Artificial intelligence for detection of microsatellite instability in colorectal cancer-a multicentric analysis of a pre-screening tool for clinical application.

BACKGROUND: Microsatellite instability (MSI)/mismatch repair deficiency (dMMR) is a key genetic feature which should be tested in every patient with colorectal cancer (CRC) according to medical guidelines. Artificial intelligence (AI) methods can detect MSI/dMMR directly in routine pathology slides, but the test performance has not been systematically investigated with predefined test thresholds. METHOD: We trained and validated AI-based MSI/dMMR detectors and evaluated predefined performance metrics using nine patient cohorts of 8343 patients across different countries and ethnicities. RESULTS: Classifiers achieved clinical-grade performance, yielding an area under the receiver operating curve (AUROC) of up to 0.96 without using any manual annotations. Subsequently, we show that the AI system can be applied as a rule-out test: by using cohort-specific thresholds, on average 52.73% of tumors in each surgical cohort [total number of MSI/dMMR = 1020, microsatellite stable (MSS)/ proficient mismatch repair (pMMR) = 7323 patients] could be identified as MSS/pMMR with a fixed sensitivity at 95%. In an additional cohort of N = 1530 (MSI/dMMR = 211, MSS/pMMR = 1319) endoscopy biopsy samples, the system achieved an AUROC of 0.89, and the cohort-specific threshold ruled out 44.12% of tumors with a fixed sensitivity at 95%. As a more robust alternative to cohort-specific thresholds, we showed that with a fixed threshold of 0.25 for all the cohorts, we can rule-out 25.51% in surgical specimens and 6.10% in biopsies. INTERPRETATION: When applied in a clinical setting, this means that the AI system can rule out MSI/dMMR in a quarter (with global thresholds) or half of all CRC patients (with local fine-tuning), thereby reducing cost and turnaround time for molecular profiling.

Tyrosine kinase-targeting drugs-associated heart failure.

BACKGROUND: The impact of cancer therapies on cardiac disease in the general adult cancer survivor population is largely unknown. Our objective was to evaluate which tyrosine kinase-targeting drugs are associated with greater risk for new-onset heart failure (HF). METHODS: A nested case-control analysis was conducted within a cohort of 27 992 patients of Clalit Health Services, newly treated with a tyrosine kinase-targeting, and/or chemotherapeutic drug, for a malignant disease, between 1 January 2005 and 31 December 2012. Each new case of HF was matched to up to 30 controls from the cohort on calendar year of cohort entry, age, gender, and duration of follow-up. Main outcome measure was odds ratio (OR) with 95% confidence interval (CI) of new-onset HF. RESULTS: There were 936 incident cases of HF during 71 742 person-years of follow-up. Trastuzumab (OR 1.90, 95% CI 1.46-2.49), cetuximab (OR 1.72, 1.10-2.69), panitumumab (OR 3.01, 1.02-8.85), and sunitinib (OR 3.39, 1.78-6.47) were associated with increased HF risk. Comorbidity independently associated with higher risk in a multivariable conditional regression model was diabetes mellitus, hypertension, chronic renal failure, ischaemic heart disease, valvular heart disease, arrhythmia, and smoking. CONCLUSIONS: Trastuzumab, cetuximab, panitumumab, and sunitinib are associated with increased risk for new-onset HF.

Characteristics and Trends in Hypnotics Consumption in the Largest Health Care System in Israel.

Objectives. To quantify and characterize hypnotics consumption habits among adult patients insured by Clalit Health Services (CHS), the largest health care provider in Israel, in 2000 and 2010. Methods. A retrospective analysis of CHS computerized pharmacy records. Data were collected for all patients over the age of 18 years who were prescribed hypnotics in 2000 and in 2010. Results. Sleep medications were consumed by 8.7% of the adult CHS population in 2000 and by 9.6% in 2010. About one-quarter of consumers were treated for more than 6 months in both years. Multiple sleeping drugs were consumed more often in 2010 (45.2%) than a decade before (22%). While in 2000 benzodiazepines accounted for 84.5% of hypnotics, in 2010 this was reduced to 73.7% (p < 0.05). Of all patients treated for longer than 6 months only 11% in 2000 and 9% in 2010 required a dose escalation suggesting the absence of tolerance. Conclusions. Nine percent of the Israeli population consumes hypnotics. There is a major increase in prescription of combination of medications between 2000 and 2010, with an increase in Z class medications use and reduction in benzodiazepines. Most patients chronically treated did not escalate dosage, suggesting the absence of tolerance.

The role of CHADS2 and CHA2 DS2 -VASc scores in the prediction of stroke in individuals without atrial fibrillation: a population-based study.

UNLABELLED: Essentials CHADS2 and CHA2 DS2 -VASc scores are used to predict stroke in atrial fibrillation (AF). These scores were calculated for a large cohort from the largest healthcare provider in Israel. The risk of stroke gradually increased with an increase in the scores in individuals without AF. Both scores have a relatively high performance for stroke prediction in individuals without AF. Click to hear Prof. Lowe's perspective on Arterial Thrombosis, Pathogenesis and Epidemiology SUMMARY: Background CHADS2 and CHA2 DS2 -VASc are validated scores used to predict stroke in patients with atrial fibrillation (AF). We aimed to examine the performance of these scores in predicting stroke in individuals without AF. Methods Using the computerized database of the largest HMO in Israel, we identified all not-anticoagulated adults, aged 50 years or older on 1 January 2012. The cohort was followed for the occurrence of stroke or transient ischemic attack (TIA) until 31 December 2014. Results Of 1 053 871 individuals without AF at baseline, 34 215 developed stroke/TIA during a follow-up of 3 014 002 person-years (stroke/TIA incidence rate, 1.14 per 100 person-years). The incidence rate of stroke/TIA increased in a graded manner with increasing CHADS2 score: 0.36, 0.89, 1.89, 2.96, 4.31, 5.37 and 6.62 per 100 person-years for CHADS2 scores of 0 to 6 points, respectively (P < 0.001). Results were similar for the CHA2 DS2 -VASc score. A similar graded increasing trend in the stroke/TIA incidence rate was observed in a cohort of 46 657 patients with AF at baseline; however, stroke/TIA rates were higher in each score stratum compared with the rates of individuals without AF. The area under the receiver operating characteristic curve was 0.718 (95% CI, 0.715-0.721) and 0.714 (0.711-0.717) for CHADS2 and CHA2 DS2 -VASc scores, respectively, in individuals without AF, and 0.606 (0.598-0.614) and 0.610 (0.602-0.618), respectively, in individuals with AF. Conclusions CHADS2 and CHA2 DS2 -VASc scores have a relatively high performance for prediction of stroke/TIA in individuals without AF, which is comparable to their performance in patients with AF.

Neutrophil to lymphocyte ratio and risk of a first episode of stroke in patients with atrial fibrillation: a cohort study.

BACKGROUND: The neutrophil to lymphocyte ratio (NLR) is associated with increased risk of cardiovascular morbidity and mortality. We aimed to assess the association between NLR and first episode of stroke in patients with atrial fibrillation. METHODS: Using the computerized database of the largest HMO in Israel, we identified a cohort of adults, aged 20 years or older, with atrial fibrillation diagnosed before 1 January 2012. Eligible subjects had no prior stroke or TIA, were not on anticoagulants at baseline, and had at least one blood cell count performed in 2011. The cohort (32,912 subjects) was followed for the first event of stroke or TIA until 31 December 2012. RESULTS: Overall 981 subjects developed stroke during a follow-up of 30,961 person-years (stroke rate, 3.17 per 100 person-years). The incidence rate of stroke increased across NLR quartiles: 2.27, 2.72, 3.26 and 4.54 per 100 person-years, respectively. Cox proportional hazard regression analysis adjusting for the individual CHA2 DS2 -VASc score risk factors showed that, compared with the lowest NLR quartile, the HR for stroke was 1.11 (95% CI, 0.91-1.35), 1.25 (1.03-1.51) and 1.56 (1.29-1.88) for the second, third and highest quartile, respectively. On stratified analysis, NLR refined the risk of stroke across all CHA2 DS2 -VASc score strata. Adding NLR to the CHA2 DS2 -VASc score increased the AUC from 0.627 (95% CI, 0.612-0.643) to 0.635 (0.619-0.651) (P = 0.037). CONCLUSIONS: The neutrophil to lymphocyte ratio is directly associated with the risk of stroke in patients with atrial fibrillation. Future studies are needed to replicate these findings.

Glycated hemoglobin and risk of first episode stroke in diabetic patients with atrial fibrillation: A cohort study.

BACKGROUND: Diabetes is associated with an increased risk of stroke in patients with atrial fibrillation. Whether glycemic control, evaluated by glycated hemoglobin, affects the risk of stroke in diabetic patients with atrial fibrillation remains unknown. OBJECTIVE: To examine the association between glycated hemoglobin and risk of first episode stroke in diabetic patients with atrial fibrillation. METHODS: By using the computerized database of the largest health maintenance organization in Israel, we identified a cohort of adults (age ≥20 years) in whom atrial fibrillation was diagnosed before January 1, 2012. Eligible subjects had no previous stroke or transient ischemic attack and were not on anticoagulants at baseline. The cohort (37,358 subjects) was followed for the first episode stroke or transient ischemic attack up to December 31, 2012. RESULTS: A total of 1052 subjects had stroke during 35,278 person-years of follow-up (stroke rate 2.98 per 100 person-years). Cox proportional hazards regression analysis adjusting for CHA2DS2-VASc score risk factors revealed that compared with subjects without diabetes, the hazard ratio for stroke was 1.04 (95% confidence interval [CI] 0.83-1.30) for the lowest glycated hemoglobin quartile (<6.35%), 1.14 (95% CI 0.92-1.42) for the second quartile (6.35%-6.90%), 1.46 (95% CI 1.19-1.79) for the third quartile (>6.90%-7.70%), and 1.63 (95% CI 1.33-2.00) for the highest quartile(>7.70%) (for trend, P < .001). In diabetic patients (n = 11,176), the hazard ratio for stroke was 1.17 (95% CI 1.09-1.26) for every 1% increment in glycated hemoglobin level. The area under the receiver operating characteristic curve was 0.585 for the CHA2DS2-VASc score, which increased to 0.604 when glycated hemoglobin was included in the model (P = .038). CONCLUSION: Glycated hemoglobin is directly associated with stroke risk, and it improves the predictive accuracy for stroke in diabetic patients with atrial fibrillation.

Statins use and risk of mortality in patient with Clostridium difficile infection.

Current evidence suggests that statins may improve outcome in infectious diseases. This study aims to assess whether statins use is associated with reduced risk of 30-day mortality in Clostridium difficile infection (CDI). Using the computerized database of Clalit, the largest healthcare provider in Israel, we identified a cohort of adult subjects (age ≥40 years) who tested positive on a C. difficile toxin assay performed between January 2011 and December 2012. Subjects were defined as current statins users if they filled at least one prescription during the 90 days before the laboratory assay date. Current users were classified into long-term users if at least one additional prescription was filled during the previous 91-180 days; otherwise they were defined as short-term users. A total 1888 patients with CDI were included. Of them, 340 (18.0%) died during the first 30 days after diagnosis. The 30-day mortality rate was lower among current statins users 89/669 (13.3%) compared with 251/1219 (20.6%) in non-users (p <0.001). A significant reduced risk of 30-day mortality existed after adjustment for potential confounders; adjusted OR = 0.57 (95% CI 0.42-0.79) and was unique to long-term users; 0.53 (0.38-0.73) but not short-term users; 1.15 (0.56-2.34). The risk of 30-day mortality decreased with increasing number of filled statins prescriptions; adjusted OR = 0.77 (95% CI 0.67-0.89) for each additional prescription. Current aspirin use was also independently associated with reduced mortality; adjusted OR = 0.64 (95% CI 0.43-0.88). In conclusion, current statins use, particularly long-term use, has a dose-response protective effect on mortality in patients with CDI.

The relationship between obesity and the increase in serum 25(OH)D levels in response to vitamin D supplementation.

UNLABELLED: This study examines the relationship between obesity and the increase in serum 25(OH)D levels in response to vitamin D supplementation among adults with baseline serum 25(OH)D levels<50 nmol/L. This study revealed that the increase in serum 25(OH)D in response to vitamin D supplementation was higher in lean subjects as compared to obese subjects. INTRODUCTION: Serum 25(OH)D is lower among obese than non-obese. This study examines the relationship between obesity and the increase in serum 25(OH)D in response to vitamin D supplementation in a large sample of adults with baseline serum 25(OH)D<50 nmol/L, relatively long average treatment duration and large average daily cholecalciferol. METHODS: The computerized database of the Clalit Health Services, which the largest nonprofit health maintenance organization in Israel, was retrospectively searched for all subjects aged≥20 years who performed serum 25(OH)D test in 2011. Subjects with more than one test at different occasions in 2011 were identified and were included if the result of the first test was <50 nmol/L, and were treated with cholecalciferol between the first and the last test in 2011 (n=16,540 subjects). RESULTS: The mean increase in serum 25(OH)D level after treatment was 28.7 (95% confidence interval (CI), 28.0-29.4) nmol/L, 23.6 (23.0-24.2) nmol/L, and 20.1 (19.6-20.6) nmol/L in subject with BMI of <25, 25-29.9, and ≥30 kg/m2, respectively (P<0.001). The results were similar after adjustment for the potential confounders. Similarly, the proportion of subjects who achieved serum 25(OH)D≥50 nmol/L after treatment was inversely associated with BMI; 65.1, 58.3, and 49.1% for BMI of <25, 25-29.9, and ≥30 kg/m2, respectively. Compared to BMI of ≥30 kg/m2, the adjusted odds ratio for achieving levels of ≥50 nmol/L were 2.12 (95 % CI, 1.94-2.31) and 1.42 (1.31-1.54) for BMI of <25 kg/m2, and BMI of 25-29.9 kg/m2, respectively. CONCLUSIONS: BMI is inversely associated with the increase in serum 25(OH)D levels in response to vitamin D supplementation.

Association of PHB 1630 C>T and MTHFR 677 C>T polymorphisms with breast and ovarian cancer risk in BRCA1/2 mutation carriers: results from a multicenter study.

BACKGROUND: The variable penetrance of breast cancer in BRCA1/2 mutation carriers suggests that other genetic or environmental factors modify breast cancer risk. Two genes of special interest are prohibitin (PHB) and methylene-tetrahydrofolate reductase (MTHFR), both of which are important either directly or indirectly in maintaining genomic integrity. METHODS: To evaluate the potential role of genetic variants within PHB and MTHFR in breast and ovarian cancer risk, 4102 BRCA1 and 2093 BRCA2 mutation carriers, and 6211 BRCA1 and 2902 BRCA2 carriers from the Consortium of Investigators of Modifiers of BRCA1 and BRCA2 (CIMBA) were genotyped for the PHB 1630 C>T (rs6917) polymorphism and the MTHFR 677 C>T (rs1801133) polymorphism, respectively. RESULTS: There was no evidence of association between the PHB 1630 C>T and MTHFR 677 C>T polymorphisms with either disease for BRCA1 or BRCA2 mutation carriers when breast and ovarian cancer associations were evaluated separately. Analysis that evaluated associations for breast and ovarian cancer simultaneously showed some evidence that BRCA1 mutation carriers who had the rare homozygote genotype (TT) of the PHB 1630 C>T polymorphism were at increased risk of both breast and ovarian cancer (HR 1.50, 95%CI 1.10-2.04 and HR 2.16, 95%CI 1.24-3.76, respectively). However, there was no evidence of association under a multiplicative model for the effect of each minor allele. CONCLUSION: The PHB 1630TT genotype may modify breast and ovarian cancer risks in BRCA1 mutation carriers. This association need to be evaluated in larger series of BRCA1 mutation carriers.

Single measurement of serum 25(OH)D: is classification into month-specific cutpoints useful in accounting for seasonal variation?

Classification into month-specific cutpoints is used to minimize misclassification associated with single measurement of serum 25(OH)D. This study aims to evaluate this strategy, and to compare it with the widely used classification into overall cutpoints. For this purpose, we studied 69,553 subjects in whom serum 25(OH)D was tested on two different occasions. The level of agreement between the quartiles of the first and second tests was 43.8% between the month-specific quartiles and 43.1% between the overall quartiles. The level of agreement between the quartiles of the two approaches was 80.0% and 94.3% in the first and second test, respectively. The extent of seasonal variation (summer-autumn as compared with winter-spring) of serum 25(OH)D was higher in males and in Jews, inversely associated with baseline levels, body mass index and age, and directly associated with socioeconomic class. The month-specific cutpoint strategy does not seem to offer advantage over the overall cutpoints strategy.

Genetic polymorphisms in fatty acid metabolism genes and colorectal cancer.

Colorectal cancer (CRC) is a leading cause of cancer death worldwide. Epidemiological risk factors for CRC included dietary fat intake; consequently, the role of genes in the fatty acid biosynthesis and metabolism pathways is of particular interest. Moreover, hyperlipidaemia has been associated with different type of cancer and serum lipid levels could be affected by genetic factors, including polymorphisms in the lipid metabolism pathway. The aim of this study is to assess the association between single-nucleotide polymorphisms (SNPs) in fatty acid metabolism genes, serum lipid levels, body mass index (BMI) and dietary fat intake and CRC risk; 30 SNPs from 8 candidate genes included in fatty acid biosynthesis and metabolism pathways were genotyped in 1780 CRC cases and 1864 matched controls from the Molecular Epidemiology of Colorectal Cancer study. Information on clinicopathological characteristics, lifestyle and dietary habits were also obtained. Logistic regression and association analysis were conducted. Several LIPC (lipase, hepatic) polymorphisms were found to be associated with CRC risk, although no particular haplotype was related to CRC. The SNP rs12299484 showed an association with CRC risk after Bonferroni correction. We replicate the association between the T allele of the LIPC SNP rs1800588 and higher serum high-density lipoprotein levels. Weak associations between selected polymorphism in the LIPC and PPARG genes and BMI were observed. A path analysis based on structural equation modelling showed a direct effect of LIPC gene polymorphisms on colorectal carcinogenesis as well as an indirect effect mediated through serum lipid levels. Genetic polymorphisms in the hepatic lipase gene have a potential role in colorectal carcinogenesis, perhaps though the regulation of serum lipid levels.

Serum 25(OH)D concentrations in sunny Israel.

SUMMARY: This study assesses vitamin D status in Israel. Serum 25(OH)D levels <25 and <50 nmol/L are common in Israel with noted differences between Arabs and Jews, Arab females were particularly at high risk. These findings may require public health intervention at the population level. INTRODUCTION: Small studies from Israel have suggested a high prevalence of hypovitaminosis D. The objective of this study was to evaluate the extent of hypovitaminosis D among demographic subgroups in Israel. METHODS: The data of this study are from the Clalit Health Services (CHS) which is a non-for-profit health maintenance organization (HMO) covering more than half of the Israeli population. We included all CHS members for whom a 25(OH)D test result in 2009 was available and who were not taking vitamin D supplements in 2008-2009 before that 25(OH)D result. Complete data were available for 198,834 members. RESULTS: The mean level of 25(OH)D was 51.9 ± 24.5 nmol/L and was higher in summer compared to winter (P < 0.0001). Level <25, <37.5, and <50 nmol/L were detected in 14.4%, 30.7%, and 49.9% of tests; 16.4% had levels >75 nmol/L. Females had higher prevalence of 25(OH)D levels < 50 nmol/L which were found in 51.8% of females versus 45.0% in males (P < 0.0001); 76.7% of the Arabs had levels <50 nmol/L versus 46.5% in Jews (P < 0.0001). Arabs females were particularly at high risk for 25(OH)D <50 nmol/L; 84.8% of them had levels <50 nmol/L versus 48.1% of Jewish females (P < 0.0001). The relation of 25(OH)D levels with age had a sinusoidal shape among Jews, a U-shape in Arab females, and inverse linear pattern in Arab males. CONCLUSIONS: 25(OH)D levels <25 and <50 nmol/L are common in Israel. Public health measures are needed for values lesser than about 30 nmol/L and further monitoring of concentrations between about 30 and 50 nmol/L to determine if there are adverse health effects.

Adiponectin gene and risk of colorectal cancer.

BACKGROUND: Genes of the adiponectin pathway are interesting candidates for colorectal cancer risk based on the potential association between colorectal cancer and obesity. However, variants of the adiponectin gene (ADIPOQ) have been demonstrated to be inconsistently associated with risk of colorectal cancer. METHODS: The current study attempted to evaluate these findings by examining several single nucleotide polymorphisms (SNPs) that were previously genotyped as part of a genome-wide association study in the ADIPOQ gene. Genotyping was also performed for a previously reported risk variant, rs266729, in 1062 individuals with a diagnosis of colorectal cancer and 1062 controls matched on age, gender and ethnicity (Jewish or not Jewish) as part of a population-based case-control study in Israel. RESULTS: No evidence was found for an association between ADIPOQ and risk of colorectal cancer. The single nucleotide variant previously associated with decreased risk of colorectal cancer, rs266729, revealed an adjusted odds ratio of 1.04; 95% confidence interval, 0.88-1.23. CONCLUSION: The SNP, rs266729, was not strongly associated with colorectal cancer in patients of Ashkenazi Jewish descent or other ethnic groups in Israel.

Double heterozygosity in the BRCA1 and BRCA2 genes in the Jewish population.

BACKGROUND: The frequency and characteristics of disease in individuals who concomitantly harbor pathogenic mutations in both BRCA1 and BRCA2 genes are not established. MATERIALS AND METHODS: Data were collected from the database of Clalit Health Services National Familial Cancer Consultation Service. Probands referred to this clinical service and their family members are routinely tested for the three Jewish founder mutations (BRCA1: 185delAG, 5382insC, BRCA2: 6174delT). In addition, carriers identified in a population-based cohort of all cases diagnosed with breast cancer in Israel in 1987-1988 allowed the estimation of the population frequency of this phenomenon. RESULTS: In the clinic-based series of 1191 carriers of mutations in BRCA1 or BRCA2 belonging to 567 families, 22 males and females (1.85%) from 17 different families (3.0%) were found to harbor two different mutations. These included 18 individuals (1.51%) who concomitantly carried the 185delAG BRCA1 and the 6174delT BRCA2 mutations and four individuals (0.34%) who carried the 5382insC BRCA1 and the 6174delT mutations. All individuals were heterozygote carriers and none had a double mutation of both founder mutations in the BRCA1 gene itself. Seven of the 16 double carrier women (46.7%) had a personal history of breast carcinoma, diagnosed at a mean age of 44.6, compared with 372/926 (40.2%) carriers of a single mutation diagnosed with a mean age at diagnosis of 48.1 [odds ratio (OR)=1.3, 95% confidence interval (CI) 0.4-4.0]. One case (6.7%) had a personal history of ovarian carcinoma diagnosed at the age of 53 compared with 55/926 (5.9%) of the women with single mutation (OR=1.1, CI=0.2-7.6). The frequency of double mutations in the population-based national breast cancer cohort was 2.2% of all carriers, and 0.3% of all breast cancer cases in the Ashkenazi population in the cohort. The mean age at diagnosis of breast cancer was younger in the carriers of two mutations. CONCLUSION: Double carriers of mutations in the BRCA genes are rare and seem to be carrying a similar probability of developing breast and ovarian cancers as carriers of single mutations.

Characterization of two Ashkenazi Jewish founder mutations in MSH6 gene causing Lynch syndrome.

Founder mutations are an important cause of Lynch syndrome and facilitate genetic testing in specific ethnic populations. Two putative founder mutations in MSH6 were analyzed in 2685 colorectal cancer (CRC) cases, 337 endometrial cancer (EnCa) cases and 3310 healthy controls of Ashkenazi Jewish (AJ) descent from population-based and hospital-based case­control studies in Israel, Canada and the United States. The carriers were haplotyped and the age of the mutations was estimated. MSH6*c.3984_3987dupGTCA was found in 8/2685 CRC cases, 2/337 EnCa cases, and 1/3310 controls, consistent with a high risk of CRC (odds ratio (OR) = 9.9, 95% confidence interval (CI) = 1.2­78.9, p = 0.0079) and a very high risk of EnCa (OR = 19.6, 95% CI = 1.8­217.2, p = 0.0006). MSH6*c.3959_3962delCAAG was identified in 3/2685 CRC cases, 2/337 EnCa cases and no controls. Each mutation was observed on separate conserved haplotypes. MSH6*c.3984_3987dupGTCA and MSH6*c.3959_3962delCAAG probably arose around 585 CE and 685 CE, respectively. No carriers were identified in Sephardi Jews (450 cases and 490 controls). Truncating mutations MSH6*c.3984_3987dupGTCA and MSH6*c.3959_3962delCAAG cause Lynch syndrome and are founder mutations in Ashkenazi Jews. Together with other AJ founder mutations, they contribute substantially to the incidence of CRC and EnCa and are important tools for the early diagnosis and appropriate management of AJ Lynch syndrome patients.

Evaluation of a candidate breast cancer associated SNP in ERCC4 as a risk modifier in BRCA1 and BRCA2 mutation carriers. Results from the Consortium of Investigators of Modifiers of BRCA1/BRCA2 (CIMBA).

BACKGROUND: In this study we aimed to evaluate the role of a SNP in intron 1 of the ERCC4 gene (rs744154), previously reported to be associated with a reduced risk of breast cancer in the general population, as a breast cancer risk modifier in BRCA1 and BRCA2 mutation carriers. METHODS: We have genotyped rs744154 in 9408 BRCA1 and 5632 BRCA2 mutation carriers from the Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA) and assessed its association with breast cancer risk using a retrospective weighted cohort approach. RESULTS: We found no evidence of association with breast cancer risk for BRCA1 (per-allele HR: 0.98, 95% CI: 0.93-1.04, P = 0.5) or BRCA2 (per-allele HR: 0.97, 95% CI: 0.89-1.06, P = 0.5) mutation carriers. CONCLUSION: This SNP is not a significant modifier of breast cancer risk for mutation carriers, though weak associations cannot be ruled out.

The TP53 Arg72Pro and MDM2 309G>T polymorphisms are not associated with breast cancer risk in BRCA1 and BRCA2 mutation carriers.

BACKGROUND: The TP53 pathway, in which TP53 and its negative regulator MDM2 are the central elements, has an important role in carcinogenesis, particularly in BRCA1- and BRCA2-mediated carcinogenesis. A single nucleotide polymorphism (SNP) in the promoter region of MDM2 (309T>G, rs2279744) and a coding SNP of TP53 (Arg72Pro, rs1042522) have been shown to be of functional significance. METHODS: To investigate whether these SNPs modify breast cancer risk for BRCA1 and BRCA2 mutation carriers, we pooled genotype data on the TP53 Arg72Pro SNP in 7011 mutation carriers and on the MDM2 309T>G SNP in 2222 mutation carriers from the Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA). Data were analysed using a Cox proportional hazards model within a retrospective likelihood framework. RESULTS: No association was found between these SNPs and breast cancer risk for BRCA1 (TP53: per-allele hazard ratio (HR)=1.01, 95% confidence interval (CI): 0.93-1.10, P(trend)=0.77; MDM2: HR=0.96, 95%CI: 0.84-1.09, P(trend)=0.54) or for BRCA2 mutation carriers (TP53: HR=0.99, 95%CI: 0.87-1.12, P(trend)=0.83; MDM2: HR=0.98, 95%CI: 0.80-1.21, P(trend)=0.88). We also evaluated the potential combined effects of both SNPs on breast cancer risk, however, none of their combined genotypes showed any evidence of association. CONCLUSION: There was no evidence that TP53 Arg72Pro or MDM2 309T>G, either singly or in combination, influence breast cancer risk in BRCA1 or BRCA2 mutation carriers.

Smoking attenuates the negative association between carotenoids consumption and colorectal cancer risk.

OBJECTIVES: Consumption of vegetables and fruits, physical activity, obesity and caloric intake are all strongly related to the risk of colorectal cancer (CRC). The association between dietary intake of carotenoids from vegetables/fruits and risk of CRC in the context of cigarette smoking was studied in a nutritionally diverse population. METHODS: The study included 1,817 age sex residence-matched case-control pairs from a population-based study in Northern Israel. Data were acquired by food-frequency questionnaire. Individual intake of carotenoid isomers was calculated using an Israeli food content database. Odds ratios (ORs) were calculated using conditional logistic regression models adjusted for known risk factors. RESULTS: Strong inverse associations were found with consumption of 9-cis-beta-carotene (OR = 0.35, 0.26-0.47), all-trans-beta-carotene (OR = 0.58, 0.44-0.76), cis-beta-cryptoxanthin (OR = 0.67, 0.50-0.90), all-trans-zeaxanthin (OR = 0.64, 0.48-0.86), and lutein (OR = 0.74, 0.57-0.96). Lycopene (OR = 2.22, 1.71-2.89) and all-trans-beta-cryptoxanthin (OR = 2.01, 1.48-2.73) were associated with increased risk of CRC. Inverse associations of most carotenoids with CRC, demonstrated in non-smokers, were much attenuated or reversed in past or current smokers with a highly significant interaction term. CONCLUSIONS: Consumption of most dietary carotenoids was found to be strongly associated with reduced risk of CRC. However, smoking significantly attenuated or reversed this observed protective effect on CRC occurrence. Smokers should be advised that smoking also hampers the potential health promoting effects of high fruit and vegetable consumption.

The risk of developing uterine sarcoma after tamoxifen use.

The treatment of breast cancer with tamoxifen results in an increased risk of uterine cancer. The objective of this study was to evaluate the association between tamoxifen use and the risk of developing uterine sarcomas and endometrial carcinomas in a historical cohort of women diagnosed with breast cancer in 1987-1988. The medical records of all women diagnosed in Israel with breast cancer in the years 1987-1988 were sought. Clinical data, including use of hormone therapy, were extracted from oncology records. In 2004, patient identifiers were linked to the Israel Cancer Registry database to identify all uterine cancers that occurred within 15 years of the diagnosis of breast cancer. The records for 1507 breast cancer cases (84%) were retrieved. Among these cases, 32 uterine malignancies were identified; 11 occurred prior to the diagnosis of breast cancer and 21 occurred during the follow-up period. Eight hundred seventy-five women in the cohort had used tamoxifen (59%). There were 17 uterine cancers observed among the 875 exposed to tamoxifen (1.9%), compared to 4 uterine cancers among the 621 women (0.6%) who did not use tamoxifen (odds ratio = 3.1; 95% CI: 1.0-9.1; P = 0.04). There were four uterine sarcomas among the tamoxifen users, but none among nonusers (P = 0.15). Five of the 875 tamoxifen users (0.6%) died of uterine cancer, compared to no deaths among nonusers (P = 0.08). We conclude that in this national breast cancer cohort, tamoxifen use was associated with elevated risks of uterine cancer incidence and mortality. Uterine sarcomas appear to be overrepresented among women who use tamoxifen.

Differences in the characteristics of families with BRCA1 and BRCA2 mutations in Israel.

Three specific mutations in the BRCA1 (185delAG, 5382insC) and BRCA2 (6174delT) genes have been reported to be of high prevalence in the Jewish Ashkenazi population. We studied the differences in phenotype of families carrying these mutations. All consecutive families found by the CHS Familial Cancer Service to carry one of the three 'Jewish' mutations of the BRCA1/BRCA2 genes were evaluated for phenotypic characteristics. Chi-squared and Student's t-test statistics were employed to study differences in a variety of clinical and demographic parameters. A total of 111 families with 1499 family members were included. Among them 454 cases of cancer (297 in breast/ovary) were reported. Ovarian cancer, but not breast cancer, was detected at a significantly younger age among carriers of 185delT compared with other mutation carriers. In families with 185delAG, 5382insC and 6174delT mutations, breast cancer was found in 20.2, 39.4 and 24.1% of all identified women (born between 1900 and 1975), correspondingly. The corresponding figures for ovarian cancer were 13.9, 6.8 and 4.9%. Families carrying the 5382insC mutation had the highest probability of expressing bilateral breast cancer (38.9% of families, 15.4% of women with cancer, 6.1% of all women in family) and metachronous breast and ovary tumours (22.2, 9.8 and 4.5% correspondingly). Other tumours were reported in 7.9, 9.1 and 12.0% of women and 9.5, 12.9 and 15.8% of men in families with 185delAG, 5382insC, 6174delT, correspondingly. Marked phenotypic differences were found between families carrying different BRCA mutations warranting mutation-specific counselling to families seeking risk-reduction advice. 5382insC emerged as a most aggressive mutation.