Profile of common prostate cancer risk variants in an unscreened Romanian population.

To find sequence variants affecting prostate cancer (PCA) susceptibility in an unscreened Romanian population we use a genome-wide association study (GWAS). The study population included 990 unrelated pathologically confirmed PCA cases and 1034 male controls. DNA was genotyped using Illumina SNP arrays, and 24.295.558 variants were imputed using the 1000 Genomes data set. An association test was performed between the imputed markers and PCA. A systematic literature review for variants associated with PCA risk identified 115 unique variants that were tested in the Romanian sample set. Thirty of the previously reported SNPs replicated (P-value < 0.05), with the strongest associations observed at: 8q24.21, 11q13.3, 6q25.3, 5p15.33, 22q13.2, 17q12 and 3q13.2. The replicated variants showing the most significant association in Romania are rs1016343 at 8q24.21 (P = 2.2 × 10-4 ), rs7929962 at 11q13.3 (P = 2.7 × 10-4 ) and rs9364554 at 6q25.2 (P = 4.7 × 10-4 ). None of the variants tested in the Romanian GWAS reached genome-wide significance (P-value <5 × 10-8 ) but 807 markers had P-values <1 × 10-4 . Here, we report the results of the first GWAS of PCA performed in a Romanian population. Our study provides evidence that a substantial fraction of previously validated PCA variants associate with risk in this unscreened Romanian population.

Identification of Lynch syndrome risk variants in the Romanian population.

Two familial forms of colorectal cancer (CRC), Lynch syndrome (LS) and familial adenomatous polyposis (FAP), are caused by rare mutations in DNA mismatch repair genes (MLH1, MSH2, MSH6, PMS2) and the genes APC and MUTYH, respectively. No information is available on the presence of high-risk CRC mutations in the Romanian population. We performed whole-genome sequencing of 61 Romanian CRC cases with a family history of cancer and/or early onset of disease, focusing the analysis on candidate variants in the LS and FAP genes. The frequencies of all candidate variants were assessed in a cohort of 688 CRC cases and 4567 controls. Immunohistochemical (IHC) staining for MLH1, MSH2, MSH6, and PMS2 was performed on tumour tissue. We identified 11 candidate variants in 11 cases; six variants in MLH1, one in MSH6, one in PMS2, and three in APC. Combining information on the predicted impact of the variants on the proteins, IHC results and previous reports, we found three novel pathogenic variants (MLH1:p.Lys84ThrfsTer4, MLH1:p.Ala586CysfsTer7, PMS2:p.Arg211ThrfsTer38), and two novel variants that are unlikely to be pathogenic. Also, we confirmed three previously published pathogenic LS variants and suggest to reclassify a previously reported variant of uncertain significance to pathogenic (MLH1:c.1559-1G>C).

Identification of a New Variant of PUF60 Gene: Case Presentation and Literature Review.

Background/Aim: The aim of the study was to report the case of a 5-month-old boy with a complex prenatal and neonatal symptomatology diagnosed with a "de novo" pathogenic variant of PUF60 gene. Case Report: Our hospital, undertook the antenatal and postnatal care of a 27-year-old pregnant lady. This was her second baby with a previously healthy boy. During her routine first-trimester anomaly scan, increased nuchal translucency was noticed. Multiple anomalies were seen throughout her subsequent antenatal visits. This triggered a sequence of tests, examinations and differential diagnosis. The final diagnosis was made at 5 months postpartum following the result of the whole exome sequence, which described a variant of unknown clinical significance (VUS, class 3 variant) in the PUF60 gene. We are mindful that changing the classification of a variant of unknown significance is challenging and requires supporting and robust criteria. Considering clinical symptomatology produced by the pathogenic mutation in the PUF gene, the identified c.1640A>G variant may be categorized as likely pathogenic. Conclusion: Our case adds new insights on the pathology and the underlying process involved in the PUF60 variant spectrum disorders. It also highlights the limits of current prenatal tests.

Frequency of the UGT1A1*28 Polymorphism in a Romanian Cohort of Gilbert Syndrome Individuals.

BACKGROUND AND AIMS: Gilbert syndrome (GS) is characterized by unconjugated hyperbilirubinemia without liver disease or overt hemolysis and it is found in 3-10% of the general population. Inherited hyperbilirubinaemia is attributable to a reduced UGT1A1 activity. The UGT1A1 promoter (TA) repeats variants are documented of being involved in abnormally elevated bilirubin levels. The aim of the present study is to analyze the impact of UGT1A1 promoter variants on bilirubin levels in Romanian patients clinically supected with GS. METHODS: The study group included 897 subjects: 292 GS patients and 605 healthy controls. Genomic DNA was extracted from the peripheral blood leukocytes. All individuals were screened for the presence of the (TA) insertion in the TATA box region of UGT1A1 gene by PCR amplification. This case-control study was conducted at the Department of Medical Genetics, Synevo, Romania. RESULTS: UGT1A1*28 (7TA) revealed the highest frequency (61.87%) of all individuals, while the UGT1A1*1 (6TA) allele was found in 36.79%. We identified two other variants of the UGT1A1 gene, depending on the number of TA repeats in the promoter: 5TA (0.61%) and 8TA (0.72%). The (TA)7/7 homozygous genotype was identified in 32.33% of all individuals, while the (TA)6/7 heterozygous genotype was the most prevalent (57.64%). The wild type (TA)6/6 was identified in 7.36% of the whole cohort. CONCLUSIONS: Because other polymorphisms have been associated with GS, the absence of the UGT1A1*28 allele does not rule out this condition. The results suggest that in the Romanian population there is a strong correlation between the UGT1A1*28 polymorphism and hyperbilirubinemia in patients with GS.

A comprehensive analysis of genome-wide association studies to identify prostate cancer susceptibility loci for the Romanian population.

The aim of this study is to examine a large dataset of single nucleotide polymorphism known to be associated with prostate cancer from previous genome-wide association studies and create a dataset of single nucleotide polymorphisms that can be used in replication studies for the Romanian population. This study will define a list of markers showing a significant association with this phenotype. We propose the results of this study as a starting point for any Romanian genome-wide association studies researching the genetic susceptibility for prostate cancer.