Zdeněk Kleibl

Laboratory of oncogenetics

Head: Zdeněk Kleibl
Prague node

zdekleje@lf1.cuni.cz
website of the Institute

HOME INSTITUTION

First Faculty of Medicine CU

RESEARCH PROGRAMME(S)

RP 4 - Early detection and prevention of tumours

Cancer in genes and genes in cancer.

COLLABORATION WITH INFRASTRUCTURES

Mission: Mapping cancer predisposition in the Czech Republic.
Vision: Reduction of cancer incidence in the Czech Republic by persons with genetic predisposition.

Hereditary tumors represent a specific subset of cancer diagnoses characterized by the presence of a germline genetic alteration affecting some of the hundreds of cancer predisposition genes that have been characterized. Carriers of pathogenic variants in these genes are at significantly increased risk of developing cancer, and their tumors, which may develop at a significantly younger age than their sporadic counterparts, may have unique clinical features caused by different biological behaviors.

Oncological prevention and early diagnosis of hereditary tumors rely on the unequivocal identification of a causal genetic alteration, which must be distinguished from the multitude of accompanying non-pathogenic individual genetic variants. In addition, the population specificity of hereditary alterations and the underlying population genotypes must be reflected in the clinical assessment of germline genetic predisposition in high-risk individuals. On the other hand, alterations in many genes are rare or even ultra-rare, and the identification of associated phenotypes requires extensive international collaboration.

The Laboratory of Oncogenetics is involved in cancer predisposition diagnostics on a national level (founding and leading the CZECANCA consortium), it contributes to the identification of hereditary cancer syndromes, the characterization of tumor markers suitable for early cancer detection in high-risk patients, and the identification of pharmacogenetic factors influencing anticancer therapy.

Research objectives

Identification of cancer predisposition using NGS approaches and modification of clinical recommendations for testing of high-risk individuals on a national level.
Characterization of carriers of germline genetic alterations responsible for the development of hereditary tumors in patients with various cancer diagnoses mapping the spectrum of hereditary cancer predisposition in the Czech Republic (in cooperation with the national consortium CZECANCA).
A complementary goal is the systematic description of tumor phenotypes in carriers of pathogenic cancer predisposition variants (in cooperation with international consortia).
Identification of pathogenic alterations in cancer predisposition and candidate genes using population, genetic or functional analyses of cancer predisposition genes and detection of alterations in their gene expression and RNA metabolism.
Identification of clinicopathologic features in carriers of inherited variants and in patients with sporadic tumors.

SELECTED PUBLICATIONS

Hovhannisyan M, Zemankova P, Nehasil P, Matejkova K, Borecka M, Cerna M, Dolezalova T, Dvorakova L, Foretova L, Horackova K, Jelinkova S, Just P, Kalousova M, Kral J, Machackova E, Nemcova B, Safarikova M, Springer D, Stastna B, Tavandzis S, Vocka M, Zima T, Soukupova J, Kleiblova P, Ernst C, Kleibl Z, Janatova M. Population-specific validation and comparison of the performance of 77- and 313-variant polygenic risk scores for breast cancer risk prediction. Cancer. 2024 May 8. DOI: 10.1002/cncr.35337
Stolarova L, Kleiblova P, Zemankova P, Stastna B, Janatova M, Soukupova J, …, Macurek L, Kleibl Z. ENIGMA CHEK2gether project: a comprehensive study identifies functionally-impaired CHEK2 germline missense variants associated with increased breast cancer risk. Clin Cancer Res. 2023;29(16):3037-3050. DOI: 10.1158/1078-0432.CCR-23-0212
Yang X, Leslie G, Doroszuk A, …, Kleibl Z, Kleiblova P, … Soukupova J, …Janatova M,…Tischkowitz M. Cancer Risks Associated With Germline PALB2 Pathogenic Variants: An International Study of 524 Families. J Clin Oncol. 2020;38(7):674-685. DOI: 10.1200/JCO.19.01907
Kleiblova P, Stolarova L, Krizova K, Lhota F, Hojny J, Zemankova P, Havranek O, Vocka M, Cerna M, Lhotova K, Borecka M, Janatova M, Soukupova J, Sevcik J, Zimovjanova M, Kotlas J, Panczak A, Vesela K, Cervenkova J, Schneiderova M, Burocziova M, Burdova K, Stranecky V, Foretova L, Machackova E, Tavanzis S, Kmoch S, Macurek L, Kleibl Z. Identification of deleterious germline CHEK2 mutations and their association with breast and ovarian cancer. Int J Cancer. 2019;145(7):1782-1797. DOI: 10.1002/ijc.32385
Meulendijks D, Henricks LM, Sonke GS, Deenen MJ, Froehlich TK, Amstutz U, Largiadèr CR, Jennings BA, Marinaki AM, Sanderson JD, Kleibl Z, Kleiblova P, Schwab M, Zanger UM, Palles C, Tomlinson I, Gross E, van Kuilenburg AB, Punt CJ, Koopman M, Beijnen JH, Cats A, Schellens JH. Clinical relevance of DPYD variants c.1679T>G, c.1236G>A/HapB3, and c.1601G>A as predictors of severe fluoropyrimidine-associated toxicity: a systematic review and meta-analysis of individual patient data. Lancet Oncol. 2015;16(16):1639-50. DOI: 10.1016/S1470-2045(15)00286-7

COLLABORATION WITHIN THE NICR

Libor Macůrek
(Prague node, Institute of Molecular Genetics of the Czech Academy of Sciences)

SPECIALIZED EXPERTISE AND TECHNOLOGY

Germline genetic testing

Variant classification

Functional analyses

RNA/splicing analyses

Pharmacogenomics

COLLABORATION WITH LARGE RESEARCH INFRASTRUCTURES AND RESEARCH CENTRES

Czech National Infrastructure for Biological Data ELIXIR CZ

Biotechnology and Biomedicine Centre of the Czech Academy of Sciences and the Charles University BIOCEV

Masaryk Memorial Cancer Institute MMCI

Central European Institute of Technology at Masaryk University CEITEC MU

Zdeněk Kleibl

Laboratory of oncogenetics

HOME INSTITUTION

RESEARCH PROGRAMME(S)

Cancer in genes and genes in cancer.

FOCUS OF RESEARCH

SELECTED PUBLICATIONS

EXPERTISE AND TECHNOLOGY

COLLABORATION WITHIN THE NICR

COLLABORATION WITH INFRASTRUCTURES

SELECTED PUBLICATIONS

COLLABORATION WITHIN THE NICR

SPECIALIZED EXPERTISE AND TECHNOLOGY

COLLABORATION WITH LARGE RESEARCH INFRASTRUCTURES AND RESEARCH CENTRES