Publications by authors named "Aniko Bozsik"

11 Publications

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Breast and Prostate Cancer Risks for Male BRCA1 and BRCA2 Pathogenic Variant Carriers Using Polygenic Risk Scores.

J Natl Cancer Inst 2021 Jul 28. Epub 2021 Jul 28.

Department of Molecular Medicine, University La Sapienza, Rome, Italy.

Background: Recent population-based female breast cancer and prostate cancer polygenic risk scores (PRS) have been developed. We assessed the associations of these PRS with breast and prostate cancer risks for male BRCA1 and BRCA2 pathogenic variant carriers.

Methods: 483 BRCA1 and 1,318 BRCA2 European ancestry male carriers were available from the Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA). A 147-single nucleotide polymorphism (SNP) prostate cancer PRS (PRSPC) and a 313-SNP breast cancer PRS were evaluated. There were three versions of the breast cancer PRS, optimized to predict overall (PRSBC), estrogen-receptor (ER) negative (PRSER-) or ER-positive (PRSER+) breast cancer risk.

Results: PRSER+ yielded the strongest association with breast cancer risk. The odds ratios (ORs) per PRSER+ standard deviation estimates were 1.40 (95% confidence interval [CI] =1.07-1.83) for BRCA1 and 1.33 (95% CI = 1.16-1.52) for BRCA2 carriers. PRSPC was associated with prostate cancer risk for both BRCA1 (OR = 1.73, 95% CI = 1.28-2.33) and BRCA2 (OR = 1.60, 95% CI = 1.34-1.91) carriers. The estimated breast cancer ORs were larger after adjusting for female relative breast cancer family history. By age 85 years, for BRCA2 carriers, the breast cancer risk varied from 7.7% to 18.4% and prostate cancer risk from 34.1% to 87.6% between the 5th and 95th percentiles of the PRS distributions.

Conclusions: Population-based prostate and female breast cancer PRS are associated with a wide range of absolute breast and prostate cancer risks for male BRCA1 and BRCA2 carriers. These findings warrant further investigation aimed at providing personalized cancer risks for male carriers and to inform clinical management.
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http://dx.doi.org/10.1093/jnci/djab147DOI Listing
July 2021

Germline Structural Variations in Cancer Predisposition Genes.

Front Genet 2021 14;12:634217. Epub 2021 Apr 14.

Department of Molecular Genetics, National Institute of Oncology, Budapest, Hungary.

In addition to single nucleotide variations and small-scale indels, structural variations (SVs) also contribute to the genetic diversity of the genome. SVs, such as deletions, duplications, amplifications, or inversions may also affect coding regions of cancer-predisposing genes. These rearrangements may abrogate the open reading frame of these genes or adversely affect their expression and may thus act as germline mutations in hereditary cancer syndromes. With the capacity of disrupting the function of tumor suppressors, structural variations confer an increased risk of cancer and account for a remarkable fraction of heritability. The development of sequencing techniques enables the discovery of a constantly growing number of SVs of various types in cancer predisposition genes (CPGs). Here, we provide a comprehensive review of the landscape of germline SV types, detection methods, pathomechanisms, and frequency in CPGs, focusing on the two most common cancer syndromes: hereditary breast- and ovarian cancer and gastrointestinal cancers. Current knowledge about the possible molecular mechanisms driving to SVs is also summarized.
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http://dx.doi.org/10.3389/fgene.2021.634217DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8081352PMC
April 2021

Germline Genetic Variants of Viral Entry and Innate Immunity May Influence Susceptibility to SARS-CoV-2 Infection: Toward a Polygenic Risk Score for Risk Stratification.

Front Immunol 2021 8;12:653489. Epub 2021 Mar 8.

Department of Molecular Genetics, National Institute of Oncology, Budapest, Hungary.

The ongoing COVID-19 pandemic caused by the novel coronavirus, SARS-CoV-2 has affected all aspects of human society with a special focus on healthcare. Although older patients with preexisting chronic illnesses are more prone to develop severe complications, younger, healthy individuals might also exhibit serious manifestations. Previous studies directed to detect genetic susceptibility factors for earlier epidemics have provided evidence of certain protective variations. Following SARS-CoV-2 exposure, viral entry into cells followed by recognition and response by the innate immunity are key determinants of COVID-19 development. In the present review our aim was to conduct a thorough review of the literature on the role of single nucleotide polymorphisms (SNPs) as key agents affecting the viral entry of SARS-CoV-2 and innate immunity. Several SNPs within the scope of our approach were found to alter susceptibility to various bacterial and viral infections. Additionally, a multitude of studies confirmed genetic associations between the analyzed genes and autoimmune diseases, underlining the versatile immune consequences of these variants. Based on confirmed associations it is highly plausible that the SNPs affecting viral entry and innate immunity might confer altered susceptibility to SARS-CoV-2 infection and its complex clinical consequences. Anticipating several COVID-19 genomic susceptibility loci based on the ongoing genome wide association studies, our review also proposes that a well-established polygenic risk score would be able to clinically leverage the acquired knowledge.
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http://dx.doi.org/10.3389/fimmu.2021.653489DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7982482PMC
April 2021

Application of Multilayer Evidence for Annotation of C-Terminal Variants.

Cancers (Basel) 2021 Feb 20;13(4). Epub 2021 Feb 20.

Department of Molecular Genetics, National Institute of Oncology, H-1122 Budapest, Hungary.

The clinical relevance of the C-terminal stop codon variants is controversial. The pathogenic role of the germline c.9976A>T and c.10095delinsGAATTATATCT variants in hereditary breast and ovarian cancer (HBOC) patients was evaluated. An association with clinicopathological parameters was performed in 2491 independent probands diagnosed with HBOC and in 122,209 cancer patients reported earlier. Loss-of-heterozygosity (LOH) in tumor samples and allelic imbalance in RNA extracted from peripheral blood cells were investigated. Neither c.10095delinsGAATTATATCT or c.9976A>T variants showed significant association with clinicopathological parameters or elevated risk for HBOC-associated tumors. Lung cancer was more prevalent in families carrying the c.9976A>T variant compared to pathogenic or carrier families. An increased prevalence of pancreatic cancer was found in families where c.9976A>T occurred together with other pathogenic variants. An increased risk for familial pancreatic, lung and upper aero-digestive tract cancers was confirmed in the validation set. Regarding C-terminal variants, no linkage with other pathogenic variants, no LOH in tumor tissue and no allelic imbalance in RNA level were confirmed. The c.9976A>T variant may be considered as a potential risk for lung cancer, and a potential modifying factor in pancreatic cancer when it occurs along with the pathogenic variant, although this observation should be validated in a larger sample cohort.
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http://dx.doi.org/10.3390/cancers13040881DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7923782PMC
February 2021

Polygenic risk scores and breast and epithelial ovarian cancer risks for carriers of BRCA1 and BRCA2 pathogenic variants.

Genet Med 2020 10 15;22(10):1653-1666. Epub 2020 Jul 15.

Royal Devon & Exeter Hospital, Department of Clinical Genetics, Exeter, UK.

Purpose: We assessed the associations between population-based polygenic risk scores (PRS) for breast (BC) or epithelial ovarian cancer (EOC) with cancer risks for BRCA1 and BRCA2 pathogenic variant carriers.

Methods: Retrospective cohort data on 18,935 BRCA1 and 12,339 BRCA2 female pathogenic variant carriers of European ancestry were available. Three versions of a 313 single-nucleotide polymorphism (SNP) BC PRS were evaluated based on whether they predict overall, estrogen receptor (ER)-negative, or ER-positive BC, and two PRS for overall or high-grade serous EOC. Associations were validated in a prospective cohort.

Results: The ER-negative PRS showed the strongest association with BC risk for BRCA1 carriers (hazard ratio [HR] per standard deviation = 1.29 [95% CI 1.25-1.33], P = 3×10). For BRCA2, the strongest association was with overall BC PRS (HR = 1.31 [95% CI 1.27-1.36], P = 7×10). HR estimates decreased significantly with age and there was evidence for differences in associations by predicted variant effects on protein expression. The HR estimates were smaller than general population estimates. The high-grade serous PRS yielded the strongest associations with EOC risk for BRCA1 (HR = 1.32 [95% CI 1.25-1.40], P = 3×10) and BRCA2 (HR = 1.44 [95% CI 1.30-1.60], P = 4×10) carriers. The associations in the prospective cohort were similar.

Conclusion: Population-based PRS are strongly associated with BC and EOC risks for BRCA1/2 carriers and predict substantial absolute risk differences for women at PRS distribution extremes.
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http://dx.doi.org/10.1038/s41436-020-0862-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7521995PMC
October 2020

Complex Characterization of Germline Large Genomic Rearrangements of the and Genes in High-Risk Breast Cancer Patients-Novel Variants from a Large National Center.

Int J Mol Sci 2020 Jun 30;21(13). Epub 2020 Jun 30.

National Institute of Oncology, Department of Molecular Genetics, H-1122 Budapest, Ráth György utca 7-9, Hungary.

Large genomic rearrangements (LGRs) affecting one or more exons of and constitute a significant part of the mutation spectrum of these genes. Since 2004, the National Institute of Oncology, Hungary, has been involved in screening for LGRs of breast or ovarian cancer families enrolled for genetic testing. LGRs were detected by multiplex ligation probe amplification method, or next-generation sequencing. Where it was possible, transcript-level characterization of LGRs was performed. Phenotype data were collected and analyzed too. Altogether 28 different types of LGRs in 51 probands were detected. Sixteen LGRs were novel. Forty-nine cases were deletions or duplications in and two affected . Rearrangements accounted for 10% of the mutations. Three exon copy gains, two complex rearrangements, and 23 exon losses were characterized by exact breakpoint determinations. The inferred mechanisms for LGR formation were mainly end-joining repairs utilizing short direct homologies. Comparing phenotype features of the LGR-carriers to that of the non-LGR mutation carriers, revealed no significant differences. Our study is the largest comprehensive report of LGRs of in familial breast and ovarian cancer patients in the Middle and Eastern European region. Our data add novel insights to genetic interpretation associated to the LGRs.
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http://dx.doi.org/10.3390/ijms21134650DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7370166PMC
June 2020

Identification of ten variants associated with risk of estrogen-receptor-negative breast cancer.

Nat Genet 2017 Dec 23;49(12):1767-1778. Epub 2017 Oct 23.

Department of Epidemiology, University of California, Irvine, Irvine, California, USA.

Most common breast cancer susceptibility variants have been identified through genome-wide association studies (GWAS) of predominantly estrogen receptor (ER)-positive disease. We conducted a GWAS using 21,468 ER-negative cases and 100,594 controls combined with 18,908 BRCA1 mutation carriers (9,414 with breast cancer), all of European origin. We identified independent associations at P < 5 × 10 with ten variants at nine new loci. At P < 0.05, we replicated associations with 10 of 11 variants previously reported in ER-negative disease or BRCA1 mutation carrier GWAS and observed consistent associations with ER-negative disease for 105 susceptibility variants identified by other studies. These 125 variants explain approximately 16% of the familial risk of this breast cancer subtype. There was high genetic correlation (0.72) between risk of ER-negative breast cancer and breast cancer risk for BRCA1 mutation carriers. These findings may lead to improved risk prediction and inform further fine-mapping and functional work to better understand the biological basis of ER-negative breast cancer.
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http://dx.doi.org/10.1038/ng.3785DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5808456PMC
December 2017

Common alleles at 6q25.1 and 1p11.2 are associated with breast cancer risk for BRCA1 and BRCA2 mutation carriers.

Hum Mol Genet 2011 Aug 18;20(16):3304-21. Epub 2011 May 18.

Department of Public Health and Primary Care, Centre for Cancer Genetic Epidemiology, University of Cambridge, Cambridge, UK.

Two single nucleotide polymorphisms (SNPs) at 6q25.1, near the ESR1 gene, have been implicated in the susceptibility to breast cancer for Asian (rs2046210) and European women (rs9397435). A genome-wide association study in Europeans identified two further breast cancer susceptibility variants: rs11249433 at 1p11.2 and rs999737 in RAD51L1 at 14q24.1. Although previously identified breast cancer susceptibility variants have been shown to be associated with breast cancer risk for BRCA1 and BRCA2 mutation carriers, the involvement of these SNPs to breast cancer susceptibility in mutation carriers is currently unknown. To address this, we genotyped these SNPs in BRCA1 and BRCA2 mutation carriers from 42 studies from the Consortium of Investigators of Modifiers of BRCA1/2. In the analysis of 14 123 BRCA1 and 8053 BRCA2 mutation carriers of European ancestry, the 6q25.1 SNPs (r(2) = 0.14) were independently associated with the risk of breast cancer for BRCA1 mutation carriers [hazard ratio (HR) = 1.17, 95% confidence interval (CI): 1.11-1.23, P-trend = 4.5 × 10(-9) for rs2046210; HR = 1.28, 95% CI: 1.18-1.40, P-trend = 1.3 × 10(-8) for rs9397435], but only rs9397435 was associated with the risk for BRCA2 carriers (HR = 1.14, 95% CI: 1.01-1.28, P-trend = 0.031). SNP rs11249433 (1p11.2) was associated with the risk of breast cancer for BRCA2 mutation carriers (HR = 1.09, 95% CI: 1.02-1.17, P-trend = 0.015), but was not associated with breast cancer risk for BRCA1 mutation carriers (HR = 0.97, 95% CI: 0.92-1.02, P-trend = 0.20). SNP rs999737 (RAD51L1) was not associated with breast cancer risk for either BRCA1 or BRCA2 mutation carriers (P-trend = 0.27 and 0.30, respectively). The identification of SNPs at 6q25.1 associated with breast cancer risk for BRCA1 mutation carriers will lead to a better understanding of the biology of tumour development in these women.
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http://dx.doi.org/10.1093/hmg/ddr226DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3652640PMC
August 2011

Molecular mechanisms for the antitumor activity of inositol hexakisphosphate (IP6).

Cancer Genomics Proteomics 2007 Jan-Feb;4(1):43-51

National Institute of Oncology, Department of Molecular Genetics, Budapest, H-1122, Hungary.

Background: Inositol hexakisphosphate (IP6), a naturally occurring polyphosphorylated carbohydrate, has been reported to have significant in vivo and in vitro anticancer activity against numerous tumors. However, the molecular mechanism of the anticancer effect of IP6 has not been fully elucidated.

Materials And Methods: Using K-562 human leukemia cells we analysed the induction of the erythroid differentiation program, as well as modulation of the gene expression profile of K-562 leukemia cells treated with IP6.

Results: A single treatment with IP6 (0.75 or 5.0 mM) resulted in a time- and dose-dependent growth inhibition of K-562 cells and also activation of the erythroid differentiation program. K-562 cells expressed a concomitant differentiation after 12 hours of exposure. Possible molecular mechanisms and key signaling pathways, as well as gene expression behind this anticancer effect were examined using oligonucleotide microarrays and quantitative real-time PCR. Treatment with IP6 (750 microM, 5 mM) had a marked impact, resulting in early (60 min) and late (12 h) modulation of expression of about 1800 and 1200 transcripts (at p<0.05). Through microarray analysis, the anticancer effect of IP6 in K-562 was found to be associated with the modulation of multiple genes involved in immunity, Wnt and IGF pathways, PI3 kinase signaling and apoptosis. Using selected subsets of genes, the microarray hits could be validated by Q-PCR. A 2-fold upregulation of the apoptosis pathway, measured using the BAX/BCL-2 ratio was observed for 12 hours. IP6 (5 mM) induced up to 6-fold increases in differentiation measured by hemoglobin synthesis, yielding up to 70% of benzidine-positive cells at 120 hours.

Conclusion: The results of this study show that IP6 is a strong inducer of differentiation (cytostatic effect) and a moderately strong inducer of apoptosis (cytotoxic effect). Evidence has been provided to show that the growth inhibitory effects of IP6 are mediated through the modulation of key signaling pathways.
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October 2007

Modulation of cancer pathways by inhibitors of guanylate metabolism.

Adv Enzyme Regul 2006 20;46:176-90. Epub 2006 Jul 20.

Department of Molecular Genetics, National Institute of Oncology, Ráth György utca 7, Budapest 1122, Hungary.

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http://dx.doi.org/10.1016/j.advenzreg.2006.01.002DOI Listing
January 2007

Marker construction and cloning of a cut1-like sequence with ARS activity in the fission yeast Schizosaccharomyces japonicus.

Yeast 2002 Apr;19(6):485-98

Department of Genetics, University of Debrecen, Debrecen, Hungary.

The dimorphic fission yeast Schizosaccharomyces japonicus has proved to be an excellent experimental model for the investigation of the eukaryotic cell. Here we show that it has a haplontic life cycle, in which the diploid phase is confined to the zygote. To make it amenable to genetic and molecular analysis, we generated genetic markers and cloned a genomic sequence which acts as ars when integrated into a plasmid. Diploids suitable for testing complementation and recombination between markers can be formed by protoplast fusion. The complementation tests and the recombination frequencies determined in octads of spores identified 28 non-allelic groups (genes) of mutations of the auxotrophic and mycelium-negative mutants. Two groups of linked markers were also identified. The cloned fragment, which expresses ars activity, encodes a putative amino acid sequence highly similar to a conserved domain of proteins Cut1 (Schizosaccharomyces pombe), BimB (Aspergillus nidulans) and Esp1 (Saccharomyces cerevisiae).
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http://dx.doi.org/10.1002/yea.853DOI Listing
April 2002
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