Kyriaki Michailidou

Kyriaki Michailidou
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Kyriaki verified their affiliation via an institutional email.
Verified
Kyriaki verified their affiliation via an institutional email.
Cyprus Institute of Neurology and Genetics · Biostatistics Unit

PhD in Cancer Genetic Epidemiology

About

444
Publications
85,713
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20,931
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Introduction
My research is focused in the fields of statistical genetics, epidemiology and genetic epidemiology of diseases. More specifically I am interested in the analyses of common and rare genetic variants identified through Genome-Wide Association Studies (GWAS) and next generation sequencing data. I am also interested in classification of Variants of Uncertain clinical Significance (VUS) in high risk genes and fine mapping of loci identified through genome wide scans.
Additional affiliations
February 2023 - present
Cyprus Institute of Neurology and Genetics
Position
  • Scientist
June 2015 - present
University of Cambridge
Position
  • Visiting researcher
September 2019 - February 2022
Cyprus Institute of Neurology and Genetics
Position
  • Research Associate
Education
January 2011 - April 2015
University of Cambridge
Field of study
  • Genetic Epidemiology of Breast Cancer
September 2008 - September 2009
University of Oxford
Field of study
  • Applied Statistics
October 2004 - July 2008
Aristotle University of Thessaloniki
Field of study
  • Mathematics

Publications

Publications (444)
Article
Full-text available
Sequencing-based genetic tests have uncovered a vast array of BRCA2 sequence variants¹. Owing to limited clinical, familial and epidemiological data, thousands of variants are considered to be variants of uncertain significance2, 3–4 (VUS). Here we have utilized CRISPR–Cas9-based saturation genome editing in a humanized mouse embryonic stem cell li...
Article
Dominantly inherited intronic GAA repeat expansions in the fibroblast growth factor 14 (FGF14) gene have recently been shown to cause spinocerebellar ataxia 27B (SCA27B). Currently, the pathogenic threshold of (GAA)≥300 repeat units is considered highly penetrant, while (GAA)250-299 is likely pathogenic with reduced penetrance. This study investiga...
Article
Full-text available
Background The 313-variant polygenic risk score (PRS313) provides a promising tool for clinical breast cancer risk prediction. However, evaluation of the PRS313 across different European populations which could influence risk estimation has not been performed. Methods We explored the distribution of PRS313 across European populations using genotyp...
Article
Background Hemoglobinopathies, including sickle cell disease (SCD) and thalassemia syndromes, represent the commonest monogenic diseases in the world, but their varying degree of clinical severity may be partly influenced by genetic modifiers. Despite the identification and characterization of several genetic modifiers by previous studies, these ar...
Article
Full-text available
Known risk loci for endometrial cancer explain approximately one third of familial endometrial cancer. However, the association of germline copy number variants (CNVs) with endometrial cancer risk remains relatively unknown. We conducted a genome-wide analysis of rare CNVs overlapping gene regions in 4115 endometrial cancer cases and 17,818 control...
Article
Full-text available
Introduction Relapsing-Remitting Multiple Sclerosis manifests various motor symptoms including impairments in corticospinal tract integrity, whose symptoms can be assessed using transcranial magnetic stimulation. Several factors, such as exercise and interlimb coordination, can influence the plastic changes in corticospinal tract. Previous work in...
Article
Purpose Most breast biopsies are diagnosed as benign breast disease (BBD), with 1.5- to fourfold increased breast cancer (BC) risk. Apart from pathologic diagnoses of atypical hyperplasia, few factors aid in BC risk assessment of these patients. We assessed whether a 313-SNP polygenic risk score (PRS) stratifies risk of BBD patients. Patients and...
Preprint
Full-text available
Clinical genetic testing identifies variants causal for hereditary cancer, information that is used for risk assessment and clinical management. Unfortunately, some variants identified are of uncertain clinical significance (VUS), complicating patient management. Case-control data is one evidence type used to classify VUS, and previous findings ind...
Article
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Pubertal timing varies considerably and is associated with later health outcomes. We performed multi-ancestry genetic analyses on ~800,000 women, identifying 1,080 signals for age at menarche. Collectively, these explained 11% of trait variance in an independent sample. Women at the top and bottom 1% of polygenic risk exhibited ~11 and ~14-fold hig...
Article
Full-text available
Purpose Mammographic density phenotypes, adjusted for age and body mass index (BMI), are strong predictors of breast cancer risk. BMI is associated with mammographic density measures, but the role of circulating sex hormone concentrations is less clear. We investigated the relationship between BMI, circulating sex hormone concentrations, and mammog...
Article
The success of precision cancer prevention and treatment hinges on accurate discrimination between benign and pathogenic germline alleles in cancer susceptibility genes. Variants of uncertain clinical significance (VUS) present a challenge for cancer risk assessment and functional data will be essential to resolve many VUS. To address this, we deve...
Preprint
Full-text available
The 313-variant polygenic risk score (PRS313) provides a promising tool for breast cancer risk prediction. However, evaluation of the PRS313 across different European populations which could influence risk estimation has not been performed. Here, we explored the distribution of PRS313 across European populations using genotype data from 94,072 fema...
Article
Full-text available
Since first publication of the American College of Medical Genetics and Genomics/Association for Medical Pathology (ACMG/AMP) variant classification guidelines, additional recommendations for application of certain criteria have been released (https://clinicalgenome.org/docs/), to improve their application in the diagnostic setting. However, none h...
Article
Background Expansion of genome-wide association studies across population groups is needed to improve our understanding of shared and unique genetic contributions to breast cancer. We performed association and replication studies guided by a priori linkage findings from African ancestry (AA) relative pairs. Methods We performed fixed-effect invers...
Article
Full-text available
Background Late-onset neonatal sepsis (LOS) is common in preterm neonates, with increasing incidence in recent years. In the present study, we examined the epidemiology, clinical presentation, and complications of LOS in Cyprus and quantified possible risk factors for the development of this condition. Methods The study subjects were preterm neona...
Article
Full-text available
Light-at-night triggers the decline of pineal gland melatonin biosynthesis and secretion and is an IARC-classified probable breast-cancer risk factor. We applied a large-scale molecular epidemiology approach to shed light on the putative role of melatonin in breast cancer. We investigated associations between breast-cancer risk and polymorphisms at...
Article
Full-text available
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 cance...
Article
Full-text available
A large number of variants identified through clinical genetic testing in disease susceptibility genes are of uncertain significance (VUS). Following the recommendations of the American College of Medical Genetics and Genomics (ACMG) and Association for Molecular Pathology (AMP), the frequency in case-control datasets (PS4 criterion) can inform the...
Article
Full-text available
Linkage and candidate gene studies have identified several breast cancer susceptibility genes, but the overall contribution of coding variation to breast cancer is unclear. To evaluate the role of rare coding variants more comprehensively, we performed a meta-analysis across three large whole-exome sequencing datasets, containing 26,368 female case...
Article
Full-text available
Background Genome-wide studies of gene–environment interactions (G×E) may identify variants associated with disease risk in conjunction with lifestyle/environmental exposures. We conducted a genome-wide G×E analysis of ~ 7.6 million common variants and seven lifestyle/environmental risk factors for breast cancer risk overall and for estrogen recept...
Article
Full-text available
Background Polygenic risk score (PRS), calculated based on genome-wide association studies (GWASs), can improve breast cancer (BC) risk assessment. To date, most BC GWASs have been performed in individuals of European (EUR) ancestry, and the generalisation of EUR-based PRS to other populations is a major challenge. In this study, we examined the pe...
Article
Full-text available
Purpose: Germline pathogenic variants in CHEK2 confer moderately elevated breast cancer risk (odds ratio, OR ∼ 2.5), qualifying carriers for enhanced breast cancer screening. Besides pathogenic variants, dozens of missense CHEK2 variants of uncertain significance (VUS) have been identified, hampering the clinical utility of germline genetic testin...
Article
Full-text available
FANCM germline protein truncating variants (PTVs) are moderate-risk factors for ER-negative breast cancer. We previously described the spectrum of FANCM PTVs in 114 European breast cancer cases. In the present, larger cohort, we report the spectrum and frequency of four common and 62 rare FANCM PTVs found in 274 carriers detected among 44,803 breas...
Preprint
Full-text available
Pubertal timing varies considerably and has been associated with a range of health outcomes in later life. To elucidate the underlying biological mechanisms, we performed multi-ancestry genetic analyses in ~800,000 women, identifying 1,080 independent signals associated with age at menarche. Collectively these loci explained 11% of the trait varian...
Article
Full-text available
Background: The distribution of ovarian tumour characteristics differs between germline BRCA1 and BRCA2 pathogenic variant carriers and non-carriers. In this study, we assessed the utility of ovarian tumour characteristics as predictors of BRCA1 and BRCA2 variant pathogenicity, for application using the American College of Medical Genetics and the...
Article
Full-text available
Background: Thoracic Aortic Aneurysms (TAAs) develop asymptomatically and are characterized by dilatation of the aorta. This is considered a life-threatening vascular disorder due to the risk of aortic dissection and rupture. There is an urgent need to identify blood-borne biomarkers for the early detection of TAA. The goal of the present study wa...
Article
Full-text available
Relapsing-remitting Multiple Sclerosis is the most common demyelinating neurodegenerative disease and is characterized by periods of relapses and generation of various motor symptoms. These symptoms are associated with the corticospinal tract integrity, which is quantified by means of corticospinal plasticity which can be probed via transcranial ma...
Article
Full-text available
Evidence from literature, including the BRIDGES study, indicates that germline protein truncating variants (PTVs) in FANCM confer moderately increased risk of ER-negative and triple-negative breast cancer (TNBC), especially for women with a family history of the disease. Association between FANCM missense variants (MVs) and breast cancer risk has b...
Article
Full-text available
Background Low-frequency variants play an important role in breast cancer (BC) susceptibility. Gene-based methods can increase power by combining multiple variants in the same gene and help identify target genes. Methods We evaluated the potential of gene-based aggregation in the Breast Cancer Association Consortium cohorts including 83,471 cases...
Article
Full-text available
Makorin RING finger protein 3 (MKRN3) is an important factor located on chromosome 15 in the imprinting region associated with Prader-Willi syndrome. Imprinted MKRN3 is expressed in hypothalamic regions essential for the onset of puberty and mutations in the gene have been found in patients with central precocious puberty. The pubertal process is l...
Article
Full-text available
Background Genome-wide association studies (GWAS) have identified multiple common breast cancer susceptibility variants. Many of these variants have differential associations by estrogen receptor (ER) status, but how these variants relate with other tumor features and intrinsic molecular subtypes is unclear. Methods Among 106,571 invasive breast c...
Article
Full-text available
Watercress (Nasturtium officinale) is a rich source of secondary metabolites with disease-preventing and/or health-promoting properties. Herein, we have utilized extraction procedures to isolate fractions of polyphenols, glucosinolates and isothiocyanates to determine their identification, and quantification. In doing so, we have utilized reproduci...
Article
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Objectives Physical inactivity and sedentary behaviour are associated with higher breast cancer risk in observational studies, but ascribing causality is difficult. Mendelian randomisation (MR) assesses causality by simulating randomised trial groups using genotype. We assessed whether lifelong physical activity or sedentary time, assessed using ge...
Preprint
Introductory paragraph Linkage and candidate gene studies have identified several breast cancer susceptibility genes, but the overall contribution of coding variation to breast cancer is unclear. To evaluate the role of rare coding variants more comprehensively, we performed a meta-analysis across three large whole-exome sequencing datasets, contai...
Article
Full-text available
Background: Thalassemias are inherited blood disorders and by far one of the most common monogenic diseases globally. Beta-thalassemia has a particularly high prevalence in Cyprus, with the IVSI-110 G>A (HBB:c.93-21G>A) pathogenic variation representing almost 79% of the total carriers. The discovery that 3% to 20% of cell-free fetal DNA (cffDNA) i...
Article
Polygenic risk scores (PRSs) are useful for predicting breast cancer risk, but the prediction accuracy of existing PRSs in women of African ancestry (AA) remains relatively low. We aim to develop optimal PRSs for prediction of overall and estrogen receptor (ER) subtype-specific breast cancer risk in AA women. The AA dataset comprised 9235 cases and...
Article
Full-text available
Use of menopausal hormone therapy (MHT) is associated with increased risk for breast cancer. However, the relevant mechanisms and its interaction with genetic variants are not fully understood. We conducted a genome-wide interaction analysis between MHT use and genetic variants for breast cancer risk in 27,585 cases and 34,785 controls from 26 obse...
Article
Full-text available
Background Mammographic density (MD) phenotypes, including percent density (PMD), area of dense tissue (DA), and area of non-dense tissue (NDA), are associated with breast cancer risk. Twin studies suggest that MD phenotypes are highly heritable. However, only a small proportion of their variance is explained by identified genetic variants. Method...
Article
Full-text available
Genome-wide association studies (GWAS) have identified more than 200 susceptibility loci for breast cancer, but these variants explain less than a fifth of the disease risk. Although gene–environment interactions have been proposed to account for some of the remaining heritability, few studies have empirically assessed this. We obtained genotype an...
Article
Full-text available
Simple Summary Heritable rare high- and moderate-risk mutations in breast cancer susceptibility genes are known of, alongside 170 common genetic low risk variants with a minor increase in risk. However, based on genetic studies, we know that over half of the breast cancer heritability is still unexplained. By analyzing combinations of chromosomal n...
Article
Full-text available
Germline copy number variants (CNVs) are pervasive in the human genome but potential disease associations with rare CNVs have not been comprehensively assessed in large datasets. We analysed rare CNVs in genes and non-coding regions for 86,788 breast cancer cases and 76,122 controls of European ancestry with genome-wide array data. Gene burden test...
Article
Full-text available
Background Genome-wide association studies (GWAS) have identified multiple common breast cancer susceptibility variants. Many of these variants have differential associations by estrogen receptor (ER) status, but how these variants relate with other tumor features and intrinsic molecular subtypes is unclear. Methods Among 106,571 invasive breast ca...
Preprint
Full-text available
Polygenic risk scores (PRSs) are useful to predict breast cancer risk, but the prediction accuracy of existing PRSs in women of African ancestry (AA) remain relatively low. We aim to develop optimal PRSs for prediction of overall and estrogen receptor (ER) subtype-specific breast cancer risk in women of African ancestry. The AA dataset comprised 9,...
Article
Full-text available
Background This study aims to characterize SARS-CoV-2 mutations which are primarily prevalent in the Cypriot population. Moreover, using computational approaches, we assess whether these mutations are associated with changes in viral virulence. Methods We utilize genetic data from 144 sequences of SARS-CoV-2 strains from the Cypriot population obt...
Article
Full-text available
Purpose Non-European populations are under-represented in genetics studies, hindering clinical implementation of breast cancer polygenic risk scores (PRSs). We aimed to develop PRSs using the largest available studies of Asian ancestry and to assess the transferability of PRS across ethnic subgroups. Methods The development data set comprised 138,...
Article
Full-text available
Hemoglobinopathies, including sickle cell disease (SCD) and thalassemia syndromes, represent the commonest monogenic diseases in the world. Although their pathogenicity is well established, the diverse clinical manifestations and the varying degree of severity are less understood and are thought to be governed, in part, by genetic modifiers. Despit...
Article
Full-text available
Background: Data support the link between the coronavirus disease 2019 (COVID-19) pandemic and mental distress in healthcare workers (HCWs). Although previous studies have documented the association between organizational policies and employees' psychological and mental status, there is still scant evidence regarding the effect of perceived organiz...
Article
Full-text available
Duchenne muscular dystrophy (DMD) is a fatal disorder characterised by progressive muscle wasting. It is caused by mutations in the dystrophin gene, which disrupt the open reading frame leading to the loss of functional dystrophin protein in muscle fibres. Antisense oligonucleotide (AON)-mediated skipping of the mutated exon, which allows productio...
Article
Full-text available
Background: During the COVID-19 pandemic, telemedicine use has increased within community pediatrics. This trend runs counter to reluctance to adaptation of the new mode of healthcare that existed prior to the pandemic. Little is known about what we can expect after the pandemic: if physicians will opt for telemedicine modalities and if tele-pediat...
Article
Full-text available
Background Despite a modest association between tobacco smoking and breast cancer risk reported by recent epidemiological studies, it is still equivocal whether smoking is causally related to breast cancer risk. Methods We applied Mendelian randomisation (MR) to evaluate a potential causal effect of cigarette smoking on breast cancer risk. Both ind...
Article
Full-text available
Breast cancer metastasis accounts for most of the deaths from breast cancer. Identification of germline variants associated with survival in aggressive types of breast cancer may inform understanding of breast cancer progression and assist treatment. In this analysis, we studied the associations between germline variants and breast cancer survival...
Article
Full-text available
Background Central precocious puberty (CPP) due to premature activation of GnRH secretion results in early epiphyseal fusion and to a significant compromise in the achieved final adult height. Currently, few genetic determinants of children with CPP have been described. In this translational study, rare sequence variants in MKRN3, DLK1, KISS1, and...
Article
Full-text available
Accurate and consistent interpretation of sequence variants is integral to the delivery of safe and reliable diagnostic genetic services. To standardize the interpretation process, in 2015, the American College of Medical Genetics and Genomics (ACMG) and the Association for Molecular Pathology (AMP) published a joint guideline based on a set of sha...
Article
Full-text available
The PRS combines multiplicatively the effects of common low-risk single nucleotide polymorphisms (SNPs) and has the potential to be used for the estimation of an individual’s risk for a trait or disease. PRS has been successfully implemented for the prediction of breast cancer risk. The combination of PRS with classical breast cancer risk factors p...