Andreas Hadjisavvas

Cyprus Institute of Neurology and Genetics · Department of Electron Microscopy and Molecular Pahtology

Background Reproductive factors have been shown to be differentially associated with risk of estrogen receptor (ER) positive and ER-negative breast cancer. However, their associations with intrinsic-like subtypes are less clear. Methods Analyses included up to 23,353 cases, and 71,072 controls pooled from 31 population-based case-control or cohort...

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 16,498 cases and 1...

Background Protein truncating variants in ATM , BRCA1 , BRCA2 , CHEK2 , and PALB2 are associated with increased breast cancer risk, but risks associated with missense variants in these genes are uncertain. Methods We analyzed data on 59,639 breast cancer cases and 53,165 controls from studies participating in the Breast Cancer Association Consorti...

Importance: Rare germline genetic variants in several genes are associated with increased breast cancer (BC) risk, but their precise contributions to different disease subtypes are unclear. This information is relevant to guidelines for gene panel testing and risk prediction. Objective: To characterize tumors associated with BC susceptibility ge...

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic has hit its second year and continues to damage lives and livelihoods across the globe. There continues to be a global effort to present serological data on SARS-CoV-2 antibodies in different individuals. As such, this study aimed to characterize the seroprevalence of SARS-Co...

BACKGROUND Protein truncating variants in ATM, BRCA1, BRCA2, CHEK2 and PALB2 are associated with increased breast cancer risk, but risks associated with missense variants in these genes are uncertain. METHODS Combining 59,639 breast cancer cases and 53,165 controls, we sampled training (80%) and validation (20%) sets to analyze rare missense varian...

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...

Background: Parkinson's disease (PD) is a neurodegenerative disorder, and literature suggests that genetics and lifestyle/environmental factors may play a key role in the triggering of the disease. This study aimed to evaluate the predictive performance of a 12-Single Nucleotide Polymorphisms (SNPs) polygenic risk score (PRS) in combination with a...

Whole genome sequencing of viral specimens following molecular diagnosis is a powerful analytical tool of molecular epidemiology that can critically assist in resolving chains of transmission, identifying of new variants or assessing pathogen evolution and allows a real-time view into the dynamics of a pandemic. In Cyprus, the first two cases of CO...

Individualized patient care is essential to reduce the global burden of traumatic brain injury (TBI). This pilot study focused on TBI patients admitted to intensive care units (ICUs) and aimed at identifying patterns of circulating biomarkers associated with the disability level at 6 months from injury, measured by the extended Glasgow outcome scal...

Although silver nanoparticles (AgNPs) appear to be promising for certain medical/ pharmaceutical applications, they present significant disadvantages when it comes to environmental applications due to the need for recovery of the metal (Ag) which is considered hazardous for the environment. The present study examines the antimicrobial properties an...

Background Next-generation sequencing (NGS) represents a significant advancement in clinical genetics. However, its use creates several technical, data interpretation and management challenges. It is essential to follow a consistent data analysis pipeline to achieve the highest possible accuracy and avoid false variant calls. Herein, we aimed to co...

Whole genome sequencing of viral specimens following molecular diagnosis is a powerful analytical tool of molecular epidemiology that can critically assist in resolving chains of transmission, identifying of new variants or assessing pathogen evolution and allows a real-time view into the dynamics of a pandemic. In Cyprus, the first two cases of CO...

We aimed to determine genetic diagnosis in the national primary ciliary dyskinesia (PCD) cohort of Cyprus, an island with a high disease prevalence. We used targeted next‐generation sequencing (NGS) of 39 PCD genes in 48 patients of Greek‐Cypriot and other ancestries. We achieved molecular diagnosis in 74% of the unrelated families tested. We ident...

Oculodentodigital dysplasia syndrome is associated with numerous pathogenic variants in GJA1, the gene encoding connexin43 gap junction protein. A novel in-frame deletion (p.Lys134del) was found in our clinic. The patient showed all the typical dysmorphic features of the syndrome. The functional consequences of this variant were also studied in an...

Background Genetic testing for breast cancer susceptibility is widely used, but for many genes, evidence of an association with breast cancer is weak, underlying risk estimates are imprecise, and reliable subtype-specific risk estimates are lacking. Methods We used a panel of 34 putative susceptibility genes to perform sequencing on samples from 6...

In Cyprus, approximately 9% of triple-negative (estrogen receptor-negative, progesterone receptor-negative, and human epidermal growth factor receptor 2-negative) breast cancer (TNBC) patients are positive for germline pathogenic variants (PVs) in BRCA1/2. However, the contribution of other genes has not yet been determined. To this end, we aimed t...

Background Alport syndrome (AS) is the second most common hereditary kidney disease caused by mutations in collagen IV genes. Patients present with microhaematuria that progressively leads to proteinuria and End Stage Renal Disease. Currently, no specific treatment exists for AS. Using mass spectrometry based proteomics, we aimed to detect early al...

Background: Approximately 50% of systemic lupus erythematosus (SLE) patients develop nephritis, which is among the most severe and frequent complications of the disease and a leading cause of morbidity and mortality. Despite intensive research, there are still no reliable lupus nephritis (LN) markers in clinical use that can assess renal damage an...

Most genetic susceptibility to cutaneous melanoma remains to be discovered. Meta-analysis genome-wide association study (GWAS) of 36,760 cases of melanoma (67% newly genotyped) and 375,188 controls identified 54 significant (P < 5 × 10−8) loci with 68 independent single nucleotide polymorphisms. Analysis of risk estimates across geographical region...

Background: Brain metastasis (BM) is an increasingly common and devastating complication of breast cancer (BC). Methods: A systematic literature search of EMBASE and MEDLINE was conducted to elucidate the current state of knowledge on known and novel prognostic factors associated with 1) the risk for BCBM and 2) the time to brain metastases (TTB...

There is ample evidence that the Mediterranean diet reduces breast cancer risk, despite the fact that evidence across studies and populations has not been consistent. The protective effect of the Mediterranean diet is in line with the fact that some of its key components, such as fruit, vegetables, folate, and olive oil, have also been shown to hav...

Introduction: Parkinson's disease (PD) is a neurodegenerative disorder affecting a substantial proportion of the elderly Cypriot population. The objective of this study was to evaluate PD risk variants that have been identified previously in Genome Wide Association Studies (GWAS) and to find environmental factors that are predictors for PD onset in...

BRCA1 BRCA2 mutational spectrum in the Middle East, North Africa, and Southern Europe is not well characterized. The unique history and cultural practices characterizing these regions, often involving consanguinity and inbreeding, plausibly led to the accumulation of population‐specific founder pathogenic sequence variants (PSVs). To determine recu...

Background Numerous single nucleotide polymorphisms (SNPs) have been implicated with cutaneous melanoma (CM) Objective: The aim of our study was to establish novel susceptibility loci for CM by assessing candidate genes in a published meta‐analysis of 11 genome‐wide association studies (GWASs). Methods 760 variants were retrieved from the MelGene...

Background: Primary ciliary dyskinesia (PCD) is an inherited ciliary motility disorder caused by mutations in at least 40 genes. RSPH9 gene mutations encoding aberrant radial spoke head proteins have been linked with PCD. The clinical spectrum extent of RSPH9 gene mutations remains to date largely unknown. We aimed to describe the diagnostic and c...

Objective To examine the effect of variants in genes encoding molecules that are implicated in leukocyte trafficking into the CNS on the development of MS. Methods A total of 389 Greek MS cases and 336 controls were recruited by 3 MS centers in Cyprus and Greece. In total, 147 tagging single nucleotide polymorphisms across 9 genes encoding for P-s...

The spectrum of of BRCA1 and BRCA2 pathogenic sequence variants in Middle Eastern, North African, and South European countries

Background: ATTRV30M amyloidosis is a lethal autosomal dominant sensorimotor and autonomic neuropathy caused by amyloid deposition composed of aggregated misfolded TTR monomers with the V30M mutation. The age of onset in patients with ATTRV30M varies in different foci and the mechanism behind it is still unknown. Methods: The tertiary neurology cen...

Herein, we maximize the labeling efficiency of cardiac progenitor cells (CPCs) using perfluorocarbon nanoparticles (PFCE-NP) and ¹⁹F MRI detectability, determine the temporal dynamics of single-cell label uptake, quantify the temporal viability/fluorescence persistence of labeled CPCs in vitro, and implement in vivo, murine cardiac CPC MRI/tracking...

Objectives: Few studies have examined the potentially therapeutic effect of increasing the production of endogenous nitric oxide (NO) in Primary Ciliary Dyskinesia (PCD) and other chronic respiratory conditions. Nasal NO is low in PCD and has been found to correlate with compromised Ciliary Beat Frequency (CBF). In this study we assessed the effec...

Background Despite evidence supporting an involvement of mitochondrial dysfunction in the pathogenesis of some neurodegenerative disorders, there are inconsistent findings concerning mitochondrial haplogroups and their association to neurodegenerative disorders, including idiopathic Parkinson’s disease (PD). Methods To test this hypothesis for the...

Odds Ratios (95% Confidence Intervals) showing associations between Cypriot mitochondrial superclusters and PD symptoms. (DOCX)

Odds Ratios (95% Confidence Intervals) showing associations between Cypriot mitochondrial superclusters and PD symptoms, after stratification by gender. (DOCX)

Odds Ratios (95% Confidence Intervals) showing associations between Cypriot mitochondrial clusters and superclusters and PD, without adjusting for any confounders. (DOCX)

Odds Ratios (95% Confidence Intervals) showing associations between MtDNA coding region branch-defining SNPs and PD, after adjusting for age, gender and maternal place of origin. (DOCX)

Objective To assess the potential effect of variants in genes encoding molecules that are implicated in leukocyte trafficking into the CNS on the clinical phenotype of multiple sclerosis (MS). Methods A total of 389 Greek MS cases and 336 controls were recruited in 3 MS centers from Cyprus and Greece. We genotyped 147 tagging single nucleotide pol...

In the Western world, the incidence of non-communicable diseases, such as cardiovascular diseases, type 2 diabetes and cancer, is increasing among the younger generation. Currently non-communicable diseases are the leading cause of mortality in the world, imposing a major burden on national economies. It is noteworthy that many cases of these compl...

Figure S1 Flow diagram showing the systematic literature search and review process. All methods were applied in accordance with the PRISMA guidelines. Table S1. Requirements for scientific reporting of proteomic biomarker data reported by Mischak et al. 2010 implemented for the 25 articles obtained in the systematic review.

Oculo-dento-digital dysplasia (ODDD) is a congenital disorder manifesting with multiple phenotypic abnormalities involving the face, eyes, teeth, and limbs in addition to neurologic symptomatology. This report aims to present a female patient with ODDD who was referred due to extensive oral restorative needs. The presence of hypoplastic enamel trig...

Purpose: Xenobiotic metabolism is related to the interplay between diet and breast cancer (BC) risk. This involves detoxification enzymes, which are polymorphic and metabolise various dietary metabolites. An important characteristic of this pathway is that chemoprotective micronutrients can act not only as substrates but also as inducers for these...

Scope: A high adherence to the Mediterranean diet (MD) was previously associated with a decreased risk of breast cancer (BC) among Greek-Cypriot women. Additionally, particular polymorphisms were shown to modulate this MD-BC association. Herein, we aimed to investigate the effect of polymorphisms-MD interactions on the levels of specific metabolit...

Advances in mass spectrometry technologies have created new opportunities for discovering novel protein biomarkers in systemic lupus erythematosus (SLE). We performed a systematic review of published reports on proteomic biomarkers identified in SLE patients using mass spectrometry-based proteomics and highlight their potential disease association...

Biomarkers

This paper presents the largest study in Cyprus evaluating the frequency and distribution of BRCA1/2 mutations in a high risk patient cohort. Deleterious mutations in the BRCA1/2 genes were identified in 68 of the 527 patients tested (13%). It is of interest that a quarter of those tested positive, did not have an extensive family history of breast...

Background: Nitric oxide (NO) is low in Primary Ciliary Dyskinesia (PCD) and has been found to be correlated with Ciliary Beat Frequency (CBF). Although low nasal NO is used in PCD diagnosis, few studies have examined the potentially therapeutic effect of increasing endogenous NO. We aimed to examine the effect of increasing NO production substrate...

Background: Infections from microorganisms and parasites have been connected with either increased or decreased cancer risk. The objective of this study was to investigate whether infection by Echinococcus granulosus is associated with cancer risk. Methods: We assembled a pilot retrospective cohort of patients who were diagnosed as being infecte...

There is ample evidence that the Mediterranean diet reduces breast cancer risk, despite the fact that findings across studies and populations have not been consistent. The protective effect of the Mediterranean diet is in line with the fact that some of its key components, such as fruit, vegetables, folate, and olive oil, have also been shown to ha...

Fanconi anemia (FA) is a rare disorder characterized by multiple congenital malformations, progressive bone marrow failure and susceptibility to malignancies. Biallelic mutations in the breast cancer 2, early onset (BRCA2) gene are responsible for the FA-D1 subgroup, which accounts for ~3% of all the FA cases. Patients with biallelic BRCA2 mutation...

Introduction. Detection of the very earliest stages of breast cancer remain challenging and the differentiation of those carcinomas that develop into aggressive invasive forms from those that remain benign has not been achieved. Consequently, removal of the tumor by total mastectomy, local excision (LE) plus adjuvant radiotherapy (RT), or LE alone...

Oxidative stress arises due to a cellular imbalance in oxidants and antioxidants and/or due to an altered activity of antioxidant enzymes, caused by SNPs. Oxidative stress increases susceptibility to breast cancer (BC) risk, and we previously showed that the Mediterranean diet (MD), which is rich in antioxidants, reduces BC risk in Greek-Cypriot wo...

Single-nucleotide polymorphisms (SNPs) within genes of the one-carbon metabolism pathway have been shown to interact with dietary folate intake to modify breast cancer (BC) risk. Our group has previously demonstrated that the Mediterranean dietary pattern, rich in beneficial one-carbon metabolism micronutrients, protects against BC in Greek-Cypriot...

Despite the manifestations of primary ciliary dyskinesia (PCD) in early life, the diagnosis is often much delayed. Since 1998 in Cyprus, we have established the only national diagnostic and clinical referral center for PCD. To review the phenotypic features at presentation of PCD patients in Cyprus in relation to age at diagnosis, with emphasis on...

Lynch syndrome is the most common form of hereditary colorectal cancer and is caused by germline mutations in the mismatch repair (MMR) genes MLH1, MSH2, MSH6 and PMS2. Mutation carriers have an increased lifetime risk of developing colorectal cancer as well as other extracolonic tumours. The aim of the current study was to evaluate the frequency a...

Abstract Ubiquitination, a fundamental post-translational modification (PTM) resulting in the covalent attachment of ubiquitin (Ub) to a target protein, is currently implicated in several key cellular processes. Although ubiquitination was initially associated with protein degradation, it is becoming increasingly evident that proteins labeled with...