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Background The androgen receptor (AR) pathway-associated gene nuclear receptor coactivator 2 (NCOA2) has an established oncogenic role in early prostate cancer and likewise is a driver of metastatic disease and castration-resistant prostate cancer. However, its significance as a biomarker in metastatic castration-resistant prostate cancer (mCRPC), both alone and in conjunction with co-occurring AR alterations using a liquid biopsy approach has not been investigated. Methods Ninety-one patients were included in this study, (n = 68 receiving an androgen receptor pathway inhibitor and n = 23 receiving taxane chemotherapy). Up to 30 ml of peripheral blood was collected before commencing treatment from each patient. Plasma cell-free DNA, along with a matched germline sample, underwent targeted next-generation sequencing using a validated, highly sensitive in-house prostate cancer panel. Variants in AR and NCOA2 were identified and correlated with clinical outcomes. Results Plasma AR and NCOA2 aberrations were identified in 35% and 13% of the cohort, respectively, whilst 8% had concurrent AR and NCOA2 alterations. NCOA2 copy number gain and any NCOA2 aberration predicted for lower prostate-specific antigen (PSA) response rates. Likewise, median overall survival was shorter for NCOA2 gain (10.1 vs. 18.3 months; p = .004), remaining significant after adjusting for covariates including circulating tumor DNA fraction and tumor suppressor gene alterations. Importantly, dual AR and NCOA2 aberrations were also associated with inferior outcomes, including no PSA responses in patients treated with AR pathway inhibitors (0% vs. 64%; p = .02). Conclusions These data highlight the importance of identifying multiple markers of AR pathway modulation in mCRPC and represent the first instance of the assessment of plasma NCOA2 status as a prognostic biomarker for standard-of-care therapies. Further assessment is warranted to determine if NCOA2 aberrations are a marker of primary resistance to AR pathway inhibitors.

Mammograms contain information that predicts breast cancer risk. We developed two novel mammogram-based breast cancer risk measures based on image brightness (Cirrocumulus) and texture (Cirrus). Their risk prediction when fitted together, and with an established measure of conventional mammographic density (Cumulus), is not known. We used three studies consisting of: 168 interval cases and 498 matched controls; 422 screen-detected cases and 1197 matched controls; and 354 younger-diagnosis cases and 944 controls frequency-matched for age at mammogram. We conducted conditional and unconditional logistic regression analyses of individually- and frequency-matched studies, respectively. We estimated measure-specific risk gradients as the change in odds per standard deviation of controls after adjusting for age and body mass index (OPERA) and calculated the area under the receiver operating characteristic curve (AUC). For interval, screen-detected and younger-diagnosis cancer risks, the best fitting models (OPERAs [95% confidence intervals]) involved: Cumulus (1.81 [1.41-2.31]) and Cirrus (1.72 [1.38-2.14]); Cirrus (1.49 [1.32-1.67]) and Cirrocumulus (1.16 [1.03 to 1.31]); and Cirrus (1.70 [1.48 to 1.94]) and Cirrocumulus (1.46 [1.27-1.68]), respectively. The AUCs were: 0.73 [0.68-0.77], 0.63 [0.60-0.66], and 0.72 [0.69-0.75], respectively. Combined, our new mammogram-based measures have twice the risk gradient for screen-detected and younger-diagnosis breast cancer (P ≤ 10-12 ), have at least the same discriminatory power as the current polygenic risk score, and are more correlated with causal factors than conventional mammographic density. Discovering more information about breast cancer risk from mammograms could help enable risk-based personalised breast screening.

Interval breast cancers (those diagnosed between recommended mammography screens) generally have poorer outcomes and are more common among women with dense breasts. We aimed to develop a risk model for interval breast cancer. We conducted a nested case–control study within the Melbourne Collaborative Cohort Study involving 168 interval breast cancer patients and 498 matched control subjects. We measured breast density using the CUMULUS software. We recorded first‐degree family history by questionnaire, measured body mass index (BMI) and calculated age‐adjusted breast tissue aging, a novel measure of exposure to estrogen and progesterone based on the Pike model. We fitted conditional logistic regression to estimate odds ratio (OR) or odds ratio per adjusted standard deviation (OPERA) and calculated the area under the receiver operating characteristic curve (AUC). The stronger risk associations were for unadjusted percent breast density (OPERA = 1.99; AUC = 0.66), more so after adjusting for age and BMI (OPERA = 2.26; AUC = 0.70), and for family history (OR = 2.70; AUC = 0.56). When the latter two factors and their multiplicative interactions with age‐adjusted breast tissue aging (p = 0.01 and 0.02, respectively) were fitted, the AUC was 0.73 (95% CI 0.69–0.77), equivalent to a ninefold interquartile risk ratio. In summary, compared with using dense breasts alone, risk discrimination for interval breast cancers could be doubled by instead using breast density, BMI, family history and hormonal exposure. This would also give women with dense breasts, and their physicians, more information about the major consequence of having dense breasts—an increased risk of developing an interval breast cancer., What's new? Breast cancers that are detected between regular screening intervals are more aggressive and have poorer outcomes than screen‐detected tumors but no valid risk model exists to predict “interval” breast cancers. Here the authors combined breast density with other breast cancer risk factors such as body mass index, family history and a novel measure of age‐adjusted hormonal exposure. Applying this to more than 150 women with interval breast cancer, they find that risk discrimination can be doubled with the combination of factors as compared with just using breast density alone, thus improving risk predictions and clinical recommendations for breast screening procedures.

The overall quality of evidence of autologous platelet‐rich plasma (PRP) for treating chronic wounds remains low. While further well‐designed clinical studies are clearly required to convincingly demonstrate the efficacy of autologous PRP in improved healing of venous leg ulcers (VLUs) and other chronic wounds, there is also an increasing need to better define the underlying mechanisms of action and whether positive outcomes can be predicted based on the analysis of PRP. This brief review will discuss the current understanding of autologous PRP in VLUs and whether molecular evaluation of PRP at the time of collection could potentially be informative to clinical outcomes. Benefits of the autologous PRP treatment strategy include that PRP is easily accessible and is relatively inexpensive and safe. Better understanding of the mechanisms involved could improve treatment, enable supplementation, and/or lead to gains in product development. Analysis of PRP could also add value to future clinical trials on efficacy and potentially personalised treatment regimens.

Benign breast disease (BBD) is an established breast cancer (BC) risk factor, but it is unclear whether the magnitude of the association applies to women at familial or genetic risk. This information is needed to improve BC risk assessment in clinical settings. Using the Prospective Family Study Cohort, we used Cox proportional hazards models to estimate hazard ratios (HRs) and 95% confidence intervals (CIs) for the association of BBD with BC risk. We also examined whether the association with BBD differed by underlying familial risk profile (FRP), calculated using absolute risk estimates from the Breast Ovarian Analysis of Disease Incidence and Carrier Estimation Algorithm (BOADICEA) model. During 176,756 person-years of follow-up (median: 10.9 years, maximum: 23.7) of 17,154 women unaffected with BC at baseline, we observed 968 incident cases of BC. A total of 4,704 (27%) women reported a history of BBD diagnosis at baseline. A history of BBD was associated with a greater risk of BC: HR = 1.31 (95% CI: 1.14–1.50), and did not differ by underlying FRP, with HRs of 1.35 (95% CI: 1.11–1.65), 1.26 (95% CI:1.00–1.60), and 1.40 (95% CI: 1.01–1.93), for categories of full-lifetime BOADICEA score

Age- and body mass index (BMI)-adjusted mammographic density is one of the strongest breast cancer risk factors. DNA methylation is a molecular mechanism that could underlie inter-individual variation in mammographic density. We aimed to investigate the association between breast cancer risk-predicting mammographic density measures and blood DNA methylation. For 436 women from the Australian Mammographic Density Twins and Sisters Study and 591 women from the Melbourne Collaborative Cohort Study, mammographic density (dense area, nondense area and percentage dense area) defined by the conventional brightness threshold was measured using the CUMULUS software, and peripheral blood DNA methylation was measured using the HumanMethylation450 (HM450) BeadChip assay. Associations between DNA methylation at >400,000 sites and mammographic density measures adjusted for age and BMI were assessed within each cohort and pooled using fixed-effect meta-analysis. Associations with methylation at genetic loci known to be associated with mammographic density were also examined. We found no genome-wide significant (p 0.05/299 = 1.7 × 10-4 ). In summary, our study did not find evidence for associations between blood DNA methylation, as measured by the HM450 assay, and conventional mammographic density measures that predict breast cancer risk.

Blood lipids have been associated with the development of a range of cancers, including breast, lung and colorectal cancer. For endometrial cancer, observational studies have reported inconsistent associations between blood lipids and cancer risk. To reduce biases from unmeasured confounding, we performed a bidirectional, two-sample Mendelian randomization analysis to investigate the relationship between levels of three blood lipids (low-density lipoprotein [LDL] and high-density lipoprotein [HDL] cholesterol, and triglycerides) and endometrial cancer risk. Genetic variants associated with each of these blood lipid levels (P

B-group vitamins, as components of the one carbon metabolism pathway, are involved in DNA synthesis, repair and methylation. Our aim was to investigate associations between circulating plasma levels of B vitamins and urothelial cell carcinoma (UCC). We conducted a nested case-control study of UCC within the Melbourne Collaborative Cohort Study. B vitamins were measured in pre-diagnostic plasma samples. Conditional logistic regression was used to estimate odds ratios (OR) for UCC risk associated with circulating B vitamins in 363 matched cases and controls. In a case-only analysis (N = 390), hazard ratios (HR) for overall survival associated with plasma B vitamins were estimated using Cox regression. There were no strong associations between UCC risk and pre-diagnostic levels of plasma B vitamins. No heterogeneity in UCC risk was observed by subtype (invasive or superficial), sex, smoking status or alcohol intake. There was no heterogeneity by country of birth for most B vitamins, except for folate (p-homogeneity = 0.03). In UCC cases, there were no strong associations between plasma B vitamins and overall survival. We found no associations between pre-diagnostic plasma concentrations of B-group vitamins and UCC risk or survival.

Nutrients involved in one-carbon metabolism may play a role in carcinogenesis through DNA replication, repair and methylation mechanisms. Most studies on urothelial cell carcinoma (UCC) have focused on folate. We sought to examine the association between B-group vitamins and methionine intake and UCC risk, overall and by subtype, and to test whether these associations are different for population subgroups whose nutritional status may be compromised. We followed participants in the Melbourne Collaborative Cohort Study (N = 41,513) for over 20 years and observed 500 UCC cases (89% originating in the bladder; superficial: 279, invasive: 221). Energy-adjusted dietary intakes of B vitamins (B1, B2, B3, B5, B6, B8, B9 and B12) and methionine were estimated from a 121-item food frequency questionnaire administered at baseline (1990-1994), using the residuals method. We used Cox regression models to compute hazard ratios (HRs) of UCC risk per standard deviation (SD) of log-transformed nutrient intakes and 95% confidence intervals, adjusted for potential confounders. We investigated associations by tumor subtype, and tested interactions with sex, country of birth, smoking and alcohol drinking. The risk of UCC appeared not to be associated with intake of B-group vitamins or methionine, and findings were consistent across tumor subtypes and across demographic and lifestyle characteristics of the participants. A potential interaction between vitamin B1 and alcohol drinking was observed (all participants: HR per 1 SD = 0.99 (0.91-1.09), never drinkers: HR = 0.81 (0.69-0.97), p-interaction = 0.02), which needs to be confirmed by other studies. Our findings do not indicate that dietary intake of nutrients involved in one-carbon metabolism are associated with UCC risk.

The association between aging and cancer is complex. Recent studies have developed measures of biological aging based on DNA methylation and called them "age acceleration." We aimed to assess the associations of age acceleration with risk of and survival from seven common cancers. Seven case-control studies of DNA methylation and colorectal, gastric, kidney, lung, prostate and urothelial cancer and B-cell lymphoma nested in the Melbourne Collaborative Cohort Study were conducted. Cancer cases, vital status and cause of death were ascertained through linkage with cancer and death registries. Conditional logistic regression and Cox models were used to estimate odds ratios (OR) and hazard ratios (HR) and 95% confidence intervals (CI) for associations of five age acceleration measures derived from the Human Methylation 450 K Beadchip assay with cancer risk (N = 3,216 cases) and survival (N = 1,726 deaths), respectively. Epigenetic aging was associated with increased cancer risk, ranging from 4% to 9% per five-year age acceleration for the 5 measures considered. Heterogeneity by study was observed, with stronger associations for risk of kidney cancer and B-cell lymphoma. An associated increased risk of death following cancer diagnosis ranged from 2% to 6% per five-year age acceleration, with no evidence of heterogeneity by cancer site. Cancer risk and mortality were increased by 15-30% for the fourth versus first quartile of age acceleration. DNA methylation-based measures of biological aging are associated with increased cancer risk and shorter cancer survival, independently of major health risk factors.

The influence of lifestyle factors on survival following a diagnosis of colorectal cancer (CRC) is not well established. We examined associations between lifestyle factors measured before diagnosis and CRC survival. The Melbourne Collaborative Cohort Study collected data on alcohol intake, cigarette smoking and physical activity, and body measurements at baseline (1990-1994) and wave 2 (2003-2007). We included participants diagnosed to 31 August 2015 with incident stages I-III CRC within 10-years post exposure assessment. Information on tumor characteristics and vital status was obtained. Tumor DNA was tested for microsatellite instability (MSI) and somatic mutations in oncogenes BRAF (V600E) and KRAS. We estimated hazard ratios (HRs) for associations between lifestyle factors and overall and CRC-specific mortality using Cox regression. Of 724 eligible CRC cases, 339 died (170 from CRC) during follow-up (average 9.0 years). Exercise (non-occupational/leisure-time) was associated with higher CRC-specific survival for stage II (HR = 0.25, 95% CI: 0.10-0.60) but not stages I/III disease (p for interaction = 0.01), and possibly for colon and KRAS wild-type tumors. Waist circumference was inversely associated with CRC-specific survival (HR = 1.25 per 10 cm increment, 95% CI: 1.08-1.44), independent of stage, anatomic site and tumor molecular status. Cigarette smoking was associated with lower overall survival, with suggestive evidence of worse survival for BRAF mutated CRC, but not with CRC-specific survival. Alcohol intake was not associated with survival. Survival did not differ by MSI status. We have identified pre-diagnostic predictors of survival following CRC that may have clinical and public health relevance.

Tumor testing of colorectal cancers (CRC) for mismatch repair (MMR) deficiency is an effective approach to identify carriers of germline MMR gene mutation (Lynch syndrome). The aim of this study was to identify MMR gene mutation carriers in two cohorts of population-based CRC utilizing a combination of tumor and germline testing approaches.

BACKGROUND Global measures of peripheral blood DNA methylation have been associated with risk of some malignancies, including breast, bladder, and gastric cancer. Here, we examined genome-wide measures of peripheral blood DNA methylation in prostate cancer and its non-aggressive and aggressive disease forms. METHODS We used a matched, case-control study of 687 incident prostate cancer samples, nested within a larger prospective cohort study. DNA methylation was measured in pre-diagnostic, peripheral blood samples using the Illumina Infinium HM450K BeadChip. Genome-wide measures of DNA methylation were computed as the median M-value of all CpG sites and according to CpG site location and regulatory function. We used conditional logistic regression to test for associations between genome-wide measures of DNA methylation and risk of prostate cancer and its subtypes, and by time between blood draw and diagnosis. RESULTS We observed no associations between the genome-wide measure of DNA methylation based on all CpG sites and risk of prostate cancer or aggressive disease. Risk of non-aggressive disease was associated with higher methylation of CpG islands (OR = 0.80; 95%CI = 0.68–0.94), promoter regions (OR = 0.79; 95%CI = 0.66–0.93), and high density CpG regions (OR = 0.80; 95%CI = 0.68–0.94). Additionally, higher methylation of all CpGs (OR = 0.66; 95%CI = 0.48–0.89), CpG shores (OR = 0.62; 95%CI = 0.45–0.84), and regulatory regions (OR = 0.68; 95% CI = 0.51–0.91) was associated with a reduced risk of overall prostate cancer within 5 years of blood draw but not thereafter. CONCLUSIONS A reduced risk of overall prostate cancer within 5 years of blood draw and non-aggressive prostate cancer was associated with higher genome-wide methylation of peripheral blood DNA. While these data have no immediate clinical utility, with further work they may provide insight into the early events of prostate carcinogenesis. Prostate 77:471–478, 2017. © 2017 Wiley Periodicals, Inc.

Ethanol in alcoholic beverages is a causative agent for colorectal cancer. Colorectal cancer is a biologically heterogeneous disease, and molecular subtypes defined by the presence of somatic mutations in BRAF and KRAS are known to exist. We examined associations between lifetime alcohol intake and molecular and anatomic subtypes of colorectal cancer. We calculated usual alcohol intake for 10-year periods from age 20 using recalled frequency and quantity of beverage-specific consumption for 38,149 participants aged 40-69 years from the Melbourne Collaborative Cohort Study. Cox regression was performed to derive hazard ratios (HRs) and 95% confidence intervals (CIs) for the association between lifetime alcohol intake and colorectal cancer risk. Heterogeneity in the HRs across subtypes of colorectal cancer was assessed. A positive dose-dependent association between lifetime alcohol intake and overall colorectal cancer risk (mean follow-up = 14.6 years; n = 596 colon and n = 326 rectal cancer) was observed (HR = 1.08, 95% CI: 1.04-1.12 per 10 g/day increment). The risk was greater for rectal than colon cancer (phomogeneity = 0.02). Alcohol intake was associated with increased risks of KRAS+ (HR = 1.07, 95% CI: 1.00-1.15) and BRAF-/KRAS- (HR = 1.05, 95% CI: 1.00-1.11) but not BRAF+ tumors (HR = 0.89, 95% CI: 0.78-1.01; phomogeneity = 0.01). Alcohol intake is associated with an increased risk of KRAS+ and BRAF-/KRAS- tumors originating via specific molecular pathways including the traditional adenoma-carcinoma pathway but not with BRAF+ tumors originating via the serrated pathway. Therefore, limiting alcohol intake from a young age might reduce colorectal cancer originating via the traditional adenoma-carcinoma pathway.

DNA methylation changes are associated with cigarette smoking. We used the Illumina Infinium HumanMethylation450 array to determine whether methylation in DNA from pre-diagnostic, peripheral blood samples is associated with lung cancer risk. We used a case-control study nested within the EPIC-Italy cohort and a study within the MCCS cohort as discovery sets (a total of 552 case-control pairs). We validated the top signals in 429 case-control pairs from another 3 studies. We identified six CpGs for which hypomethylation was associated with lung cancer risk: cg05575921 in the AHRR gene (p-valuepooled = 4 × 10-17 ), cg03636183 in the F2RL3 gene (p-valuepooled = 2 × 10 - 13 ), cg21566642 and cg05951221 in 2q37.1 (p-valuepooled = 7 × 10-16 and 1 × 10-11 respectively), cg06126421 in 6p21.33 (p-valuepooled = 2 × 10-15 ) and cg23387569 in 12q14.1 (p-valuepooled = 5 × 10-7 ). For cg05951221 and cg23387569 the strength of association was virtually identical in never and current smokers. For all these CpGs except for cg23387569, the methylation levels were different across smoking categories in controls (p-valuesheterogeneity ≤ 1.8 x10 - 7 ), were lowest for current smokers and increased with time since quitting for former smokers. We observed a gain in discrimination between cases and controls measured by the area under the ROC curve of at least 8% (p-values ≥ 0.003) in former smokers by adding methylation at the 6 CpGs into risk prediction models including smoking status and number of pack-years. Our findings provide convincing evidence that smoking and possibly other factors lead to DNA methylation changes measurable in peripheral blood that may improve prediction of lung cancer risk.

Background: Evidence suggests that specific allergen sensitizations are associated with different allergic diseases which may reflect different underlying immune profiles. We aimed to examine the cytokine profiles of individuals sensitized to eight common aeroallergens. Methods: We used data from the Tasmanian Longitudinal Health Study a population-based cohort study of 45-year-olds. Serum cytokines (IL-4, IL-5, IL-6, IL-8, IL-10, TNF-α) were measured in 1157 subjects using the LINCOplex assays. Participants underwent skin prick testing for house dust mite, cat, grasses and moulds. Multivariable linear regression was used to compare serum cytokine levels between sensitized and nonatopic subjects. Results: The prevalence of allergic sensitization to any aeroallergen was 51% (95% CI 47–54). Being sensitized to any aeroallergen was strongly associated with current asthma (OR = 3.7, 95% CI 2.6–5.3), and being sensitized to any moulds was associated with a very high risk of current asthma (OR = 6.40, 95% CI 4.06–10.1). The geometric mean (GM) levels of Th2 cytokines (IL-4, IL-5 and IL-6) for adults sensitized to Cladosporium were significantly lower than the levels for nonatopic individuals (IL-4 ratio of GMs = 0.25, 95% CI 0.10–0.62, P = 0.003; IL-5 GM = 0.55, 95% CI 0.30–0.99, P = 0.05; and IL-6 GM = 0.50, 95% CI 0.24–1.07, P = 0.07). Individuals sensitized to other aeroallergens all showed elevated Th2 cytokine levels. Conclusion: Our study is the first large population-based study to demonstrate reduced Th2 cytokines levels in people sensitized to mould. Underlying biological mechanisms driving allergic inflammatory responses in adults sensitized to moulds may differ from those sensitized to other aeroallergens. These findings suggest that it may be necessary to tailor treatments in individuals sensitized to moulds compared with other aeroallergens in order to optimize outcomes.

Previous genome-wide association studies among women of European ancestry identified two independent breast cancer susceptibility loci represented by single nucleotide polymorphisms (SNPs) rs13281615 and rs11780156 at 8q24. A fine-mapping study across 2.06 Mb (chr8:127,561,724-129,624,067, hg19) in 55,540 breast cancer cases and 51,168 controls within the Breast Cancer Association Consortium was conducted. Three additional independent association signals in women of European ancestry, represented by rs35961416 (OR = 0.95, 95% CI = 0.93-0.97, conditional p = 5.8 × 10(-6) ), rs7815245 (OR = 0.94, 95% CI = 0.91-0.96, conditional p = 1.1 × 10(-6) ) and rs2033101 (OR = 1.05, 95% CI = 1.02-1.07, conditional p = 1.1 × 10(-4) ) were found. Integrative analysis using functional genomic data from the Roadmap Epigenomics, the Encyclopedia of DNA Elements project, the Cancer Genome Atlas and other public resources implied that SNPs rs7815245 in Signal 3, and rs1121948 in Signal 5 (in linkage disequilibrium with rs11780156, r(2) = 0.77), were putatively functional variants for two of the five independent association signals. The results highlighted multiple 8q24 variants associated with breast cancer susceptibility in women of European ancestry.

Germline mutations in the DNA base excision repair gene MUTYH are known to increase a carrier's risk of colorectal cancer. However, the risks of other (extracolonic) cancers for MUTYH mutation carriers are not well defined. We identified 266 probands (91% Caucasians) with a MUTYH mutation (41 biallelic and 225 monoallelic) from the Colon Cancer Family Registry. Mutation status, sex, age and histories of cancer from their 1,903 first- and 3,255 second-degree relatives were analyzed using modified segregation analysis conditioned on the ascertainment criteria. Compared with incidences for the general population, hazard ratios (HRs) (95% confidence intervals [CIs]) for biallelic MUTYH mutation carriers were: urinary bladder cancer 19 (3.7-97) and ovarian cancer 17 (2.4-115). The HRs (95% CI) for monoallelic MUTYH mutation carriers were: gastric cancer 9.3 (6.7-13); hepatobiliary cancer 4.5 (2.7-7.5); endometrial cancer 2.1 (1.1-3.9) and breast cancer 1.4 (1.0-2.0). There was no evidence for an increased risk of cancers at the other sites examined (brain, pancreas, kidney or prostate). Based on the USA population incidences, the estimated cumulative risks (95% CI) to age 70 years for biallelic mutation carriers were: bladder cancer 25% (5-77%) for males and 8% (2-33%) for females and ovarian cancer 14% (2-65%). The cumulative risks (95% CI) for monoallelic mutation carriers were: gastric cancer 5% (4-7%) for males and 2.3% (1.7-3.3%) for females; hepatobiliary cancer 3% (2-5%) for males and 1.4% (0.8-2.3%) for females; endometrial cancer 3% (2%-6%) and breast cancer 11% (8-16%). These unbiased estimates of both relative and absolute risks of extracolonic cancers for people, mostly Caucasians, with MUTYH mutations will be important for their clinical management.

Epithelial-mesenchymal transition (EMT) is a process whereby epithelial cells assume mesenchymal characteristics to facilitate cancer metastasis. However, EMT also contributes to the initiation and development of primary tumors. Prior studies that explored the hypothesis that EMT gene variants contribute to epithelial ovarian carcinoma (EOC) risk have been based on small sample sizes and none have sought replication in an independent population. We screened 15,816 single-nucleotide polymorphisms (SNPs) in 296 genes in a discovery phase using data from a genome-wide association study of EOC among women of European ancestry (1,947 cases and 2,009 controls) and identified 793 variants in 278 EMT-related genes that were nominally (P < 0.05) associated with invasive EOC. These SNPs were then genotyped in a larger study of 14,525 invasive-cancer patients and 23,447 controls. A P-value

The survival of breast cancer patients is largely influenced by tumor characteristics, such as TNM stage, tumor grade and hormone receptor status. However, there is growing evidence that inherited ...

BACKGROUND: Polygenic risk scores comprising established susceptibility variants have shown to be informative classifiers for several complex diseases including prostate cancer. For prostate cancer it is unknown if inclusion of genetic markers that have so far not been associated with prostate cancer risk at a genome-wide significant level will improve disease prediction. METHODS: We built polygenic risk scores in a large training set comprising over 25,000 individuals. Initially 65 established prostate cancer susceptibility variants were selected. After LD pruning additional variants were prioritized based on their association with prostate cancer. Six-fold cross validation was performed to assess genetic risk scores and optimize the number of additional variants to be included. The final model was evaluated in an independent study population including 1,370 cases and 1,239 controls. RESULTS: The polygenic risk score with 65 established susceptibility variants provided an area under the curve (AUC) of 0.67. Adding an additional 68 novel variants significantly increased the AUC to 0.68 (P = 0.0012) and the net reclassification index with 0.21 (P = 8.5E-08). All novel variants were located in genomic regions established as associated with prostate cancer risk. CONCLUSIONS: Inclusion of additional genetic variants from established prostate cancer susceptibility regions improves disease prediction.

Mammographic density (MD) is an intermediate phenotype for breast cancer. Previous studies have identified genetic variants associated with MD; however, much of the genetic contribution to MD is unexplained. We conducted a two-stage genome-wide association analysis among the participants in the "Determinants of Density in Mammographies in Spain" study, together with a replication analysis in women from the Australian MD Twins and Sisters Study. Our discovery set covered a total of 3,351 Caucasian women aged 45 to 68 years, recruited from Spanish breast cancer screening centres. MD was blindly assessed by a single reader using Boyd's scale. A two-stage approach was employed, including a feature selection phase exploring 575,374 SNPs in 239 pairs of women with extreme phenotypes and a verification stage for the 183 selected SNPs in the remaining sample (2,873 women). Replication was conducted in 1,786 women aged 40 to 70 years old recruited via the Australian Twin Registry, where MD were measured using Cumulus-3.0, assessing 14 SNPs with a p value

A large genotyping project within the Breast Cancer Association Consortium (BCAC) recently identified 41 associations between single nucleotide polymorphisms (SNPs) and overall breast cancer (BC) risk. We investigated whether the effects of these 41 SNPs, as well as six SNPs associated with estrogen receptor (ER) negative BC risk are modified by 13 environmental risk factors for BC. Data from 22 studies participating in BCAC were pooled, comprising up to 26,633 cases and 30,119 controls. Interactions between SNPs and environmental factors were evaluated using an empirical Bayes-type shrinkage estimator. Six SNPs showed interactions with associated p-values (pint )

BACKGROUND Inflammation has been implicated in prostate cancer (PCa) pathogenesis. Promoter DNA variants responsible for differential expression of key cytokines may therefore influence susceptibility to PCa. METHODS Two interleukin-6 (IL-6) promoter variants, −174G>C and −6331T>C, were genotyped for association with PCa risk and survival using the Risk Factors for Prostate Cancer Study (RFPCS, 825 cases and 732 controls) and the Melbourne Collaborative Cohort Study (MCCS, 818 cases and 1,745 controls). Impact of genotypes on IL-6 transcriptional activity was measured using Low Density Arrays. RESULTS A significant increase in IL-6 transcriptional activity in malignant compared to benign prostate tissue supports a role for IL-6 in PCa. The −174G>C variant showed no association with PCa risk, overall survival, or IL-6 transcriptional activity. The −6331 C-allele was significantly associated with an increased risk in the RFPCS (OR = 1.29, 95% CI = 1.08–1.54), but not in the MCCS. In the MCCS however, cases presenting with a CC genotype conferred a higher risk of mortality (HR = 2.27, 95% CI = 1.34–3.85), which was maintained although reduced overall in the pooled analysis with RFPCS (HR = 1.68, 95% CI = 1.10–2.54). Furthermore, we associate the minor C-allele with a significant decrease in IL-6 transcriptional activity. CONCLUSIONS While our study refutes a role for IL-6 −174G>C, it is the first to implicate −6331T>C with PCa risk and poor survival. Our observation that −6331T>C has a significant impact on IL-6 transcriptional activity, calls for further investigations into the role of this variant as a novel PCa biomarker. Prostate 72:1701–1707, 2012. © 2012 Wiley Periodicals, Inc.

Cancer risks for a person who has inherited a MUTYH mutation from only one parent (monoallelic mutation carrier) are uncertain. Using the Colon Cancer Family Registry and Newfoundland Familial Colon Cancer Registry, we identified 2,179 first- and second-degree relatives of 144 incident colorectal cancer (CRC) cases who were monoallelic or biallelic mutation carriers ascertained by sampling population complete cancer registries in the United States, Canada and Australia. Using Cox regression weighted to adjust for sampling on family history, we estimated that the country-, age- and sex-specific standardized incidence ratios (SIRs) for monoallelic mutation carriers, compared to the general population, were: 2.04 (95% confidence interval, CI 1.56-2.70; p < 0.001) for CRC, 3.24 (95%CI 2.18-4.98; p < 0.001) for gastric cancer, 3.09 (95%CI 1.07-12.25; p = 0.07) for liver cancer and 2.33 (95%CI 1.18-5.08; p = 0.02) for endometrial cancer. Age-specific cumulative risks to age 70 years, estimated using the SIRs and US population incidences, were: for CRC, 6% (95%CI 5-8%) for men and 4% (95%CI 3-6%) for women; for gastric cancer, 2% (95%CI 1-3%) for men and 0.7% (95%CI 0.5-1%) for women; for liver cancer, 1% (95%CI 0.3-3%) for men and 0.3% (95%CI 0.1-1%) for women and for endometrial cancer, 4% (95%CI 2-8%). There was no evidence of increased risks for cancers of the brain, pancreas, kidney, lung, breast or prostate. Monoallelic MUTYH mutation carriers with a family history of CRC, such as those identified from screening multiple-case CRC families, are at increased risk of colorectal, gastric, endometrial and possibly liver cancers.

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.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 TGFbetaRII) and somatic k-ras mutations. We measured SMAD4 protein expression using immunohistochemistry and SMAD4 copy number using quantitative real-time PCR.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 TGFbetaR11 mutation status, SMAD4 copy number, family history, MSI status, tumour stage or grade.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.

Haplotype-based association studies have been proposed as a powerful comprehensive approach to identify causal genetic variation underlying complex diseases. Data comparisons within families offer the additional advantage of dealing naturally with complex sources of noise, confounding and population stratification. Two problems encountered when investigating associations between haplotypes and a continuous trait using data from sibships are (i) the need to define within-sibship comparisons for sibships of size greater than two and (ii) the difficulty of resolving the joint distribution of haplotype pairs within sibships in the absence of parental genotypes. We therefore propose first a method of orthogonal transformation of both outcomes and exposures that allow the decomposition of between- and within-sibship regression effects when sibship size is greater than two. We conducted a simulation study, which confirmed analysis using all members of a sibship is statistically more powerful than methods based on cross-sectional analysis or using subsets of sib-pairs. Second, we propose a simple permutation approach to avoid errors of inference due to the within-sibship correlation of any errors in haplotype assignment. These methods were applied to investigate the association between mammographic density (MD), a continuously distributed and heritable risk factor for breast cancer, and single nucleotide polymorphisms (SNPs) and haplotypes from the VDR gene using data from a study of 430 twins and sisters. We found evidence of association between MD and a 4-SNP VDR haplotype. In conclusion, our proposed method retains the benefits of the between- and within-pair analysis for pairs of siblings and can be implemented in standard software.

LAMBDA is a model that estimates the probability an Ashkenazi Jewish (AJ) woman carries an ancestral BRCA1 or BRCA2 mutation from her personal and family cancer history. LAMBDA is relevant to clinical practice, and its implementation does not require a computer. It was developed principally from Australian and UK data. We conducted a validation study using 1286 North American AJ women tested for the mutations 185delAG and 5382insC in BRCA1 and 6174delT in BRCA2. Most had a personal or family history of breast cancer. We observed 197 carriers. The area under the receiver operator characteristic (ROC) curve (a measure of ranking) was 0.79 [95% confidence interval (CI) = 0.77-0.81], similar to that for the model-generating data (0.78; 95% CI = 0.75-0.82). LAMBDA predicted 232 carriers (18% more than observed; p = 0.002) and was overdispersed (p = 0.009). The Bayesian computer program BRCAPRO gave a similar area under the ROC curve (0.78; 95% CI = 0.76-0.80), but predicted 367 carriers (86% more than observed; p < 0.0001), and was substantially overdispersed (p < 0.0001). Therefore, LAMBDA is comparable to BRCAPRO for ranking AJ women according to their probability of being a BRCA1 or BRCA2 mutation carrier and is more accurate than brcapro which substantially overpredicts carriers in this population.

Moderate to high-dose radiotherapy is known to increase the risk of breast cancer. Uncertainties remain about the effects of low-dose chest X-rays, particularly in individuals at increased genetic risk. We analyzed case-control data from the Breast Cancer Family Registry. Self-reported data on therapeutic and diagnostic radiation exposures to the chest were available for 2,254 breast cancer cases and 3,431 controls (1,556 unaffected sisters and 1,875 unrelated population controls). We used unconditional logistic regression analyses to estimate odds ratios (OR) and 95% confidence intervals (CI) associated with radiation exposure, after adjusting for age, study center, country of birth, and education. Increased risks for breast cancer were found for women who had radiotherapy for a previous cancer (OR=3.55, CI=1.47-8.54) and diagnostic chest X-rays for tuberculosis (OR=2.49, CI=1.82-3.40) or pneumonia (OR=2.19, CI=1.38-3.47). Risks were highest for women with a large number of exposures at a young age or exposed in earlier calendar years. There was no evidence of increased risk associated with other diagnostic chest X-rays (not including tuberculosis or pneumonia), both in women with and without indicators of increased genetic risk (i.e., diagnosed at age

Published in International Journal of Cancer, 2007; 120 (4):776-780 at www.interscience.wiley.com

Various statistical methods have been proposed to evaluate associations between measured genetic variants and disease, including some using family designs. For breast cancer and rare variants, we applied a modified segregation analysis method that uses the population cancer incidence and population-based case families in which a mutation is known to be segregating. Here we extend the method to a common polymorphism, and use a regressive logistic approach to model familial aggregation by conditioning each individual on their mother's breast cancer history. We considered three models: 1) class A regressive logistic model; 2) age-of-onset regressive logistic model; and 3) proportional hazards familial model. Maximum likelihood estimates were calculated using the software MENDEL. We applied these methods to data from the Australian Breast Cancer Family Study on the CYP17 5'UTR T--C MspA1 polymorphism measured for 1,447 case probands, 787 controls, and 213 relatives of case probands found to have the CC genotype. Breast cancer data for first- and second-degree relatives of case probands were used. The three methods gave consistent estimates. The best-fitting model involved a recessive inheritance, with homozygotes being at an increased risk of 47% (95% CI, 28-68%). The cumulative risk of the disease up to age 70 years was estimated to be 10% or 22% for a CYP17 homozygote whose mother was unaffected or affected, respectively. This analytical approach is well-suited to the data that arise from population-based case-control-family studies, in which cases, controls and relatives are studied, and genotype is measured for some but not all subjects.

Only a minority of prostate cancers lead to death. Because no tissue biomarkers of aggressiveness other than Gleason score are available at diagnosis, many nonlethal cancers are treated aggressively. We evaluated whether a panel of biomarkers, associated with a range of disease outcomes in previous studies, could predict death from prostate cancer for men with localized disease. Using a case-only design, subjects were identified from three Australian epidemiological studies. Men who had died of their disease, “cases” (N = 83), were matched to “referents” (N = 232), those who had not died of prostate cancer, using incidence density sampling. Diagnostic tissue was retrieved to assess expression of AZGP1, MUC1, NKX3.1, p53, and PTEN by semiquantitative immunohistochemistry (IHC). Poisson regression was used to estimate mortality rate ratios (MRRs) adjusted for age, Gleason score, and stage and to estimate survival probabilities. Expression of MUC1 and p53 was associated with increased mortality (MRR 2.51, 95% CI 1.14–5.54, P = 0.02 and 3.08, 95% CI 1.41–6.95, P = 0.005, respectively), whereas AZGP1 expression was associated with decreased mortality (MRR 0.44, 95% CI 0.20–0.96, P = 0.04). Analyzing all markers under a combined model indicated that the three markers were independent predictors of prostate cancer death and survival. For men with localized disease at diagnosis, assessment of AZGP1, MUC1, and p53 expression in diagnostic tissue by IHC could potentially improve estimates of risk of dying from prostate cancer based only on Gleason score and clinical stage.

BACKGROUND Women with breast carcinoma diagnosed before age 40 years have a greater prevalence of germline BRCA1 and BRCA2 mutations than women with breast carcinoma diagnosed at older ages. Several recognizable histologic characteristics have been identified in breast carcinoma from studies of BRCA1/2 mutation carriers who belong to multiple-case families. The authors attempted to determine whether breast carcinoma occurring before age 40 years in BRCA1 or BRCA2 mutation carriers who were not selected for family history could be distinguished histologically from one another and from breast carcinoma in women of a similar age without a germline BRCA1 or BRCA2 mutation. METHODS The study undertook a histologic assessment of breast carcinomas diagnosed before age 40 years identified from a population-based study. RESULTS Breast carcinoma in BRCA1 mutation carriers was associated with a distinct histologic appearance; these tumors were high grade, and had exceptionally high mean mitotic counts, a syncytial growth pattern, pushing margins, and confluent necrosis. Atypical medullary carcinoma was overrepresented in BRCA1 mutation carriers. All low grade tumors and tumors with low mitotic rates belonged to the group without BRCA1 or BRCA2 mutations. Pleomorphic lobular carcinomas and extensive intraduct carcinomas were more common in BRCA2 mutation carriers. CONCLUSIONS Breast carcinoma occurring in women with a germline BRCA1 or BRCA2 mutation have recognizable histologic phenotypes, which may be useful in identifying individuals more likely to carry germline mutations. Histologic examination of breast carcinoma should become an important part of the evaluation of women seeking genetic testing for germline mutations in these breast carcinoma susceptibility genes. [See editorial on pages 2251-4, this issue.] Cancer 1998;83:2335-2345. © 1998 American Cancer Society.

pression, whereas the other contained two clonal populations and was controlled only after treatment with antineoplastic chemotherapy. Conclusion. This study has demonstrated two cases of PTLPD that were derived from donor lymphoid tissue. Although both cases were associated with EBV and remained localized to allograft tissue, their clonality and response to therapy differed. Cancer 1994;74:2436-41.

The message of our Editorial, summarized in its title, wasthat molecular screening of colorectal cancer tumors for mis-match repair loss followed by germline testing of mismatchrepair (MMR) genes, when applied to cases of colorectal can-cer diagnosed before the age of 50 years, was an efficientmethod to identify MMR gene mutation carriers.A study of a series of 501 colorectal cancer patients unse-lected for family history by Hampel and colleagues

Familial aggregation of prostate cancer is likely to be due to multiple susceptibility loci, perhaps acting in conjunction with shared lifestyle risk factors. Models that assume a single mode of inheritance may be unrealistic. We analyzed genetic models of susceptibility to prostate cancer using segregation analysis of occurrence in families ascertained through population-based series totaling 4390 incident cases. We investigated major gene models (dominant, recessive, general, X-linked), polygenic models, and mixed models of susceptibility using the pedigree analysis software MENDEL. The hypergeometric model was used to approximate polygenic inheritance. The best-fitting model for the familial aggregation of prostate cancer was the mixed recessive model. The frequency of the susceptibility allele in the population was estimated to be 0.15 (95% confidence interval (CI) 0.11-0.20), with a relative risk for homozygote carriers of 94 (95% Cl 46-192), and a polygenic standard deviation of 2.01 (95% Cl 1.72-2.34). These analyses suggest that one or more genes having a strong recessively inherited effect on risk, as well as a number of genes with variants having small multiplicative effects on risk, may account for the genetic susceptibility to prostate cancer. The recessive component would predict the observed higher familial risk for siblings of cases than for fathers, but this could also be due to other factors such as shared lifestyle by siblings, targeted screening effects, and/or non-additive effects of one or more genes. Genet. Epidemiol. 34:42-50, 2010. (c) 2009 Wiley-Liss, Inc.

There has been recent interest in the risk of various cancers in cystic fibrosis (CF) patients and carriers of cystic fibrosis transmembrane conductance regulator (CFTR) mutations. It has been proposed that a CFTR mutation may protect against breast cancer, based on evidence that elevated extracellular adenosine triphosphate (ATP) is known to inhibit breast cancer cell line growth and that CFTR pumps ATP out of epithelial cells. A CFTR mutation would therefore result in higher concentrations of serum ATP. A CFTR knockout mouse model had high serum concentrations of ATP and showed reduced breast tumour implantibility and decreased breast cancer growth rates. We have evaluated the relationship between the deltaF508 CFTR mutation and the risk of breast cancer before the age of 40. The deltaF508 CFTR mutation carrier rate in 272 cases (2.2%) was no different from the carrier rate observed in 171 controls (1.8%). If there was a protective effect resulting from the postulated elevation in serum ATP levels, tumours arising in deltaF508 CFTR carriers would have been expected to be generally less aggressive. When the histological features of the breast cancers with a deltaF508 CFTR mutation were reviewed and graded using a combined architectural and cytological grading system, all were found to be grade III, poorly differentiated tumours, contrary to the predictions. A combination of our data with other large population-based samples of cases and controls is required to resolve this issue.

OBJECTIVE: To use a large population-based case-control study to test the association between the common genetic variant rs743572 (−34 T to C), prostate cancer risk and circulating levels of several hormones.SUBJECTS AND METHODS: A previous meta-analysis concluded that reported associations between rs743572 in the promoter of CYP17A1 and prostate cancer risk might reflect publication bias, but a few recent studies reported associations with prostate cancer risk and data suggesting that rs743572 is functional. We genotyped 824 prostate cancer cases and 737 population-based controls, and applied unconditional logistic regression to estimate the association between rs743572 and prostate cancer risk. We also used linear regression of transformed testosterone, androstanediol glucuronide, dehydroepiandrosterone sulphate, androstenedione, sex hormone-binding globulin and oestradiol (circulating levels) measured for controls, to estimate the association between these levels and rs743572. The linear models were adjusted for age and laboratory batch.RESULTS: Men with different genotypes had similar circulating levels of all the hormones measured (all P < 0.05). In the case-control comparison using unconditional unadjusted logistic regression, the odds ratios (95% confidence interval) for prostate cancer were 1.07 (0.87-1.32) and 0.94 (0.71-1.25) for the dominant and recessive models, respectively, and for the co-dominant model, 1.10 (0.88-1.36) and 0.99 (0.73-1.35) for carriers of one or two copies of the C allele, respectively. There was no evidence of heterogeneity in the odds ratios by tumour stage (all P > 0.3) and grade (all P > 0.3).CONCLUSION: The results of the present study are consistent with the conclusions of the previous meta-analysis, and suggest that rs743572 has no role in the risk of prostate cancer for men of Caucasian origin.