The BOADICEA model of genetic susceptibility to breast and ovarian cancers: updates and extensions

Multiple genetic loci confer susceptibility to breast and ovarian cancers. We have previously developed a model (BOADICEA) under which susceptibility to breast cancer is explained by mutations in BRCA1 and BRCA2, as well as by the joint multiplicative effects of many genes (polygenic component). We have now updated BOADICEA using additional family data from two UK population-based studies of breast cancer and family data from BRCA1 and BRCA2 carriers identified by 22 population-based studies of breast or ovarian cancer. The combined data set includes 2785 families (301 BRCA1 positive and 236 BRCA2 positive). Incidences were smoothed using locally weighted regression techniques to avoid large variations between adjacent intervals. A birth cohort effect on the cancer risks was implemented, whereby each individual was assumed to develop cancer according to calendar period-specific incidences. The fitted model predicts that the average breast cancer risks in carriers increase in more recent birth cohorts. For example, the average cumulative breast cancer risk to age 70 years among BRCA1 carriers is 50% for women born in 1920-1929 and 58% among women born after 1950. The model was further extended to take into account the risks of male breast, prostate and pancreatic cancer, and to allow for the risk of multiple cancers. BOADICEA can be used to predict carrier probabilities and cancer risks to individuals with any family history, and has been implemented in a user-friendly Web-based program (http://www.srl.cam.ac.uk/genepi/boadicea/boadicea_home.html).     

CLPTM1L/CRR9 ectodomain interaction with GRP78 at the cell surface signals for survival and chemoresistance upon ER stress in pancreatic adenocarcinoma cells

Altered regulation of endoplasmic reticulum (ER) homeostasis has been implicated in many cancers and has recently become a therapeutic and chemosensitization target of interest. We have identified Cleft Lip and Palate Transmembrane 1-Like (CLPTM1L)/Cisplatin Resistance Related Protein 9 (CRR9) as an ER stress related mediator of cytoprotection in pancreatic cancer. We recently demonstrated that CLPTM1L is highly expressed in pancreatic ductal adenocarcinoma and associated with poor outcome. Furthermore, we have discovered that CLPTM1L interacts with phosphoinositol-3-kinase-alpha at the tumor cell surface and causes up-regulation of Bcl-xL and pAkt mediated survival signaling. Here, we demonstrate surface relocalization and survival signaling by CLPTM1L triggered by endoplasmic reticular (ER) stress. We demonstrate the interaction of CLPTM1L with the central ER stress survival mediator, Glucose Regulated Protein 78 (GRP78)/Binding Immunoglobulin Protein (BiP) and PI3K-alpha /p110α. This interaction and surface relocalization of CLPTM1L and GRP78 is induced by ER stress, including that caused by treatment with gemcitabine. We demonstrate that the extracellular loop of CLPTM1L is required for gemcitabine resistance and interaction with GRP78. This interaction and the chemoresistance effect conferred by this pathway is targetable with our recently developed inhibitory CLPTM1L antibodies, which may represent novel modalities of chemosensitization and treatment of pancreatic adenocarcinoma. Anchorage independent growth, GRP78-mediated chemoresistance, and Akt phosphorylation were abrogated by inhibition of CLPTM1L. These findings demonstrate a novel and potentially targetable mechanism of cytoprotection and chemoresistance in pancreatic tumors.     

Occupation and risk of oesophageal adenocarcinoma and squamous‐cell carcinoma: The Nordic Occupational Cancer Study

To assess associations between occupation and risk of oesophageal adenocarcinoma (AC) and squamous‐cell carcinoma (SCC), data from the Nordic Occupational Cancer Study, a large population‐based cohort with long‐term follow‐up, was used. The Nordic Occupational Cancer Study includes 12.9 million individuals aged 30–64 years who participated in national censuses in Finland, Iceland, Norway and Sweden in 1960–1990. Individuals were assigned to one of the 54 occupational categories, and individuals with oesophageal cancer were identified through nationwide cancer registries with follow‐up through 2005. Country‐specific standardised incidence ratios (SIRs) with 95% confidence intervals (CIs) were estimated. During follow‐up, 4,722 ACs and 14,496 SCCs were observed. Among men, increased risks of AC and SCC were observed among waiters (SIR = 2.58, 95% CI 1.41–4.32 and SIR = 3.22, 95% CI 2.30–4.38 for AC and SCC, respectively), cooks and stewards (1.72, 1.04–2.69 and 2.53, 1.94–3.25), seamen (1.52, 1.16–1.95 and 1.77, 1.53–2.05), food workers (1.51, 1.18–1.90 and 1.21, 1.03–1.42), miscellaneous construction workers (1.24, 1.04–1.48 and 1.39, 1.25–1.54) and drivers (1.16, 1.01–1.33 and 1.23, 1.13–1.34). Decreased risks of AC and SCC were observed among technical workers, physicians, teachers, religious workers and gardeners. The SIR for AC was significantly different from that for SCC in six occupational categories. Among women, increased risks among food workers and waiters and decreased risks among teachers, nurses and assistant nurses were observed for SCC only. In both sexes, increased risks were observed among waiters and food workers, and decreased risks were observed among teachers. This large cohort study indicates that the risk of oesophageal cancer varies by occupation, but not by histological type in most occupational categories.     

Occupational solvent exposure and adult chronic lymphocytic leukemia: No risk in a population‐based case–control study in four Nordic countries

The aim of this study was to assess the effect of occupational solvent exposure on the risk of adult chronic lymphocytic leukemia (CLL). The current case–control study was nested in the Nordic Occupational Cancer Study (NOCCA) cohort. 20,615 CLL cases diagnosed in 1961–2005 in Finland, Iceland, Norway, and Sweden, and 103,075 population‐based controls matched by year of birth, sex, and country were included. Occupational histories for cases and controls were obtained from census records in 1960, 1970, 1980/1981, and 1990. Exposure to selected solvents was estimated by using the NOCCA job‐exposure matrix (NOCCA‐JEM). Odds ratios (OR) and 95% confidence intervals (95% CI) were estimated by using conditional logistic regression models. Overall, nonsignificant CLL risk elevations were observed for methylene chloride, perchloroethylene, and 1,1,1‐trichloroethane. Compared to unexposed, significantly increased risks were observed for cumulative perchloroethylene exposure ≤13.3 ppm‐years (OR = 1.85, 95% CI 1.16–2.96) and average life‐time perchloroethylene exposure ≤2.5 ppm (1.61, 95% CI 1.01–2.56) among women, and cumulative methylene chloride exposure ≤12.5 ppm‐years (OR = 1.19, 95% CI 1.01–1.41) and 12.5–74.8 ppm‐years (OR = 1.23, 95% CI 1.01–1.51) among men in an analysis with 5 years lag‐time, though without dose–response pattern. Decreased CLL risk was observed for aliphatic and alicyclic hydrocarbon solvents and toluene. This study did not support associations for solvent exposure and CLL. Observed weak associations for methylene chloride, perchloroethylene, 1,1,1‐trichloroethane exposures, aliphatic and alicyclic hydrocarbons and toluene were not consistent across sexes, and showed no gradient with amount of exposure.     

Gastrointestinal and liver disease in Adult Life After Childhood Cancer in Scandinavia: A population‐based cohort study

Survival after childhood cancer diagnosis has remarkably improved, but emerging evidence suggests that cancer‐directed therapy may have adverse gastrointestinal late effects. We aimed to comprehensively assess the frequency of gastrointestinal and liver late effects among childhood cancer survivors and compare this frequency with the general population. Our population‐based cohort study included all 1‐year survivors of childhood and adolescent cancer in Denmark, Finland, Iceland, Norway and Sweden diagnosed from the 1940s and 1950s. Our outcomes of interest were hospitalization rates for gastrointestinal and liver diseases, which were ascertained from national patient registries. We calculated standardized hospitalization rate ratios (RRs) and absolute excess rates comparing hospitalizations of any gastrointestinal or liver disease and for specific disease entities between survivors and the general population. The study included 31,132 survivors and 207,041 comparison subjects. The median follow‐up in the hospital registries were 10 years (range: 0–42) with 23% of the survivors being followed at least to the age of 40 years. Overall, survivors had a 60% relative excess of gastrointestinal or liver diseases [RR: 1.6, 95% confidence interval (CI): 1.6–1.7], which corresponds to an absolute excess of 360 (95% CI: 330–390) hospitalizations per 100,000 person‐years. Survivors of hepatic tumors, neuroblastoma and leukemia had the highest excess of gastrointestinal and liver diseases. In addition, we observed a relative excess of several specific diseases such as esophageal stricture (RR: 13; 95% CI: 9.2–20) and liver cirrhosis (RR: 2.9; 95% CI: 2.0–4.1). Our findings provide useful information about the breadth and magnitude of late complications among childhood cancer survivors and can be used for generating hypotheses about potential exposures related to these gastrointestinal and liver late effects.     

Minerals and trace elements in Icelandic dairy products and meat

The aim of this study was to update the Icelandic Food Composition Database with respect to minerals (Ca, K, Mg, Na, and P) and trace elements (Cu, Fe, Hg, Se, and Zn) in frequently consumed agricultural products and to study the seasonal and geographical variation for these elements. Five food products typical for the Icelandic food basket were analysed: whole milk, fresh cheese (skyr), firm cheese (Gouda), lamb meat and minced beef together with skimmed milk, cream and whey. Concentrations of minerals and trace elements were determined by an inductively coupled plasma mass spectrometer (ICP-MS). Seasonal and geographical variation in whole milk was found only for selenium. Concentration of selenium in meat was variable and especially low for beef (1.4–9.6 μg/100 g fresh weight). Mercury was below the detection limit of 0.3 μg/100 g except for one sample of cheese. Skyr was rich in protein, calcium and phosphorus and retains almost all selenium in the skimmed milk used for its production. Skyr whey contains more calcium, magnesium, phosphorus and zinc than cheese whey. Skyr whey is a nutritious product, almost as rich in calcium, potassium and zinc as whole milk and could be used more by the Icelandic food industry.