Studies of the inherited or germline genome have identified rare mutations with large effects and common polymorphisms of more modest effect sizes that are associated with cancer risk. This research ...has substantially illuminated the etiology and development of cancer, with particular relevance to cancer prevention. In parallel, studies of the somatic or tumor genome have been instrumental in identifying the key drivers of cancer progression, significantly informing modern cancer therapy. While these studies have thus far largely been performed separately, integrative studies where the germline and somatic genomes are mapped in the same individuals have the potential to yield novel and holistic insights into cancer biology. In this issue of Cancer Research, Liu and colleagues report the results of integrative germline-somatic analyses in over 12,000 patients with cancer and 11 cancer types, identifying several associations where inherited variants that regulate the expression of a nearby gene in normal tissues are associated with tumor mutations in the same gene or with genome-wide somatic traits such as the tumor mutational burden. Although considerable follow-up work is required, the study is an important contribution to an emerging body of evidence that is demonstrating that the germline has a vital role in shaping the tumor genome. See related article by Liu et al., p. 1191.
The Lancet has helped bring global attention to the problem of violence against doctors in China through its Editorials in 2012 (May 12, p 1764)1 and 2014 (March 22, p 1013),2 and has stimulated ...local discussion on potential solutions. India's health system faces a similar crisis and the magnitude of the Indian problem is, perhaps, greater.
Clonal hematopoiesis (CH), the clonal expansion of a blood stem cell and its progeny driven by somatic driver mutations, affects over a third of people, yet remains poorly understood. Here we analyze ...genetic data from 200,453 UK Biobank participants to map the landscape of inherited predisposition to CH, increasing the number of germline associations with CH in European-ancestry populations from 4 to 14. Genes at new loci implicate DNA damage repair (PARP1, ATM, CHEK2), hematopoietic stem cell migration/homing (CD164) and myeloid oncogenesis (SETBP1). Several associations were CH-subtype-specific including variants at TCL1A and CD164 that had opposite associations with DNMT3A- versus TET2-mutant CH, the two most common CH subtypes, proposing key roles for these two loci in CH development. Mendelian randomization analyses showed that smoking and longer leukocyte telomere length are causal risk factors for CH and that genetic predisposition to CH increases risks of myeloproliferative neoplasia, nonhematological malignancies, atrial fibrillation and blood epigenetic ageing.
Smoking is a well-established cause of lung cancer and there is strong evidence that smoking also increases the risk of several other cancers. Alcohol consumption has been inconsistently associated ...with cancer risk in observational studies. This mendelian randomisation (MR) study sought to investigate associations in support of a causal relationship between smoking and alcohol consumption and 19 site-specific cancers.
We used summary-level data for genetic variants associated with smoking initiation (ever smoked regularly) and alcohol consumption, and the corresponding associations with lung, breast, ovarian, and prostate cancer from genome-wide association studies consortia, including participants of European ancestry. We additionally estimated genetic associations with 19 site-specific cancers among 367,643 individuals of European descent in UK Biobank who were 37 to 73 years of age when recruited from 2006 to 2010. Associations were considered statistically significant at a Bonferroni corrected p-value below 0.0013. Genetic predisposition to smoking initiation was associated with statistically significant higher odds of lung cancer in the International Lung Cancer Consortium (odds ratio OR 1.80; 95% confidence interval CI 1.59-2.03; p = 2.26 × 10-21) and UK Biobank (OR 2.26; 95% CI 1.92-2.65; p = 1.17 × 10-22). Additionally, genetic predisposition to smoking was associated with statistically significant higher odds of cancer of the oesophagus (OR 1.83; 95% CI 1.34-2.49; p = 1.31 × 10-4), cervix (OR 1.55; 95% CI 1.27-1.88; p = 1.24 × 10-5), and bladder (OR 1.40; 95% CI 1.92-2.65; p = 9.40 × 10-5) and with statistically nonsignificant higher odds of head and neck (OR 1.40; 95% CI 1.13-1.74; p = 0.002) and stomach cancer (OR 1.46; 95% CI 1.05-2.03; p = 0.024). In contrast, there was an inverse association between genetic predisposition to smoking and prostate cancer in the Prostate Cancer Association Group to Investigate Cancer Associated Alterations in the Genome consortium (OR 0.90; 95% CI 0.83-0.98; p = 0.011) and in UK Biobank (OR 0.90; 95% CI 0.80-1.02; p = 0.104), but the associations did not reach statistical significance. We found no statistically significant association between genetically predicted alcohol consumption and overall cancer (n = 75,037 cases; OR 0.95; 95% CI 0.84-1.07; p = 0.376). Genetically predicted alcohol consumption was statistically significantly associated with lung cancer in the International Lung Cancer Consortium (OR 1.94; 95% CI 1.41-2.68; p = 4.68 × 10-5) but not in UK Biobank (OR 1.12; 95% CI 0.65-1.93; p = 0.686). There was no statistically significant association between alcohol consumption and any other site-specific cancer. The main limitation of this study is that precision was low in some analyses, particularly for analyses of alcohol consumption and site-specific cancers.
Our findings support the well-established relationship between smoking and lung cancer and suggest that smoking may also be a risk factor for cancer of the head and neck, oesophagus, stomach, cervix, and bladder. We found no evidence supporting a relationship between alcohol consumption and overall or site-specific cancer risk.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
The study investigates the erosion phenomenon of the micro-electrical discharge milling (µED-milling) while fabricating microslots on titanium grade 2 alloy. Control parameters such as voltage, ...capacitance and depth of cut (DOC) are varied during experimentation. Material removal rate (MRR), tool wear rate (TWR) and electrode wear ratio (EWR) are the response measures evaluated to visualize the effect of variation of control parameters. An in-depth analysis of the erosion mechanism is done by characterizing the optical microscopy images of the machined cavities and the worn-out tools. Empirical models of MRR, TWR and EWR as functions of the control parameters are formulated by regression analysis. Thereafter, desirability analysis is applied to simultaneously optimize all the responses by assigning equal weightage and importance. Maximum composite desirability of 0.646 is attained at 10
4
pF, 110 V and 1000 µm. The analysis of variance test revealed that capacitance and voltage are more significant to all the responses than the DOC. A good correlation between the experimental and predicted values is achieved from residual analysis, which signifies the adequacy of the regression models. From the confirmation test, the highest error of 7.77% is observed between the experimental and predicted values of TWR, which justifies the desirability approach in simultaneous optimization of all the responses.
Breast cancer (BC) has the highest cancer incidence and mortality in women worldwide. Observational epidemiological studies suggest a positive association between testosterone, estradiol, ...dehydroepiandrosterone sulphate (DHEAS) and other sex steroid hormones with postmenopausal BC. We used a two-sample Mendelian randomization analysis to investigate this association.
Genetic instruments for nine sex steroid hormones and sex hormone-binding globulin (SHBG) were obtained from genome-wide association studies (GWAS) of UK Biobank (total testosterone (TT) N: 230,454, bioavailable testosterone (BT) N: 188,507 and SHBG N: 189,473), The United Kingdom Household Longitudinal Study (DHEAS N: 9722), the LIFE-Adult and LIFE-Heart cohorts (estradiol N: 2607, androstenedione N: 711, aldosterone N: 685, progesterone N: 1259 and 17-hydroxyprogesterone N: 711) and the CORtisol NETwork (CORNET) consortium (cortisol N: 25,314). Outcome GWAS summary statistics were obtained from the Breast Cancer Association Consortium (BCAC) for overall BC risk (N: 122,977 cases and 105,974 controls) and subtype-specific analyses.
We found that a standard deviation (SD) increase in TT, BT and estradiol increased the risk of overall BC (OR 1.14, 95% CI 1.09-1.21, OR 1.19, 95% CI 1.07-1.33 and OR 1.03, 95% CI 1.01-1.06, respectively) and ER + BC (OR 1.19, 95% CI 1.12-1.27, OR 1.25, 95% CI 1.11-1.40 and OR 1.06, 95% CI 1.03-1.09, respectively). An SD increase in DHEAS also increased ER + BC risk (OR 1.09, 95% CI 1.03-1.16). Subtype-specific analyses showed similar associations with ER+ expressing subtypes: luminal A-like BC, luminal B-like BC and luminal B/HER2-negative-like BC.
TT, BT, DHEAS and estradiol increase the risk of ER+ type BCs similar to observational studies. Understanding the role of sex steroid hormones in BC risk, particularly subtype-specific risks, highlights the potential importance of attempts to modify and/or monitor hormone levels in order to prevent BC.
The Rho GTPase family consists of 20 genes encoding intracellular signalling proteins that influence cytoskeletal dynamics, cell migration and cell cycle progression. They are implicated in breast ...cancer progression but their role in breast cancer aetiology is unknown. As aberrant Rho GTPase activity could be associated with breast cancer, we aimed to determine the potential for a causal role of Rho GTPase gene expression in breast cancer risk, using two-sample Mendelian randomization (MR). MR was undertaken in 122,977 breast cancer cases and 105,974 controls, including 69,501 estrogen receptor positive (ER+) cases and 105,974 controls, and 21,468 ER negative (ER-) cases and 105,974 controls. Single nucleotide polymorphisms (SNPs) underlying expression quantitative trait loci (eQTLs) obtained from normal breast tissue, breast cancer tissue and blood were used as genetic instruments for Rho GTPase expression. As a sensitivity analysis, we undertook co-localisation to examine whether findings reflected shared causal variants or genomic confounding. We identified genetic instruments for 14 of the 20 human Rho GTPases. Using eQTLs obtained from normal breast tissue and normal blood, we identified evidence of a causal role of RHOD in overall and ER+ breast cancers (overall breast cancer: odds ratio (OR) per standard deviation (SD) increase in expression level 1.06; (95% confidence interval (CI) 1.03, 1.09; P = 5.65 × 10
) and OR 1.22 (95% CI 1.11, 1.35; P = 5.22 × 10
) in normal breast tissue and blood respectively). There was a consistent direction of association for ER- breast cancer, although the effect-estimate was imprecisely estimated. Using eQTLs from breast cancer tissue and normal blood there was some evidence that CDC42 was negatively associated with overall and ER + breast cancer risk. The evidence from colocalization analyses strongly supported our MR results particularly for RHOD. Our study suggests a potential causal role of increased RHOD gene expression, and, although the evidence is weaker, a potential protective role for CDC42 gene expression, in overall and ER+ breast cancers. These finding warrant validation in independent samples and further biological investigation to assess whether they may be suitable targets for drug targeting.
Cortisol's immunosuppressive, obesogenic, and hyperglycaemic effects suggest that it may play a role in cancer development. However, whether cortisol increases cancer risk is not known. We ...investigated the potential causal association between plasma cortisol and risk of overall and common site-specific cancers using Mendelian randomisation.
Three genetic variants associated with morning plasma cortisol levels at the genome-wide significance level (P < 5 × 10
) in the Cortisol Network consortium were used as genetic instruments. Summary-level genome-wide association study data for the cancer outcomes were obtained from large-scale cancer consortia, the UK Biobank, and the FinnGen consortium. Two-sample Mendelian randomisation analyses were performed using the fixed-effects inverse-variance weighted method. Estimates across data sources were combined using meta-analysis.
A standard deviation increase in genetically predicted plasma cortisol was associated with increased risk of endometrial cancer (odds ratio 1.50, 95% confidence interval 1.13-1.99; P = 0.005). There was no significant association between genetically predicted plasma cortisol and risk of other common site-specific cancers, including breast, ovarian, prostate, colorectal, lung, or malignant skin cancer, or overall cancer.
These results indicate that elevated plasma cortisol levels may increase the risk of endometrial cancer but not other cancers. The mechanism by which this occurs remains to be investigated.
The present study investigates fabrication of microrod using block electrical discharge grinding process and performs in situ drilling and milling of thin sheets using the fabricated rods by the ...microelectrical discharge machining process. The microrods are fabricated at a wide range of discharge energy (DE) by varying voltage and capacitance, and their effect on machining time (MT), material removal rate, average diameter and standard deviation in diameter (SDD) are evaluated. To get the benefit of both higher efficiency as well as dimensional accuracy, a technique of variable energy setting is coined, wherein higher DE is applied initially to increase efficiency followed by lower DE to improve dimensional accuracy and precision. The fabricated microrods are then used as tools for in situ microelectrical discharge drilling (µED-drilling) and microelectrical discharge milling (µED-milling) on brass and titanium sheet. In µED-drilling, MT and tool wear (TW) of brass is lower as compared to titanium, whereas overcut of brass is higher than titanium. ‘To and fro’ technique is used to compensate the TW in µED-milling and to achieve dimensional accuracy. The technique is successful in achieving fairly straight microslot in brass with SDD of 17 µm as compared to titanium with SDD of 113.50 µm.
PDF
