Genetic epidemiology of breast cancer in CYPRUS: A case -control study of DNA repair genes

This thesis was submitted for the degree of Doctor of Philosophy and awarded by Brunel University.The occurrence of early-onset breast cancer (EOBC) has been associated with germline mutations in the BRCA1 and BRCA2 genes. The first aim of this thesis was to evaluate the frequency and distribution of mutations in these genes, in a group of Cypriot women diagnosed with EOBC. Pathogenic mutations were identified in 6 of the 26 unrelated patients. This study supports a strong correlation between the early onset breast cancer phenotype and the presence of pathogenic BRCA1/2 mutations. It is of interest that pathogenic mutations were detected in patients without a family history of the disease. Based on these results, we recommend that BRCA1/2 screening should be offered to patients with a diagnosis of EOBC irrespective of their family history. The known breast cancer susceptibility genes explain only about 5% of breast cancer cases. Thus, it is likely that other breast cancer susceptibility genes exist. The second aim of the present thesis was to assess whether alterations in DNA repair genes modify breast cancer risk in the Cypriot population. Towards this objective, blood samples were collected and genomic DNA isolated from 1109 Cypriot female breast cancer patients diagnosed between 40-70 years old, and from 1177 age-matched healthy female controls. A total of 79 single nucleotide polymorphisms (SNPs) were genotyped in all samples. Significant associations with breast cancer risk were observed for eight of the SNPs studied. Five SNPs in the BRCA2, MRE11A, MUS81, PBOV1 and XRCC1 genes, were associated with an increased risk for breast cancer, while two SNPs in the NBS1 gene and one SNP in the MRE11A gene appeared to be associated with reduced risk for the disease. The data from this study support the hypothesis that genetic variants in DNA repair genes influence breast cancer risk and provides further evidence for the existence of a polygenic model for breast cancer

Climate change impacts and adaptation options in the Mediterranean basin

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A comparative study on phyllosilicate and tectosilicate mineral structural properties

Natural minerals are widely used in numerous environmental applications, mainly as sorbents in ion exchange and sorption processes. Minerals, such as zeolites and clays, can be found all over the world, but they are mined containing a variety of different impurities; this prevents their accurate characterization. The present study examines various methods used for the characterization of three common natural silicate minerals, one zeolite (clinoptilolite) and two clays (montmorillonite and vermiculite). Their characterization was performed through a series of analytical measurements so as to gather all the information needed regarding their structural properties. Therefore, “similar” minerals such as clinoptilolite vs. heulandite and vermiculite vs. hydrobiotite can be distinguished; revealing important properties when comes to their practical application. The methods used in the present study are X-ray powder diffraction (XRD), X-ray fluorescence, Fourier transform infrared (FTIR) spectroscopy, TG/DTG/DTA and N2-porosimetry (BET). An extensive literature review of the natural silicate minerals has been conducted and the relevant results and methods are comparatively reported. The analytical results enabled the distinguish of the examined minerals. XRD, FTIR, TG/DTG/DTA showed that all three minerals have characteristic bands that can be used to easily distinguish from others

Muddles and puzzles: Metaphor use associated with disease progression in Primary Progressive Aphasia

Background: Primary Progressive Aphasia describes a language-led dementia and its variants. There is little research exploring the experiences of living with this disease. Metaphor, words that represent something else, have been studied extensively in health-related narratives to gain a more intimate insight into health experiences. // Aims: This study explored the metaphors used spontaneously by people with PPA, their care partners (family), and speech and language therapists/pathologists (SLT/Ps) providing support along the continuum of care. // Methods & Procedures: This study examined two previously collected data sets comprising naturalistic talk where metaphors were not the specific focus, the first from focus groups conducted with people with PPA and their families and the second from focus groups conducted with SLT/Ps working with people with PPA. Transcribed data were analysed for metaphor use through an iterative narrative approach. // Outcomes & Results: In all, 237 examples of metaphorical language were identified in the data, with 14 metaphors from people with PPA, 116 from the families and 106 from SLT/Ps. Different metaphors were used by participants to describe their experiences depending on which variant of PPA they were living with, and people also described their disease differently over time. SLT/Ps also used metaphors, however, their language reflected the structured, professional perspective of delivering speech and language therapy services. // Conclusions & Implications: SLT/Ps should listen for and recognise the metaphorical language used by people with PPA and their families to ensure therapeutic alignment, see beyond the PPA to recognise the individual’s needs, and provide person-centred and empathic support

'Like going into a chocolate shop, blindfolded': What do people with primary progressive aphasia want from speech and language therapy?

BACKGROUND: Primary progressive aphasia (PPA) describes a group of language-led dementias. PPAs are complex, diverse and difficult to diagnose, and therefore conventional models of aphasia and dementia treatment do not meet their needs. The research evidence on intervention for PPA is developing, but to date there are only a few case studies exploring the experiences of people with PPA (PwPPA) themselves. AIMS: To explore the experiences and opinions of PwPPA and their communication partners (CPs) to understand how speech and language therapy (SLT) services can better meet their needs. METHODS & PROCEDURES: A qualitative research approach was used whereby PwPPA and their friends or family members were recruited to participate in focus groups, via advertisements in the Rare Dementia Support PPA group newsletters. Consenting participants were allocated to attend one of four focus groups hosted on an online video conferencing platform. Participants were asked about their communication difficulties, and how SLT could address these needs. All meetings were transcribed, and data were examined using reflexive thematic analysis. OUTCOMES & RESULTS: Six PwPPA and 14 CPs representing all three PPA variants and mixed PPA participated in the focus groups. Four main themes were identified during the analysis of the focus group discussions: (1) CPs' burden, (2) adjusting to the diagnosis, (3) communication abilities and difficulties and (4) beyond language. A further 10 subthemes were identified. CONCLUSIONS & IMPLICATIONS: This study provides a greater understanding of the experiences and needs of PwPPA and their families in relation to SLT. This work underlines the importance of a person-centred approach that considers the broader needs of both the PwPPA and the people around them. This will enable service providers to deliver SLT that meets the needs of PwPPA and their families and will also inform future research in this field. WHAT THIS PAPER ADDS: What is already known on this subject We know that PwPPA can maintain or even make improvements in word retrieval and speech fluency with SLT exercises. There is also developing evidence of the benefits of interventions such as CP training, communication aid support and other functional interventions. What this paper adds to existing knowledge This study provides an understanding of the experiences and opinions of people living with PPA and their families in relation to SLT. Results demonstrate that PwPPA and their families have to navigate a complex journey, identifying strategies to support communication but also the influence of personality and other cognitive symptoms. SLT was useful, but not always available. What are the potential or actual clinical implications of this work? This study will enable service providers to better plan, justify funding for and delivery of SLT that will meet the needs of PwPPA and their families. Most importantly this work underlines the importance of a person-centred approach, incorporating the broader needs of the person with PPA and those around them

Multi-gene panel testing and association analysis in Cypriot breast cancer cases and controls

Introduction: It is estimated that around 5% of breast cancer cases carry pathogenic variants in established breast cancer susceptibility genes. However, the underlying prevalence and gene-specific population risk estimates in Cyprus are currently unknown.Methods: We performed sequencing on a population-based case-control study of 990 breast cancer cases and 1094 controls from Cyprus using the BRIDGES sequencing panel. Analyses were conducted separately for protein-truncating and rare missense variants.Results: Protein-truncating variants in established breast cancer susceptibility genes were detected in 3.54% of cases and 0.37% of controls. Protein-truncating variants in BRCA2 and ATM were associated with a high risk of breast cancer, whereas PTVs in BRCA1 and PALB2 were associated with a high risk of estrogen receptor (ER)-negative disease. Among participants with a family history of breast cancer, PTVs in ATM, BRCA2, BRCA1, PALB2 and RAD50 were associated with an increased risk of breast cancer. Furthermore, an additional 19.70% of cases and 17.18% of controls had at least one rare missense variant in established breast cancer susceptibility genes. For BRCA1 and PALB2, rare missense variants were associated with an increased risk of overall and triple-negative breast cancer, respectively. Rare missense variants in BRCA1, ATM, CHEK2 and PALB2 domains, were associated with increased risk of disease subtypes.Conclusion: This study provides population-based prevalence and gene-specific risk estimates for protein-truncating and rare missense variants. These results may have important clinical implications for women who undergo genetic testing and be pivotal for a substantial proportion of breast cancer patients in Cyprus

An investigation of breast cancer risk factors in Cyprus: a case control study

Background: Breast cancer is the most common form of malignancy affecting women worldwide. It is also the leading cancer in females in Cyprus, with approximately 400 new cases diagnosed annually. It is well recognized that genetic variation as well as environmental factors modulate breast cancer risk. The main aim of this study was to assess the strength of associations between recognized risk factors and breast cancer among Cypriot women. This is the first epidemiological investigation on risk factors of breast cancer among the Cypriot female population.Methods: We carried out a case-control study, involving 1,109 breast cancer patients and a group of 1,177 controls who were recruited while participating in the National screening programme for breast cancer. Information on demographic characteristics and potential risk factors were collected from both groups during a standardized interview. Logistic regression analysis was used to assess the strength of the association between each risk factor and breast cancer risk, before and after adjusting for the possible confounding effect of other factors.Results: In multivariable models, family history of breast cancer (OR 1.64, 95% CI 1.23, 2.19) was the strongest predictor of breast cancer risk in the Cypriot population. Late menarche (OR 0.64, 95% CI 0.45, 0.92 among women reaching menarche after the age of 15 vs. before the age of 12) and breastfeeding (OR 0.74, 95% CI 0.59, 0.92) exhibited a strong protective effect. In the case of breastfeeding, the observed effect appeared stronger than the effect of pregnancy alone. Surprisingly, we also observed an inverse association between hormone replacement therapy (HRT) although this may be a product of the retrospective nature of this study.Conclusion: Overall the findings of our study corroborate with the results of previous investigations on descriptive epidemiology of risk factors for breast cancer. This investigation provides important background information for designing detailed studies that aim to improve our understanding of the epidemiology of breast cancer in the Cypriot population, including the study of gene-environment interactions. Furthermore, our study provides the first scientific evidence for formulating targeted campaigns for prevention and early diagnosis of breast cancer in Cyprus