi:10.1038/bjc.2013.295
PMCID: PMC3708559  PMID: 23787919
PALB2; hereditary; breast cancer; tumour morphology
8.  Second to fourth digit ratio (2D : 4D), breast cancer risk factors, and breast cancer risk: a prospective cohort study 
British Journal of Cancer  2012;107(9):1631-1636.
Background:
We aimed to assess whether 2D : 4D measures are associated with breast cancer risk.
Methods:
We derived the ratio of the lengths of the index and ring fingers (2D : 4D), and right minus left 2D : 4D (Δr−l) from digit lengths measured from photocopies of participants' hands collected during a recent follow-up of the Melbourne Collaborative Cohort Study, a prospective study including 24 469 women. Of the 9044 women with available data, we identified 573 incident breast cancer cases. Hazard ratios (HR) and 95% confidence intervals (CI) for a one standard deviation difference in 2D : 4D measures were obtained from Weibull survival models, and linear regression models were used to examine potential associations between 2D : 4D measures and age at menarche and menopause.
Results:
We found a direct association between left 2D : 4D and breast cancer risk, an inverse association between Δr−l and risk of breast cancer, but no association between right 2D : 4D and breast cancer risk. Among breast cancer cases, both right 2D : 4D and Δr−l were inversely associated with age at diagnosis. We also observed associations between both right 2D : 4D and Δr−l and age at menopause, with increasing digit ratio measures related to earlier mean age at menopause.
Conclusion:
Digit ratio measures might be associated with breast cancer risk and age at onset of breast cancer. If confirmed in other studies, this suggests that lower exposure or sensitivity to prenatal testosterone might be associated with lower risk of breast cancer.
doi:10.1038/bjc.2012.418
PMCID: PMC3493764  PMID: 22990654
breast cancer; hormones; digit ratio; 2D : 4D; prenatal hormones
9.  PREDICT Plus: development and validation of a prognostic model for early breast cancer that includes HER2 
British Journal of Cancer  2012;107(5):800-807.
Background:
Predict (www.predict.nhs.uk) is an online, breast cancer prognostication and treatment benefit tool. The aim of this study was to incorporate the prognostic effect of HER2 status in a new version (Predict+), and to compare its performance with the original Predict and Adjuvant!.
Methods:
The prognostic effect of HER2 status was based on an analysis of data from 10 179 breast cancer patients from 14 studies in the Breast Cancer Association Consortium. The hazard ratio estimates were incorporated into Predict. The validation study was based on 1653 patients with early-stage invasive breast cancer identified from the British Columbia Breast Cancer Outcomes Unit. Predicted overall survival (OS) and breast cancer-specific survival (BCSS) for Predict+, Predict and Adjuvant! were compared with observed outcomes.
Results:
All three models performed well for both OS and BCSS. Both Predict models provided better BCSS estimates than Adjuvant!. In the subset of patients with HER2-positive tumours, Predict+ performed substantially better than the other two models for both OS and BCSS.
Conclusion:
Predict+ is the first clinical breast cancer prognostication tool that includes tumour HER2 status. Use of the model might lead to more accurate absolute treatment benefit predictions for individual patients.
doi:10.1038/bjc.2012.338
PMCID: PMC3425970  PMID: 22850554
breast cancer; HER2; prognostic model; HER2
10.  The association between waist circumference and risk of mortality considering body mass index in 65- to 74-year-olds: a meta-analysis of 29 cohorts involving more than 58 000 elderly persons 
Background For the elderly, the association between waist circumference (WC) and mortality considering body mass index (BMI) remains unclear, and thereby also the evidence base for using these anthropometric measures in clinical practice. This meta-analysis examined the association between WC categories and (cause-specific) mortality within BMI categories. Furthermore, the association of continuous WC with lowest and increased mortality risks was examined.
Methods Age- and smoking-adjusted relative risks (RRs) of mortality associated with WC–BMI categories and continuous WC (including WC and WC2) were calculated by the investigators and pooled by means of random-effects models.
Results During a 5-year-follow-up of 32 678 men and 25 931 women, we ascertained 3318 and 1480 deaths, respectively. A large WC (men: ≥102 cm, women: ≥88 cm) was associated with increased all-cause mortality RRs for those in the ‘healthy’ weight {1.7 [95% confidence interval (CI): 1.2–2.2], 1.7 (95% CI: 1.3–2.3)}, overweight [1.1(95% CI: 1.0–1.3), 1.4 (95%: 1.1–1.7)] and obese [1.1 (95% CI: 1.0–1.3), 1.6 (95% CI: 1.3–1.9)] BMI category compared with the ‘healthy’ weight (20–24.9 kg/m2) and a small WC (<94 cm, men; <80 cm, women) category. Underweight was associated with highest all-cause mortality RRs in men [2.2 (95% CI: 1.8–2.8)] and women [2.3 (95% CI: 1.8–3.1]. We found a J-shaped association for continuous WC with all-cause, cardiovascular (CVD) and cancer, and a U-shaped association with respiratory disease mortality (P < 0.05). An all-cause (CVD) mortality RR of 2.0 was associated with a WC of 132 cm (123 cm) in men and 116 cm (105 cm) in women.
Conclusions Our results showed increased mortality risks for elderly people with an increased WC—even across BMI categories— and for those who were classified as ‘underweight’ using BMI. The results provide a solid basis for re-evaluation of WC cut-points in ageing populations.
doi:10.1093/ije/dys008
PMCID: PMC4492417  PMID: 22467292
Waist circumference; body mass index; elderly; mortality
11.  Evaluation of variation in the phosphoinositide-3-kinase catalytic subunit alpha oncogene and breast cancer risk 
Stevens, K N | Garcia-Closas, M | Fredericksen, Z | Kosel, M | Pankratz, V S | Hopper, J L | Dite, G S | Apicella, C | Southey, M C | Schmidt, M K | Broeks, A | Van ‘t Veer, L J | Tollenaar, R A E M | Fasching, P A | Beckmann, M W | Hein, A | Ekici, A B | Johnson, N | Peto, J | dos Santos Silva, I | Gibson, L | Sawyer, E | Tomlinson, I | Kerin, M J | Chanock, S | Lissowska, J | Hunter, D J | Hoover, R N | Thomas, G D | Milne, R L | Pérez, JI Arias | González-Neira, A | Benítez, J | Burwinkel, B | Meindl, A | Schmutzler, R K | Bartrar, C R | Hamann, U | Ko, Y D | Brüning, T | Chang-Claude, J | Hein, R | Wang-Gohrke, S | Dörk, T | Schürmann, P | Bremer, M | Hillemanns, P | Bogdanova, N | Zalutsky, J V | Rogov, Y I | Antonenkova, N | Lindblom, A | Margolin, S | Mannermaa, A | Kataja, V | Kosma, V-M | Hartikainen, J | Chenevix-Trench, G | Chen, X | Peterlongo, P | Bonanni, B | Bernard, L | Manoukian, S | Wang, X | Cerhan, J | Vachon, C M | Olson, J | Giles, G G | Baglietto, L | McLean, C A | Severi, G | John, E M | Miron, A | Winqvist, R | Pylkäs, K | Jukkola-Vuorinen, A | Grip, M | Andrulis, I | Knight, J A | Glendon, G | Mulligan, A M | Cox, A | Brock, I W | Elliott, G | Cross, S S | Pharoah, P P | Dunning, A M | Pooley, K A | Humphreys, M K | Wang, J | Kang, D | Yoo, K-Y | Noh, D-Y | Sangrajrang, S | Gabrieau, V | Brennan, P | McKay, J | Anton-Culver, H | Ziogas, A | Couch, F J | Easton, D F
British Journal of Cancer  2011;105(12):1934-1939.
Background:
Somatic mutations in phosphoinositide-3-kinase catalytic subunit alpha (PIK3CA) are frequent in breast tumours and have been associated with oestrogen receptor (ER) expression, human epidermal growth factor receptor-2 overexpression, lymph node metastasis and poor survival. The goal of this study was to evaluate the association between inherited variation in this oncogene and risk of breast cancer.
Methods:
A single-nucleotide polymorphism from the PIK3CA locus that was associated with breast cancer in a study of Caucasian breast cancer cases and controls from the Mayo Clinic (MCBCS) was genotyped in 5436 cases and 5280 controls from the Cancer Genetic Markers of Susceptibility (CGEMS) study and in 30 949 cases and 29 788 controls from the Breast Cancer Association Consortium (BCAC).
Results:
Rs1607237 was significantly associated with a decreased risk of breast cancer in MCBCS, CGEMS and all studies of white Europeans combined (odds ratio (OR)=0.97, 95% confidence interval (CI) 0.95–0.99, P=4.6 × 10−3), but did not reach significance in the BCAC replication study alone (OR=0.98, 95% CI 0.96–1.01, P=0.139).
Conclusion:
Common germline variation in PIK3CA does not have a strong influence on the risk of breast cancer
doi:10.1038/bjc.2011.448
PMCID: PMC3251877  PMID: 22033276
genetic susceptibility; neoplasms; association study
12.  Second to fourth digit ratio (2D:4D) and prostate cancer risk in the Melbourne Collaborative Cohort Study 
British Journal of Cancer  2011;105(3):438-440.
Background:
The ratio of the lengths of index and ring fingers (2D:4D) is a marker of prenatal exposure to sex hormones, with low 2D:4D being indicative of high prenatal androgen action. Recent studies have reported a strong association between 2D:4D and risk of prostate cancer.
Methods:
A total of 6258 men participating in the Melbourne Collaborative Cohort Study had 2D:4D assessed. Of these men, we identified 686 incident prostate cancer cases. Hazard ratios (HRs) and confidence intervals (CIs) were estimated for a standard deviation increase in 2D:4D.
Results:
No association was observed between 2D:4D and prostate cancer risk overall (HRs 1.00; 95% CIs, 0.92–1.08 for right, 0.93–1.08 for left). We observed a weak inverse association between 2D:4D and risk of prostate cancer for age <60, however 95% CIs included unity for all observed ages.
Conclusion:
Our results are not consistent with an association between 2D:4D and overall prostate cancer risk, but we cannot exclude a weak inverse association between 2D:4D and early onset prostate cancer risk.
doi:10.1038/bjc.2011.253
PMCID: PMC3172910  PMID: 21730975
digit ratio; 2D:4D; prostate cancer; cohort study
14.  Morphological predictors of BRCA1 germline mutations in young women with breast cancer 
British Journal of Cancer  2011;104(6):903-909.
Background:
Knowing a young woman with newly diagnosed breast cancer has a germline BRCA1 mutation informs her clinical management and that of her relatives. We sought an optimal strategy for identifying carriers using family history, breast cancer morphology and hormone receptor status data.
Methods:
We studied a population-based sample of 452 Australian women with invasive breast cancer diagnosed before age 40 years for whom we conducted extensive germline mutation testing (29 carried a BRCA1 mutation) and a systematic pathology review, and collected three-generational family history and tumour ER and PR status. Predictors of mutation status were identified using multiple logistic regression. Areas under receiver operator characteristic (ROC) curves were estimated using five-fold stratified cross-validation.
Results:
The probability of being a BRCA1 mutation carrier increased with number of selected histology features even after adjusting for family history and ER and PR status (P<0.0001). From the most parsimonious multivariate model, the odds ratio for being a carrier were: 9.7 (95% confidence interval: 2.6–47.0) for trabecular growth pattern (P=0.001); 7.8 (2.7–25.7) for mitotic index over 50 mitoses per 10 high-powered field (P=0.0003); and 2.7 (1.3–5.9) for each first-degree relative with breast cancer diagnosed before age 60 years (P=0.01).The area under the ROC curve was 0.87 (0.83–0.90).
Conclusion:
Pathology review, with attention to a few specific morphological features of invasive breast cancers, can identify almost all BRCA1 germline mutation carriers among women with early-onset breast cancer without taking into account family history.
doi:10.1038/bjc.2011.41
PMCID: PMC3065278  PMID: 21343941
BRCA1; early-onset breast cancer; tumour morphology
15.  Dietary patterns and risk of breast cancer 
British Journal of Cancer  2010;104(3):524-531.
Background:
Evidence is emerging that prudent/healthy dietary patterns might be associated with a reduced risk of breast cancer.
Methods:
Using data from the prospective Melbourne Collaborative Cohort Study, we applied principal factor analysis to 124 foods and beverages to identify dietary patterns and estimated their association with breast cancer risk overall and by tumour characteristics using Cox regression.
Results:
During an average of 14.1 years of follow-up of 20 967 women participants, 815 invasive breast cancers were diagnosed. Among the four dietary factors that we identified, only that characterised by high consumption of fruit and salad was associated with a reduced risk, with stronger associations observed for tumours not expressing oestrogen (ER) and progesterone receptors (PR). Compared with women in the lowest quintile of the factor score, the hazard ratio for women in the highest quintile was 0.92 (95% confidence interval (CI)=0.70–1.21; test for trend, P=0.5) for ER-positive or PR-positive tumours and 0.48 (95% CI=0.26–0.86; test for trend, P=0.002) for ER-negative and PR-negative tumours (test for homogeneity, P=0.01).
Conclusion:
Our study provides additional support for the hypothesis that a dietary pattern rich in fruit and salad might protect against invasive breast cancer and that the effect might be stronger for ER- and PR-negative tumours.
doi:10.1038/sj.bjc.6606044
PMCID: PMC3049555  PMID: 21157446
breast cancer; dietary patterns; factor analysis; prospective study
16.  The role of SMAD4 in early-onset colorectal cancer 
Objective
Chromosomal loss within the region of 18q and loss of SMAD4 expression have been reported to be frequent somatic events during colorectal cancer tumour progression; however, their associations with age at onset have not been widely studied.
Method
We analysed 109 tumours from a population-based case-family study based on colorectal cancers diagnosed before the age of 45 years. These patients with early-onset colorectal cancer had been previously screened for germ-line mismatch repair gene mutations, microsatellite instability (that included the mononucleotide repeat in TGFβRII) and somatic k-ras mutations. We measured SMAD4 protein expression using immunohistochemistry and SMAD4 copy number using quantitative real-time PCR.
Results
Loss of SMAD4 protein expression was observed in 27/109 (25%) of cancers tested and was more commonly observed in rectal tumours (15/41, 36%) when compared with tumours arising in the colon (11/66, 17%) (P = 0.04). There was no association between SMAD4 protein expression and TGFβR11 mutation status, SMAD4 copy number, family history, MSI status, tumour stage or grade.
Conclusion
Loss of SMAD4 expression is a common feature of early-onset colorectal tumours as it is in colorectal cancers diagnosed in other age-groups. Taken together, the molecular pathways (genetic and epigenetic) now known to be involved in early-onset colorectal cancer only explain a small proportion of the disease and require further exploration.
doi:10.1111/j.1463-1318.2009.01779.x
PMCID: PMC3228835  PMID: 19183329
Early-onset colorectal cancer; SMAD4; 18q; copy number
17.  Increased cancer risks for relatives of very early-onset breast cancer cases with and without BRCA1 and BRCA2 mutations 
British Journal of Cancer  2010;103(7):1103-1108.
Background:
Little is known regarding cancer risks for relatives of women with very early-onset breast cancer.
Methods:
We studied 2208 parents and siblings of 504 unselected population-based Caucasian women with breast cancer diagnosed before age 35 years (103 from USA, 124 from Canada and 277 from Australia), 41 known to carry a mutation (24 in BRCA1, 16 in BRCA2 and one in both genes). Cancer-specific standardised incidence ratios (SIRs) were estimated by comparing the number of affected relatives (50% verified overall) with that expected based on incidences specific for country, sex, age and year of birth.
Results:
For relatives of carriers, the female breast cancer SIRs were 13.13 (95% CI 6.57–26.26) and 12.52 (5.21–30.07) for BRCA1 and BRCA2, respectively. The ovarian cancer SIR was 12.38 (3.1–49.51) for BRCA1 and the prostate cancer SIR was 18.55 (4.64–74.17) for BRCA2. For relatives of non-carriers, the SIRs for female breast, prostate, lung, brain and urinary cancers were 4.03 (2.91–5.93), 5.25 (2.50–11.01), 7.73 (4.74–12.62), 5.19 (2.33–11.54) and 4.35 (1.81–10.46), respectively. For non-carriers, the SIRs remained elevated and were statistically significant for breast and prostate cancer when based on verified cancers.
Conclusion:
First-degree relatives of women with very early-onset breast cancer are at increased risk of cancers not explained by BRCA1 and BRCA2 mutations.
doi:10.1038/sj.bjc.6605876
PMCID: PMC2965877  PMID: 20877337
brain cancer; breast cancer; lung cancer; ovarian cancer; prostate cancer; urinary cancers
19.  BCL2 in breast cancer: a favourable prognostic marker across molecular subtypes and independent of adjuvant therapy received 
British Journal of Cancer  2010;103(5):668-675.
Background:
Breast cancer is heterogeneous and the existing prognostic classifiers are limited in accuracy, leading to unnecessary treatment of numerous women. B-cell lymphoma 2 (BCL2), an antiapoptotic protein, has been proposed as a prognostic marker, but this effect is considered to relate to oestrogen receptor (ER) status. This study aimed to test the clinical validity of BCL2 as an independent prognostic marker.
Methods:
Five studies of 11 212 women with early-stage breast cancer were analysed. Individual patient data included tumour size, grade, lymph node status, endocrine therapy, chemotherapy and mortality. BCL2, ER, progesterone receptor (PR) and human epidermal growth factor receptor 2 (HER2) levels were determined in all tumours. A Cox model incorporating the time-dependent effects of each variable was used to explore the prognostic significance of BCL2.
Results:
In univariate analysis, ER, PR and BCL2 positivity was associated with improved survival and HER2 positivity with inferior survival. For ER and PR this effect was time dependent, whereas for BCL2 and HER2 the effect persisted over time. In multivariate analysis, BCL2 positivity retained independent prognostic significance (hazard ratio (HR) 0.76, 95% confidence interval (CI) 0.66–0.88, P<0.001). BCL2 was a powerful prognostic marker in ER− (HR 0.63, 95% CI 0.54–0.74, P<0.001) and ER+ disease (HR 0.56, 95% CI 0.48–0.65, P<0.001), and in HER2− (HR 0.55, 95% CI 0.49–0.61, P<0.001) and HER2+ disease (HR 0.70, 95% CI 0.57–0.85, P<0.001), irrespective of the type of adjuvant therapy received. Addition of BCL2 to the Adjuvant! Online prognostic model, for a subset of cases with a 10-year follow-up, improved the survival prediction (P=0.0039).
Conclusions:
BCL2 is an independent indicator of favourable prognosis for all types of early-stage breast cancer. This study establishes the rationale for introduction of BCL2 immunohistochemistry to improve prognostic stratification. Further work is now needed to ascertain the exact way to apply BCL2 testing for risk stratification and to standardise BCL2 immunohistochemistry for this application.
doi:10.1038/sj.bjc.6605736
PMCID: PMC2938244  PMID: 20664598
BCL2; breast cancer; prognosis
20.  Plasma concentration of Propionibacterium acnes antibodies and prostate cancer risk: results from an Australian population-based case–control study 
British Journal of Cancer  2010;103(3):411-415.
Background:
Recent studies in prostatic tissue suggest that Propionibacterium acnes (P. acnes), a bacterium associated with acne that normally lives on the skin, is the most prevalent bacterium in the prostate and in men with benign prostatic hyperplasia. Its prevalence is higher in samples from patients subsequently diagnosed with prostate cancer. The aim of our study was to test whether circulating levels of P. acnes antibodies are associated with prostate cancer risk and tumour characteristics using plasma samples from a population-based case–control study.
Methods:
We measured plasma concentration of P. acnes antibodies for 809 cases and 584 controls using a recently developed ELISA assay. We compared antibody titres between cases and controls using unconditional logistic regression adjusted for batch and variables associated with the study design (i.e., age, year of selection and centre). The primary analysis included P. acnes titres in the model as a dichotomous variable using the median value for controls as the cut-off value.
Results:
P. acnes antibody titres for both cases and controls ranged from 1 : 16 (i.e., low concentration) to 1 : 65 536 (i.e., high concentration; median value=1 : 1024). The odds ratio for prostate cancer associated with titres at or above the median value was 0.73 (95% CI 0.58–0.91, P=0.005). The association appeared to be particularly strong for advanced prostate cancer (AJCC Stage grouping III–IV) for which the odds ratio was 0.59 (95% CI 0.43–0.81, P=0.001) but there was insufficient evidence that the association differed by tumour stage (p heterogeneity=0.07).
Conclusion:
These results need to be confirmed in prospective studies but they are consistent with the hypothesis that P. acnes has a role in prostate cancer.
doi:10.1038/sj.bjc.6605757
PMCID: PMC2920014  PMID: 20606679
prostate cancer; risk factor; acne; P. acnes; case–control study
21.  Risk of brain tumours in relation to estimated RF dose from mobile phones: results from five Interphone countries 
Objectives
The objective of this study was to examine the associations of brain tumours with radio frequency (RF) fields from mobile phones.
Methods
Patients with brain tumour from the Australian, Canadian, French, Israeli and New Zealand components of the Interphone Study, whose tumours were localised by neuroradiologists, were analysed. Controls were matched on age, sex and region and allocated the ‘tumour location’ of their matched case. Analyses included 553 glioma and 676 meningioma cases and 1762 and 1911 controls, respectively. RF dose was estimated as total cumulative specific energy (TCSE; J/kg) absorbed at the tumour's estimated centre taking into account multiple RF exposure determinants.
Results
ORs with ever having been a regular mobile phone user were 0.93 (95% CI 0.73 to 1.18) for glioma and 0.80 (95% CI 0.66 to 0.96) for meningioma. ORs for glioma were below 1 in the first four quintiles of TCSE but above 1 in the highest quintile, 1.35 (95% CI 0.96 to 1.90). The OR increased with increasing TCSE 7+ years before diagnosis (p-trend 0.01; OR 1.91, 95% CI 1.05 to 3.47 in the highest quintile). A complementary analysis in which 44 glioma and 135 meningioma cases in the most exposed area of the brain were compared with gliomas and meningiomas located elsewhere in the brain showed increased ORs for tumours in the most exposed part of the brain in those with 10+ years of mobile phone use (OR 2.80, 95% CI 1.13 to 6.94 for glioma). Patterns for meningioma were similar, but ORs were lower, many below 1.0.
Conclusions
There were suggestions of an increased risk of glioma in long-term mobile phone users with high RF exposure and of similar, but apparently much smaller, increases in meningioma risk. The uncertainty of these results requires that they be replicated before a causal interpretation can be made.
doi:10.1136/oemed-2011-100155
PMCID: PMC3158328  PMID: 21659469
Mobile phones; RF exposure assessment; epidemiological study; epidemiology; cancer; electromagnetic fields; non-ionising radiation; ionising radiation; physics; hygiene/occupational hygiene; risk assessment
22.  Liver Transplantation in Biliary Atresia with Concomitant Hepatoma* 
SUMMARY
Two cases are reported in which the very infrequently reported association was found of liver cell carcinoma and biliary cirrhosis secondary to congenital biliary atresia. A search of the literature revealed 4 previous reports of cases with similar pathology. Our 2 patients were both operated upon within the first few months of life, at which time congenital biliary atresia was documented, and in 1 instance temporarily corrected. They ran a progressive downhill course until they both received replacement livers, one at 4 years of age and the other at 12, at which times hepatoma was found in the excised cirrhotic livers. One patient is in good health 18 months post-transplantation. The other developed metastases but died of gastro-intestinal bleeding and pneumonia 76 days post-transplantation.
PMCID: PMC3086410  PMID: 4341515
23.  Identification of a novel prostate cancer susceptibility variant in the KLK3 gene transcript 
Human Genetics  2011;129(6):687-694.
Genome-wide association studies (GWAS) have identified more than 30 prostate cancer (PrCa) susceptibility loci. One of these (rs2735839) is located close to a plausible candidate susceptibility gene, KLK3, which encodes prostate-specific antigen (PSA). PSA is widely used as a biomarker for PrCa detection and disease monitoring. To refine the association between PrCa and variants in this region, we used genotyping data from a two-stage GWAS using samples from the UK and Australia, and the Cancer Genetic Markers of Susceptibility (CGEMS) study. Genotypes were imputed for 197 and 312 single nucleotide polymorphisms (SNPs) from HapMap2 and the 1000 Genome Project, respectively. The most significant association with PrCa was with a previously unidentified SNP, rs17632542 (combined P = 3.9 × 10−22). This association was confirmed by direct genotyping in three stages of the UK/Australian GWAS, involving 10,405 cases and 10,681 controls (combined P = 1.9 × 10−34). rs17632542 is also shown to be associated with PSA levels and it is a non-synonymous coding SNP (Ile179Thr) in KLK3. Using molecular dynamic simulation, we showed evidence that this variant has the potential to introduce alterations in the protein or affect RNA splicing. We propose that rs17632542 may directly influence PrCa risk.
Electronic supplementary material
The online version of this article (doi:10.1007/s00439-011-0981-1) contains supplementary material, which is available to authorized users.
doi:10.1007/s00439-011-0981-1
PMCID: PMC3092928  PMID: 21465221
24.  A novel association between a SNP in CYBRD1 and serum ferritin levels in a cohort study of HFE Hereditary Haemochromatosis 
British journal of haematology  2009;147(1):140-149.
There is emerging evidence that there are genetic modifiers of iron indices for HFE gene mutation carriers at risk of hereditary hemochromatosis. A random sample stratified by HFE genotype of 863 from a cohort of 31,192 people of northern European descent provided blood samples for genotyping of 476 SNPs in 44 genes involved in iron metabolism. Single SNP association testing using linear regression models adjusted for sex, menopause and HFE genotype was conducted for four continuously distributed outcomes: serum ferritin (log transformed), transferrin saturation, serum transferrin, and serum iron. The SNP rs884409 in CYBRD1 is a novel modifier specific to HFE C282Y homozygotes. Median unadjusted serum ferritin concentration decreased from 1194 µg/L (N=27) to 387 µg/L (N=16) for male C282Y homozygotes and from 357 µg/L (N=42) to 69 µg/L (N=12) for females, comparing those with no copies to those with one copy of rs884409. Functional testing of this CYBRD1 promoter polymorphism using a heterologous expression assay resulted in a 30% decrease in basal promoter activity relative to the common genotype (p=0.004). This putative genetic modifier of iron overload expression accounts for 11% (95% CI 0.4%, 22.6%) of the variance in serum ferritin levels of C282Y homozygotes.
doi:10.1111/j.1365-2141.2009.07843.x
PMCID: PMC2767327  PMID: 19673882
haemochromatosis; iron overload; iron adsorption; iron metabolism; genetic analysis

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