Ofra Barnett-Griness

Common Breast Cancer-Predisposition Alleles Are Associated with Breast Cancer Risk in BRCA1 and BRCA2 Mutation Carriers

Germline mutations in BRCA1 and BRCA2 confer high risks of breast cancer. However, evidence suggests that these risks are modified by other genetic or environmental factors that cluster in families. A recent genome-wide association study has shown that common alleles at single nucleotide polymorphisms (SNPs) in FGFR2 (rs2981582), TNRC9 (rs3803662), and MAP3K1 (rs889312) are associated with increased breast cancer risks in the general population. To investigate whether these loci are also associated with breast cancer risk in BRCA1 and BRCA2 mutation carriers, we genotyped these SNPs in a sample of 10,358 mutation carriers from 23 studies. The minor alleles of SNP rs2981582 and rs889312 were each associated with increased breast cancer risk in BRCA2 mutation carriers (per-allele hazard ratio [HR] = 1.32, 95% CI: 1.20-1.45, p(trend) = 1.7 x 10(-8) and HR = 1.12, 95% CI: 1.02-1.24, p(trend) = 0.02) but not in BRCA1 carriers. rs3803662 was associated with increased breast cancer risk in both BRCA1 and BRCA2 mutation carriers (per-allele HR = 1.13, 95% CI: 1.06-1.20, p(trend) = 5 x 10(-5) in BRCA1 and BRCA2 combined). These loci appear to interact multiplicatively on breast cancer risk in BRCA2 mutation carriers. The differences in the effects of the FGFR2 and MAP3K1 SNPs between BRCA1 and BRCA2 carriers point to differences in the biology of BRCA1 and BRCA2 breast cancer tumors and confirm the distinct nature of breast cancer in BRCA1 mutation carriers.

Clinical implications of UGT1A1*28 genotype testing in colorectal cancer patients

Metastatic colorectal cancer is frequently treated with irinotecan, a topoisomerase‐I inhibitor. The UGT1A1 gene encodes for an enzyme that metabolizes irinotecan, and its genetic variants were shown to be associated with increased drug toxicity. We evaluated clinical outcomes associated with the UGT1A1*28 variant.

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.

MutYH mutation carriers have increased breast cancer risk

Variants of the mutY homolog gene MutYH, a DNA repair gene, are associated with increased risk of colorectal cancer; however, it remains unclear whether these variants also are associated with the risk of other cancers. The authors studied the risk of breast cancer associated with MutYH variants in a unique ethnic group of Sephardi Jews in Israel with a high prevalence of MutYH mutations.

The association between obesity and urinary tract infection.

BACKGROUND Few studies examined the relationship between obesity and urinary tract infection (UTI), showing inconsistent results. This study aims to examine the association between obesity and UTI, and to assess whether this association is independent of diabetes mellitus and 25(OH)D level. METHODS Using the computerized database of the largest healthcare provider in Israel, we identified a cohort of subjects ≥18years old with available BMI and serum 25(OH)D level measurements between January 2009 and December 2009. The cohort was followed for the first UTI diagnosis from January 2010 through June 2011. Cox proportional hazard model was used to test the relationship between obesity and UTI. RESULTS During follow-up, 25,145/110,736 (22.7%) females, and 4032/42,703 (9.4%) males had UTI. The crude HR for UTI in those with BMI≥50 compared to BMI<25 was 2.54 (95% CI, 1.50-4.30) in males and 1.39 (1.14-1.69) in females. After adjusting for age, 25(OH)D level, and history of diabetes mellitus, the HR for UTI in those with BMI≥50 compared to BMI<25 was 2.38 (1.40-4.03) in males and 1.25 (1.03-1.52) in females. The HR for those in the lowest quartile of serum 25(OH)D compared to the highest quartile was 1.23 (1.13-1.35) in males and 0.98 (0.95-1.02) in females. The HR for subjects with diabetes was 1.23 (1.16-1.32) in males, and 1.25 (1.20-1.28) in females. CONCLUSIONS Obesity is independently associated with UTI particularly in males. Low serum 25(OH)D levels are associated with increased risk of UTI in males.

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

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.

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

Essentials CHADS2 and CHA2DS2‐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.

The association between red cell distribution width and stroke in patients with atrial fibrillation.

OBJECTIVE Red cell distribution width is associated with increased risk of cardiovascular morbidity and mortality. We aimed to assess its association with stroke in patients with atrial fibrillation. METHODS By using the computerized database of the largest Health Maintenance Organization in Israel, we identified a cohort of adults with atrial fibrillation diagnosed before January 1, 2012. Eligible subjects were not taking anticoagulants at baseline and had at least 1 blood cell count performed in 2011 (41,140 subjects). The cohort was followed for the first occurrence of stroke until December 31, 2012. RESULTS Overall, 1692 subjects developed stroke during 38,024 person-years of follow-up (stroke rate, 4.45 per 100 person-years). Stroke incidence rate increased across red cell distribution width quartiles: 3.26, 3.71, 5.01, and 6.05 per 100 person-years in the lowest (≤ 13.4%), second (13.4%-14.1%), third (14.1%-15.0%), and highest (>15%) red cell distribution width quartiles, respectively. On multivariate analysis adjusting for Congestive heart failure, Hypertension, Age ≥ 75, Diabetes, and Prior Stroke or TIA (doubled) (CHADS2) score risk factors, the hazard ratio for stroke was 1.29 (95% confidence interval, 1.17-1.42) in subjects with red cell distribution width >14.5% compared with those with values ≤ 14.5% and was similar in subjects with and without anemia. When analyzed as quartiles, the hazard ratio for stroke was 1.33 (confidence interval, 1.15-1.53) in the highest quartile compared with the lowest quartile and was similar in subjects with and without anemia. The area under the receiver operating characteristic curve was 0.598 for (CHADS2) score and increased to 0.618 when red cell distribution width was included in the model (P < .001). CONCLUSIONS Red cell distribution width is directly associated with the risk of stroke regardless of anemia status and improves the predictive accuracy for stroke in patients with atrial fibrillation.

BRCA1 Breast Cancer Risk Is Modified by CYP19 Polymorphisms in Ashkenazi Jews

Exposure to sex hormones is a major risk factor for breast cancer and current treatments include hormone modifying drugs, among them aromatase inhibitors. We studied the association of CYP19 (Val80 and [TTTA]n) polymorphisms, the gene translated to aromatase, and the risk of breast cancer in BRCA carriers and noncarriers. The study consisted of 958 cancer cases and 931 healthy controls, including 474 carriers and 1,415 noncarriers. Cases and controls came from a population-based study of breast cancer in Israel, enriched with BRCA carriers from a clinical familial cancer service. Val80 G/G genotype was associated with significantly increased risk of breast cancer compared with the Val80 A/A genotype in BRCA1 carriers ages <50 years (odds ratio, 2.81; 95% confidence interval, 1.09-7.22; P = 0.032) but not in BRCA2 carriers or noncarriers of any age. A similar magnitude suggestive association, although nonstatistically significant, was found between Val80 polymorphism and estrogen receptor-negative status of the breast tumors. A common haplotype composed of the Val80 G allele and three haplotype-tagging single nucleotide polymorphisms (rs727479, rs10046, and rs4646) in the CYP19 coding region showed a trend to association with breast cancer risk in BRCA1 carriers ages <50 years. Published expression data show higher estrogen levels with higher repeats in [TTTA]n found in linkage disequilibrium with Val80. The present study suggests that the CYP19 Val80 polymorphism and a haplotype that includes this polymorphism are associated with increased breast cancer risk in young women with BRCA1 mutations. (Cancer Epidemiol Biomarkers Prev 2009;18(5):1617–23)

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.