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The CZECANCA panel (CZEch CAncer paNel for Clinical Application) was developed at the Laboratory of Oncogenetics, First Faculty of Medicine, Charles University, Prague, as a diagnostic tool for cancer predisposition. Its main purpose is to provide a reliable and cost-effective next-generation sequencing (NGS)-based approach (a gene panel) for germline genetic testing of patients with a various cancer types in the Czech Republic.

The panel is available to the members of CZECANCA consortium, a nationwide network of collaborating clinical and research laboratories aimed to:

• improve germline genetic testing in cancer patients,
• maintain the national genotype-to-phenotype database,
• reach consensual interpretation of germline variants,
• update national standards for clinical management of germline pathogenic variant carriers.

Cancer is the second leading cause of death in the Czech Republic. The majority of cases (up to 95%) are so-called “sporadic cancer” which are caused by lifetime accumulation of DNA alterations in an affected tissue. Therefore, the overall cancer incidence increases with age. Prevention of sporadic cancer includes a healthy lifestyle, regular preventive examinations, and regular population screening for the most frequent cancer diagnoses (reimbursed from mandatory health insurance for early detection of breast, cervical, colorectal and lung cancers).

Hereditary cancers are caused by inherited DNA mutations that affect one of hundreds of known cancer predisposition genes. The causal mutation is passed from generation to generation in an affected family. The inheritance of cancer predisposition is almost always autosomal dominant, meaning that there is a 50% chance that a mutation will be passed from parent to offspring. Unlike sporadic cancers, hereditary cancers are much less common (less than 5% of all cancers). However, hereditary cancers are recognized as clinically important diagnoses because of their specific characteristics, including a high frequency of cancer diagnoses in affected families, development of tumors at a young age, and an increased risk of multiple primary tumors in mutation carriers.

Until 2015, the genetic analyses of cancer predisposition genes were performed by laborious single-gene tests. Current approaches are based on next-generation sequencing (NGS), that allows a multi-parallel analysis of large gene collections (so called gene panels), which, in a case of hereditary cancer diagnostics, can include all known or candidate cancer predisposition genes in a single analysis. The introduction of NGS represented a real revolution into the genetic diagnostics and made the analyzes more accessible, faster, accurate and finally cheaper. On the other hand, the analysis of "only" 226 genes in the CZECANCA panel reveals hundreds of germline genetic variants in each patient and among them it is necessary to correctly "identify" a single causal mutation (if present at all).

The timely-scheduled analysis of hereditary cancer predisposition is of crucial importance for high-risk individuals to detect the germ-line DNA variant responsible for an increased cancer risk in an individual or a family.

High-risk individuals represent in general oncology patients who:

• develop cancer diagnose at unusually young age
• develop multiple primary tumors
• have increased number of relatives with (early onset) tumors.

Germline genetic testing is offered to all individuals who fulfill germline genetic testing criteria in Czechia (see References). The indication is in vast majority offered to adult-only patients. The analysis is fully reimbursed from mandatory health insurance in Czechia.

The clinical interpretation represents the most challenging part of germline genetic testing. From the clinical point of view, the final outcome is the decision whether a causal germline alteration associated with the underlying cancer diagnose has been detected or not.

Identification of a pathogenic germline alteration warrants inclusion of the carriers to a specialized follow-up programs focused on prevention or early tumor detection reducing development of malignant disease or improving prognosis of cancer diagnose.

The most causal mutations are rare DNA variants (with a frequency in the population much lower than 0.1%). To find and to interpret such a rare variant, it is important to know the results of panel analyses in thousands of subjects and to consider many individual characteristics in mutation carriers and also non-carriers.

The knowledge of the prevalence of DNA variants in a given population is crucial for the correct identification of a causal pathogenic variant (hidden among thousands of germline variants that normally occur in each analyzed individual). The CZECANCA consortium, consisting of collaborating diagnostic laboratories in the Czech Republic, jointly contributes to the development of an anonymized CZECANCA database, a collection of genetic variants found in analyzed high-risk Czech patients. In addition, the consortium members cooperate in the analysis of population controls, which provide important information about the population-specific genetic background. The database allows us to improve the clinical utility of cancer predisposition test results. The database is available only to members of the CZECANCA consortium