Integration of genetic and epigenetic markers for risk stratification: opportunities and challenges

Common genetic susceptibility variants could be used for risk stratification in risk-tailored cancer screening and prevention programmes. Combining genetic variants with environmental risk factors would improve risk stratification. Epigenetic changes are surrogate markers of environmental exposures during individual's lifetime. Integrating epigenetic markers, in lieu of environmental exposure data, with genetic markers would potentially improve risk stratification. Epigenetic changes are reversible and acquired gradually, providing potentials for prevention and early detection strategies. The epigenetic changes are tissue-specific and stage-of-development-specific, raising challenges in choice of sample and timing for evaluation of cancer-associated changes. The Horizon 2020 funded research programme, FORECEE, using empirical data, will investigate the value of integration of epigenomics with genomics for risk prediction and prevention of women-specific cancers

Locus of control as a moderator of the effects of COVID-19 perceptions on job insecurity, psychosocial, organisational and job outcomes for MENA region hospitality employees

We develop and test an integrated model to understand how individual differences based on internal or external locus of control influence the effects of COVID-19 perceptions on job insecurity, anxiety, alienation, job satisfaction, customer orientation, organisational citizenship behaviour (OCB), and turnover intention among customer service employees within hospitality organisations in the Middle East and North African (MENA) region. The investigation utilises variance-based structural equation modelling to evaluate a sample of 847 subject responses. We found that externally controlled employees are more likely to develop negative emotions resulting from pandemic-triggered job insecurity as well as poorer customer orientation and engagement in OCB due to worsened job satisfaction than those internally controlled. Wholistically, COVID-19 perceptions tend to indirectly hit externally controlled employees’ anxiety, customer orientation, and OCB more intensely than those with internal locus of control

Who’s more vulnerable? A generational investigation of COVID-19 perceptions’ effect on Organisational citizenship Behaviours in the MENA region: job insecurity, burnout and job satisfaction as mediators

Background This paper is an empirical investigation that examines a path model linking COVID-19 perceptions to organisational citizenship behaviour (OCBs) via three mediators: job insecurity, burnout, and job satisfaction. The research examines the path model invariance spanning Generations X, Y, and Z. Three countries in the Middle East and North Africa (MENA) were the focus of the study. Methods The data was collected from a sample of employees in service companies (n = 578). We used a Partial Least Square Structural Equation Modelling (PLS-SEM) to analyse the data. Results Our findings reveal that COVID-19 perceptions positively predict job insecurity, which positively impacts burnout levels. Burnout negatively predicts job satisfaction. The findings established that job satisfaction positively predicts OCBs. The mediation analysis determined that job insecurity, burnout and job satisfaction convey the indirect effects of COVID-19 perceptions onto OCBs. Finally, our hypothesised model is non-equivalent across Generations X, Y and Z. In that regard, our multi-group analysis revealed that the indirect effects of COVID-19 perceptions on OCBs were only valid amongst younger generations, i.e., Generation Y and Generation Z. Specifically, younger generations are substantially more vulnerable to the indirect effects of COVID-19 perceptions on their engagement in OCBs than Generation X whose job satisfaction blocks the effects of COVID-19 perceptions on OCBs. Conclusions The present study extends our knowledge of workplace generational differences in responding to the perceptions of crises or pandemics. It offers evidence that suggests that burnout, job attitudes and organisational outcomes change differently across generations in pandemic times

The DNA methylome of cervical cells can predict the presence of ovarian cancer

The vast majority of epithelial ovarian cancer arises from tissues that are embryologically derived from the Müllerian Duct. Here, we demonstrate that a DNA methylation signature in easy-to-access Müllerian Duct-derived cervical cells from women with and without ovarian cancer (i.e. referred to as the Women’s risk IDentification for Ovarian Cancer index or WID-OC-index) is capable of identifying women with an ovarian cancer in the absence of tumour DNA with an AUC of 0.76 and women with an endometrial cancer with an AUC of 0.81. This and the observation that the cervical cell WID-OC-index mimics the epigenetic program of those cells at risk of becoming cancerous in BRCA1/2 germline mutation carriers (i.e. mammary epithelium, fallopian tube fimbriae, prostate) further suggest that the epigenetic misprogramming of cervical cells is an indicator for cancer predisposition. This concept has the potential to advance the field of risk-stratified cancer screening and prevention

Epigenetic reprogramming of fallopian tube fimbriae in BRCA mutation carriers defines early ovarian cancer evolution

The exact timing and contribution of epigenetic reprogramming to carcinogenesis are unclear. Women harbouring BRCA1/2 mutations demonstrate a 30–40-fold increased risk of high-grade serous extra-uterine Müllerian cancers (HGSEMC), otherwise referred to as ‘ovarian carcinomas’, which frequently develop from fimbrial cells but not from the proximal portion of the fallopian tube. Here we compare the DNA methylome of the fimbrial and proximal ends of the fallopian tube in BRCA1/2 mutation carriers and non-carriers. We show that the number of CpGs displaying significant differences in methylation levels between fimbrial and proximal fallopian tube segments are threefold higher in BRCA mutation carriers than in controls, correlating with overexpression of activation-induced deaminase in their fimbrial epithelium. The differentially methylated CpGs accurately discriminate HGSEMCs from non-serous subtypes. Epigenetic reprogramming is an early pre-malignant event integral to BRCA1/2 mutation-driven carcinogenesis. Our findings may provide a basis for cancer-preventative strategies

Methylation patterns in serum DNA for early identification of disseminated breast cancer

BACKGROUND: Monitoring treatment and early detection of fatal breast cancer (BC) remains a major unmet need. Aberrant circulating DNA methylation (DNAme) patterns are likely to provide a highly specific cancer signal. We hypothesized that cell-free DNAme markers could indicate disseminated breast cancer, even in the presence of substantial quantities of background DNA. METHODS: We used reduced representation bisulfite sequencing (RRBS) of 31 tissues and established serum assays based on ultra-high coverage bisulfite sequencing in two independent prospective serum sets (n = 110). The clinical use of one specific region, EFC#93, was validated in 419 patients (in both pre- and post-adjuvant chemotherapy samples) from SUCCESS (Simultaneous Study of Gemcitabine-Docetaxel Combination adjuvant treatment, as well as Extended Bisphosphonate and Surveillance-Trial) and 925 women (pre-diagnosis) from the UKCTOCS (UK Collaborative Trial of Ovarian Cancer Screening) population cohort, with overall survival and occurrence of incident breast cancer (which will or will not lead to death), respectively, as primary endpoints. RESULTS: A total of 18 BC specific DNAme patterns were discovered in tissue, of which the top six were further tested in serum. The best candidate, EFC#93, was validated for clinical use. EFC#93 was an independent poor prognostic marker in pre-chemotherapy samples (hazard ratio [HR] for death = 7.689) and superior to circulating tumor cells (CTCs) (HR for death = 5.681). More than 70% of patients with both CTCs and EFC#93 serum DNAme positivity in their pre-chemotherapy samples relapsed within five years. EFC#93-positive disseminated disease in post-chemotherapy samples seems to respond to anti-hormonal treatment. The presence of EFC#93 serum DNAme identified 42.9% and 25% of women who were diagnosed with a fatal BC within 3–6 and 6–12 months of sample donation, respectively, with a specificity of 88%. The sensitivity with respect to detecting fatal BC was ~ 4-fold higher compared to non-fatal BC. CONCLUSIONS: Detection of EFC#93 serum DNAme patterns offers a new tool for early diagnosis and management of disseminated breast cancers. Clinical trials are required to assess whether EFC#93-positive women in the absence of radiological detectable breast cancers will benefit from anti-hormonal treatment before the breast lesions become clinically apparent

Understanding the Relationship Between Job Insecurity and Performance: Hindrance or Challenge Effect?

This study aims to propose a theoretical model that explains the psychological processes underlying the job insecurity-performance relationship. To accomplish this goal, we draw on a two-dimensional stressor framework. Job insecurity may undermine performance through a hindrance effect, because it causes strain reactions and withdrawal behaviours. In contrast, it can trigger productive behaviours as a form of job preservation strategy, when reacting actively. These competing predictions are integrated in the same structural equation modeling by testing the negative indirect effect of job insecurity on task and contextual performance, mediated by job satisfaction and affective commitment. The positive challenge effect is examined by testing the remaining direct path to performance. To provide convergence of evidence, two studies were conducted with the purpose to replicate patters and findings across different measures and samples. The results provide support only for negative and passive reactions to job insecurity, leading to lower performance

DNA methylation markers for early detection of women's cancer: promise and challenges

Breast, ovarian and endometrial cancers cause significant morbidity and mortality. Despite the presence of existing screening, diagnostic and treatment modalities, they continue to pose considerable unsolved challenges. Overdiagnosis is a growing problem in breast cancer screening and neither screening nor early diagnosis of ovarian or endometrial cancer is currently possible. Moreover, treatment of the diversity of these cancers presenting in the clinic is not sufficiently personalized at present. Recent technological advances, including reduced representation bisulfite sequencing, methylation arrays, digital PCR, next-generation sequencing and advanced statistical data analysis, enable the analysis of methylation patterns in cell-free tumor DNA in serum/plasma. Ongoing work is bringing these methods together for the analysis of samples from large clinical trials, which have been collected well in advance of cancer diagnosis. These efforts pave the way for the development of a noninvasive method that would enable us to overcome existing challenges to personalized medicine