The Association of the COMT V158M Polymorphism with Endometrial/Ovarian Cancer in HNPCC Families Adhering to the Amsterdam Criteria

Catechol-O-methyltransferase (COMT) is vital for the conjugation of catechol estrogens that are produced during oestrogen metabolism. The efficiency of this process varies due to a polymorphism in COMT, which changes valine to methionine (V158M). The Met genotypes slow the metabolism of catechol oestrogens, which are agents that are capable of causing DNA damage through the formation of DNA adducts and reactive oxygen species (ROS) production. The slower metabolism of catechol oestrogens results in there being a higher circulating concentration of these oeastrogens and consequently greater probability of DNA damage. To determine whether metabolic inefficiencies of oeastrogen metabolism are associated with the development of malignancy in hereditary non-polyposis colorectal cancer (HNPCC), we studied the V158M polymorphism in COMT in a large cohort of 498 HNPCC patients from Australia and Poland that were either mutation positive (n = 331) or negative (n = 167) for mismatch repair (MMR) gene mutations (hMLH1 or hMSH2). HNPCC is a familial predisposition to colorectal cancer (CRC) and extracolonic cancers that include endometrial cancer

Hormone replacement therapy and the risk of ovarian cancer in BRCA1 and BRCA2 mutation carriers

Abstract Objective. Hormone replacement therapy (HRT) is commonly prescribed to alleviate the climacteric symptoms of menopause. Recent findings from the Women's Health Initiative has raised questions about the routine use of HRT due to the increased observed incidence of cardiovascular disease and of breast and ovarian cancers in the treatment arm of the trial. In the general population, the association between HRT use and risk of ovarian cancer has not yet been resolved. This association has not been evaluated in BRCA1 or BRCA2 mutation carriers who face very high lifetime risks of both breast and ovarian cancers. Methods. We conducted a matched case-control study on 162 matched sets of women who carry a deleterious mutation in either the BRCA1 or BRCA2 gene. Women who had been diagnosed with ovarian cancer were matched to control subjects by mutation, year of birth, and age at menopause. Information on HRT use was derived from a questionnaire routinely administered to women who were found to be carriers of a mutation in either gene. Conditional logistic regression was used to estimate the association between HRT use and the risk of ovarian cancer, stratified by mutation status and type of HRT. Results. Compared with those who had never used HRT, the odds ratio associated with ever use of HRT was 0.93 (95% CI = 0.56 -1.56). There was no significant relationship with increasing duration of HRT use. There was a suggestion that progestinbased HRT regimens might protect against ovarian cancer (odds ratio = 0.57) but this association was not statistically significant ( P = 0.20). Conclusion. HRT use does not appear to adversely influence the risk of ovarian cancer in BRCA mutation carriers.

Fine-mapping identifies multiple prostate cancer risk loci at 5p15, one of which associates with TERT expression

Associations between single nucleotide polymorphisms (SNPs) at 5p15 and multiple cancer types have been reported. We have previously shown evidence for a strong association between prostate cancer (PrCa) risk and rs2242652 at 5p15, intronic in the telomerase reverse transcriptase (TERT) gene that encodes TERT. To comprehensively evaluate the association between genetic variation across this region and PrCa, we performed a fine-mapping analysis by genotyping 134 SNPs using a custom Illumina iSelect array or Sequenom MassArray iPlex, followed by imputation of 1094 SNPs in 22 301 PrCa cases and 22 320 controls in The PRACTICAL consortium. Multiple stepwise logistic regression analysis identified four signals in the promoter or intronic regions of TERT that independently associated with PrCa risk. Gene expression analysis of normal prostate tissue showed evidence that SNPs within one of these regions also associated with TERT expression, providing a potential mechanism for predisposition to disease

Evaluation of polygenic risk scores for breast and ovarian cancer risk prediction in BRCA1 and BRCA2 mutation carriers

Background: Genome-wide association studies (GWAS) have identified 94 common single-nucleotide polymorphisms (SNPs) associated with breast cancer (BC) risk and 18 associated with ovarian cancer (OC) risk. Several of these are also associated with risk of BC or OC for women who carry a pathogenic mutation in the high-risk BC and OC genes BRCA1 or BRCA2. The combined effects of these variants on BC or OC risk for BRCA1 and BRCA2 mutation carriers have not yet been assessed while their clinical management could benefit from improved personalized risk estimates. Methods: We constructed polygenic risk scores (PRS) using BC and OC susceptibility SNPs identified through population-based GWAS: for BC (overall, estrogen receptor [ER]-positive, and ER-negative) and for OC. Using data from 15 252 female BRCA1 and 8211 BRCA2 carriers, the association of each PRS with BC or OC risk was evaluated using a weighted cohort approach, with time to diagnosis as the outcome and estimation of the hazard ratios (HRs) per standard deviation increase in the PRS. Results: The PRS for ER-negative BC displayed the strongest association with BC risk in BRCA1 carriers (HR = 1.27, 95% confidence interval [CI] = 1.23 to 1.31, P = 8.2 x 10(53)). In BRCA2 carriers, the strongest association with BC risk was seen for the overall BC PRS (HR = 1.22, 95% CI = 1.17 to 1.28, P = 7.2 x 10(-20)). The OC PRS was strongly associated with OC risk for both BRCA1 and BRCA2 carriers. These translate to differences in absolute risks (more than 10% in each case) between the top and bottom deciles of the PRS distribution; for example, the OC risk was 6% by age 80 years for BRCA2 carriers at the 10th percentile of the OC PRS compared with 19% risk for those at the 90th percentile of PRS. Conclusions: BC and OC PRS are predictive of cancer risk in BRCA1 and BRCA2 carriers. Incorporation of the PRS into risk prediction models has promise to better inform decisions on cancer risk management

BRCA2 polymorphic stop codon K3326X and the risk of breast, prostate, and ovarian cancers

Background: The K3326X variant in BRCA2 (BRCA2*c.9976A>T; p.Lys3326*; rs11571833) has been found to be associated with small increased risks of breast cancer. However, it is not clear to what extent linkage disequilibrium with fully pathogenic mutations might account for this association. There is scant information about the effect of K3326X in other hormone-related cancers. Methods: Using weighted logistic regression, we analyzed data from the large iCOGS study including 76 637 cancer case patients and 83 796 control patients to estimate odds ratios (ORw) and 95% confidence intervals (CIs) for K3326X variant carriers in relation to breast, ovarian, and prostate cancer risks, with weights defined as probability of not having a pathogenic BRCA2 variant. Using Cox proportional hazards modeling, we also examined the associations of K3326X with breast and ovarian cancer risks among 7183 BRCA1 variant carriers. All statistical tests were two-sided. Results: The K3326X variant was associated with breast (ORw = 1.28, 95% CI = 1.17 to 1.40, P = 5.9x10- 6) and invasive ovarian cancer (ORw = 1.26, 95% CI = 1.10 to 1.43, P = 3.8x10-3). These associations were stronger for serous ovarian cancer and for estrogen receptor–negative breast cancer (ORw = 1.46, 95% CI = 1.2 to 1.70, P = 3.4x10-5 and ORw = 1.50, 95% CI = 1.28 to 1.76, P = 4.1x10-5, respectively). For BRCA1 mutation carriers, there was a statistically significant inverse association of the K3326X variant with risk of ovarian cancer (HR = 0.43, 95% CI = 0.22 to 0.84, P = .013) but no association with breast cancer. No association with prostate cancer was observed. Conclusions: Our study provides evidence that the K3326X variant is associated with risk of developing breast and ovarian cancers independent of other pathogenic variants in BRCA2. Further studies are needed to determine the biological mechanism of action responsible for these associations

Quantum state preparation and macroscopic entanglement in gravitational-wave detectors

Long-baseline laser-interferometer gravitational-wave detectors are operating at a factor of 10 (in amplitude) above the standard quantum limit (SQL) within a broad frequency band. Such a low classical noise budget has already allowed the creation of a controlled 2.7 kg macroscopic oscillator with an effective eigenfrequency of 150 Hz and an occupation number of 200. This result, along with the prospect for further improvements, heralds the new possibility of experimentally probing macroscopic quantum mechanics (MQM) - quantum mechanical behavior of objects in the realm of everyday experience - using gravitational-wave detectors. In this paper, we provide the mathematical foundation for the first step of a MQM experiment: the preparation of a macroscopic test mass into a nearly minimum-Heisenberg-limited Gaussian quantum state, which is possible if the interferometer's classical noise beats the SQL in a broad frequency band. Our formalism, based on Wiener filtering, allows a straightforward conversion from the classical noise budget of a laser interferometer, in terms of noise spectra, into the strategy for quantum state preparation, and the quality of the prepared state. Using this formalism, we consider how Gaussian entanglement can be built among two macroscopic test masses, and the performance of the planned Advanced LIGO interferometers in quantum-state preparation

Searching for a Stochastic Background of Gravitational Waves with LIGO

The Laser Interferometer Gravitational-wave Observatory (LIGO) has performed the fourth science run, S4, with significantly improved interferometer sensitivities with respect to previous runs. Using data acquired during this science run, we place a limit on the amplitude of a stochastic background of gravitational waves. For a frequency independent spectrum, the new limit is $\Omega_{\rm GW} < 6.5 \times 10^{-5}$. This is currently the most sensitive result in the frequency range 51-150 Hz, with a factor of 13 improvement over the previous LIGO result. We discuss complementarity of the new result with other constraints on a stochastic background of gravitational waves, and we investigate implications of the new result for different models of this background.Comment: 37 pages, 16 figure

Role of germline aberrations affecting CTNNA1, MAP3K6 and MYD88 in gastric cancer susceptibility

Background: In approximately 10% of all gastric cancer (GC) cases, a heritable cause is suspected. A subset of these cases have a causative germline CDH1 mutation; however, in most cases the cause remains unknown. Our objective was to assess to what extent these remaining cases may be explained by germline mutations in the novel candidate GC predisposing genes CTNNA1, MAP3K6 or MYD88. Methods: We sequenced a large cohort of unexplained young and/or familial patients with GC (n=286) without a CDH1germline mutation for germline variants affecting CTNNA1, MAP3K6 and MYD88 using a targeted next-generation sequencing approach based on single-molecule molecular inversion probes. Results: Predicted deleterious germline variants were not encountered in MYD88, but recurrently observed in CTNNA1 (n=2) and MAP3K6 (n=3) in our cohort of patients with GC. In contrast to deleterious variants in CTNNA1, deleterious variants in MAP3K6 also occur frequently in the general population. Conclusions: Based on our results MAP3K6 should no longer be considered a GC predisposition gene, whereas deleterious CTNNA1 variants are confirmed as an infrequent cause of GC susceptibility. Biallelic MYD88 germline mutations are at most a very rare cause of GC susceptibility as no additional cases were identified

Ассоциативно-семантическая группа как языковая основа концепта

Статья посвящена описанию особой лексико-семантической парадигмы ассоциативно-семантической группы, которая является частью ассоциативно- семантического комплекса и рассматривается как языковая основа концепта. Исследование проведено с применением описательного, структурного и функционального методов.Статтю присвячено опису особливої лексико-семантичної парадигми асоціативно-семантичної групи, яка є частиною асоціативно-семантичного комплексу і являє собою мовну основу концепту. Дослідження проведено із застосуванням описового, структурного та функціонального методів.The particular lexico-semantic paradigm – associative-semantic group (ASG) which is the part of associative-semantic complex (ASC) – is investigated in the article as a linguistic base of concept. Descriptive, structural, and functional methods were used

A Genome-Wide Analysis of Populations from European Russia Reveals a New Pole of Genetic Diversity in Northern Europe

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