Nelson L.S. Tang

Average Risks of Breast and Ovarian Cancer Associated with BRCA1 or BRCA2 Mutations Detected in Case Series Unselected for Family History: A Combined Analysis of 22 Studies

Germline mutations in BRCA1 and BRCA2 confer high risks of breast and ovarian cancer, but the average magnitude of these risks is uncertain and may depend on the context. Estimates based on multiple-case families may be enriched for mutations of higher risk and/or other familial risk factors, whereas risk estimates from studies based on cases unselected for family history have been imprecise. We pooled pedigree data from 22 studies involving 8,139 index case patients unselected for family history with female (86%) or male (2%) breast cancer or epithelial ovarian cancer (12%), 500 of whom had been found to carry a germline mutation in BRCA1 or BRCA2. Breast and ovarian cancer incidence rates for mutation carriers were estimated using a modified segregation analysis, based on the occurrence of these cancers in the relatives of mutation-carrying index case patients. The average cumulative risks in BRCA1-mutation carriers by age 70 years were 65% (95% confidence interval 44%-78%) for breast cancer and 39% (18%-54%) for ovarian cancer. The corresponding estimates for BRCA2 were 45% (31%-56%) and 11% (2.4%-19%). Relative risks of breast cancer declined significantly with age for BRCA1-mutation carriers (P trend.0012) but not for BRCA2-mutation carriers. Risks in carriers were higher when based on index breast cancer cases diagnosed at <35 years of age. We found some evidence for a reduction in risk in women from earlier birth cohorts and for variation in risk by mutation position for both genes. The pattern of cancer risks was similar to those found in multiple-case families, but their absolute magnitudes were lower, particularly for BRCA2. The variation in risk by age at diagnosis of index case is consistent with the effects of other genes modifying cancer risk in carriers.

Pathology of fatal human infection associated with avian influenza A H5N1 virus

Eighteen cases of human influenza A H5N1 infection were identified in Hong Kong from May to December 1997. Two of the six fatal cases had undergone a full post‐mortem which showed reactive hemophagocytic syndrome as the most prominent feature. Other findings included organizing diffuse alveolar damage with interstitial fibrosis, extensive hepatic central lobular necrosis, acute renal tubular necrosis and lymphoid depletion. Elevation of soluble interleukin‐2 receptor, interleukin‐6 and interferon‐γ was demonstrated in both patients, whereas secondary bacterial pneumonia was not observed. Virus detection using isolation, reverse transcription‐polymerase chain reaction and immunostaining were all negative. It is postulated that in fatal human infections with this avian subtype, initial virus replication in the respiratory tract triggers hypercytokinemia complicated by the reactive hemophagocytic syndrome. These findings suggest that the pathogenesis of influenza A H5N1 infection might be different from that of the usual human subtypes H1‐H3. J. Med. Virol. 63:242–246, 2001.

Avoiding cardiopulmonary bypass in multivessel CABG reduces cytokine response and myocardial injury

BACKGROUND Proinflammatory cytokines play a key role in the inflammatory cascade after cardiopulmonary bypass and may induce cardiac dysfunction. We compared the production of cytokines and the degree of postoperative myocardial injury in patients with multivessel coronary artery disease undergoing coronary artery bypass grafting through median sternotomy with or without cardiopulmonary bypass. METHODS Forty-four consecutive patients were studied. Patients were selected for off-pump coronary artery bypass grafting whenever complete revascularization was technically feasible. There were no differences between the two groups with respect to age, sex, symptoms, or functional class. Plasma levels of tumor necrosis factor-alpha, interleukin (IL)-6, IL-8, and IL-10 were measured before the operation, at the end of the procedure, and 2, 4, 8, 24, and 48 hours thereafter. Levels of the MB isoenzyme of creatine kinase and cardiac troponin-I were also measured after the operation. RESULTS The number of grafts was 2+/-0.7 in the off-pump group (n = 18) and 3+/-0.8 in the cardiopulmonary bypass group (n = 26). There were no deaths or major complications in either group. Levels of tumor necrosis factor-alpha were low in both groups. No significant intergroup differences were noted regarding serial IL-6 measurements. However, IL-8 and IL-10 levels after the operation were lower in the off-pump group (IL-8, 4+/-1 versus 38+/-12 pg/mL, p < 0.01; IL-10, 5+/-2 versus 191+/-33 pg/mL, p < 0.001). Whereas postoperative creatine kinase-MB values were similar in the two groups, cardiac troponin-I levels were significantly lower in the off-pump group (8 hours, p < 0.005; 24 hours, p < 0.02, respectively). Moreover, cardiac troponin-I values 24 hours after operation correlated strongly with IL-8 levels (r = 0.61, p < 0.005), indicating that the degree of myocardial injury may be related to IL-8 production. CONCLUSIONS Compared with conventional coronary artery bypass grafting, coronary revascularization without cardiopulmonary bypass is associated with reduced cytokine responses and less myocardial injury.

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).

Common variants near CAV1 and CAV2 are associated with primary open-angle glaucoma

We conducted a genome-wide association study for primary open-angle glaucoma (POAG) in 1,263 affected individuals (cases) and 34,877 controls from Iceland. We identified a common sequence variant at 7q31 (rs4236601[A], odds ratio (OR) = 1.36, P = 5.0 × 10−10). We then replicated the association in sample sets of 2,175 POAG cases and 2,064 controls from Sweden, the UK and Australia (combined OR = 1.18, P = 0.0015) and in 299 POAG cases and 580 unaffected controls from Hong Kong and Shantou, China (combined OR = 5.42, P = 0.0021). The risk variant identified here is located close to CAV1 and CAV2, both of which are expressed in the trabecular meshwork and retinal ganglion cells that are involved in the pathogenesis of POAG.

Gender and telomere length: Systematic review and meta-analysis

BACKGROUND It is widely believed that females have longer telomeres than males, although results from studies have been contradictory. METHODS We carried out a systematic review and meta-analyses to test the hypothesis that in humans, females have longer telomeres than males and that this association becomes stronger with increasing age. Searches were conducted in EMBASE and MEDLINE (by November 2009) and additional datasets were obtained from study investigators. Eligible observational studies measured telomeres for both females and males of any age, had a minimum sample size of 100 and included participants not part of a diseased group. We calculated summary estimates using random-effects meta-analyses. Heterogeneity between studies was investigated using sub-group analysis and meta-regression. RESULTS Meta-analyses from 36 cohorts (36,230 participants) showed that on average females had longer telomeres than males (standardised difference in telomere length between females and males 0.090, 95% CI 0.015, 0.166; age-adjusted). There was little evidence that these associations varied by age group (p=1.00) or cell type (p=0.29). However, the size of this difference did vary by measurement methods, with only Southern blot but neither real-time PCR nor Flow-FISH showing a significant difference. This difference was not associated with random measurement error. CONCLUSIONS Telomere length is longer in females than males, although this difference was not universally found in studies that did not use Southern blot methods. Further research on explanations for the methodological differences is required.

Breast and ovarian cancer risks to carriers of the BRCA1 5382insC and 185delAG and BRCA2 6174delT mutations: a combined analysis of 22 population based studies

A recent report estimated the breast cancer risks in carriers of the three Ashkenazi founder mutations to be higher than previously published estimates derived from population based studies. In an attempt to confirm this, the breast and ovarian cancer risks associated with the three Ashkenazi founder mutations were estimated using families included in a previous meta-analysis of populatrion based studies. The estimated breast cancer risks for each of the founder BRCA1 and BRCA2 mutations were similar to the corresponding estimates based on all BRCA1 or BRCA2 mutations in the meta-analysis. These estimates appear to be consistent with the observed prevalence of the mutations in the Ashkenazi Jewish population.

Association between mu opioid receptor gene polymorphisms and Chinese heroin addicts.

Mu opioid receptor (MOR) has been shown to be associated with alcoholism and opioid dependence. The present study examined the involvement of a polymorphism in A118G in exon 1 and C1031G in intron 2 of the MOR gene in 200 Chinese heroin-dependent and 97 control subjects. Results showed a significant association for both A118G and C1031G polymorphisms and opioid dependence. The G allele is more common in the heroin-dependent group (39.5% and 30.8% for A118G and C1031G polymorphisms, respectively) when compared to the controls (29.4% and 21.1% for A118G and C1031G polymorphisms, respectively). This study suggests that the variant G allele of both A118G and C1031G polymorphisms may contribute to the vulnerability to heroin dependence.

Melatonin receptor 1B (MTNR1B) gene polymorphism is associated with the occurrence of adolescent idiopathic scoliosis.

Study Design. A genetic association study to comprehensively investigate variations of melatonin receptor 1B gene polymorphism by a set of tagging single nucleotide polymorphisms (tagSNPs) derived from the International Hapmap project. Objectives. To determine whether melatonin receptor 1B (MTNR1B) gene polymorphisms are associated with the predisposition and/or disease severity of adolescent idiopathic scoliosis (AIS). Summary of Background Data. Linkage studies suggested a genetic predisposition for AIS. In addition, evidence showed that AIS might be related to melatonin deficiency and dysfunction of melatonin signaling pathway. Locating in one of the chromosomal regions linked to AIS, MTNR1B gene is a potential candidate gene for AIS. Methods. This study was carried out in 2-stage case-control analysis: 1) initial screening (472 cases and 304 controls) and 2) separate replication test (342 cases and 347 controls) to confirm results in the screening. In the first screening stage, 5 tagSNPs were selected to cover most of the genetic variation in the MTNR1B gene. In the second stage, SNPs showing association in the screening stage were studied in a separate replication sample set to confirm the association. Genotyping was performed by PCR-RFLP. Results. The first stage showed a putative association between rs4753426 and AIS, which was confirmed in the replication sample set. By meta-analysis, the frequency of C allele of this SNP locating in the promoter was significantly higher in the cases than controls (P = 0.006 aftermeta-analysis). Subjects with the CC genotype had an odds ratio of 1.29 for AIS. Another SNP rs741837 in promoter region, being moderate linkage disequilibrium with rs4753426, was also marginally associated with AIS. Conclusion. Polymorphisms of the promoter of MTNR1B gene were associated with AIS, but not with the curve severity in AIS patients. This suggested that MTNR1B was an AIS predisposition gene.

Frequent hypermethylation of promoter region of RASSF1A in tumor tissues and voided urine of urinary bladder cancer patients

High frequency loss of 3p21.3 region where RASSF1A located was demonstrated in several tumors. We aimed to investigate the methylation status of RASSF1A and the frequency of LOH in 3p21.3 region in bladder cancer. Three bladder cancer cell lines, 40 cases of bladder TCC and 14 cases of paired voided urine samples were subjected to methylation analysis. By methylation specific PCR, complete methylation of promoter region of RASSF1A gene were detected in cell lines T24 and UMUC3. Demethylation treatment re‐expressed RASSF1A in these 2 cell lines. Methylation of RASSF1A was also detected in 47.5% (19/40) of the TCC cases but not in 6 carcinoma in situ (CIS) or 6 normal urothelium samples. For LOH study, loss of 3p21.3 region was detected in 57.9% (11/19) of our cases. Interestingly, methylation of RASSF1A was found in 72.7% (8/11) of the cases with LOH but only in 12.5% (1/8) of the cases without LOH. Methylation of RASSF1A was detected in 50% (7/14) of voided urine samples, but not in normal control. It showed a higher sensitivity than conventional urine cytology in detecting cancer cells, especially for low grade cases. In conclusion, our results demonstrated a high frequency of RASSF1A methylation with frequent LOH in 3p21.3 region in bladder cancer. It suggested that it may be a potential tumor suppressor gene in this chromosomal region and can be silenced by promoter hypermethylation. Detection of aberrant gene methylation in routine voided urine was feasible and may provide a non‐invasive and sensitive approach for cancer detection.