AIMS: Amyloidosis is caused by deposition of abnormal protein fibrils, leading to damage of organ function. Hereditary amyloidosis represents a monogenic disease caused by germline mutations in 11 amyloidogenic precursor protein genes. One of the important but non-specific symptoms of amyloidosis is hypertrophic cardiomyopathy. Diagnostics of hereditary amyloidosis is complicated and the real cause can remain overlooked. We aimed to design hereditary amyloidosis gene panel and to introduce new next-generation sequencing (NGS) approach to investigate hereditary amyloidosis in a cohort of patients with hypertrophic cardiomyopathy of unknown significance. METHODS: Design of target enrichment DNA library preparation using Haloplex Custom Kit containing 11 amyloidogenic genes was followed by MiSeq Illumina sequencing and bioinformatics identification of germline variants using tool VarScan in a cohort of 40 patients. RESULTS: We present design of NGS panel for 11 genes (TTR, FGA, APOA1, APOA2, LYZ, GSN, CST3, PRNP, APP, B2M, ITM2B) connected to various forms of amyloidosis. We detected one mutation, which is responsible for hereditary amyloidosis. Some other single nucleotide variants are so far undescribed or rare variants or represent common polymorphisms in European population. CONCLUSIONS: We report one positive case of hereditary amyloidosis in a cohort of patients with hypertrophic cardiomyopathy of unknown significance and set up first panel for NGS in hereditary amyloidosis. This work may facilitate successful implementation of the NGS method by other researchers or clinicians and may improve the diagnostic process after validation.

• MeSH
• Adult MeSH
• Amyloidosis, Familial diagnosis   genetics   MeSH
• Phenotype MeSH
• Gene Frequency MeSH
• Genetic Predisposition to Disease MeSH
• Genetic Markers MeSH
• Cardiomyopathy, Hypertrophic diagnosis   genetics   MeSH
• Polymorphism, Single Nucleotide * MeSH
• Middle Aged MeSH
• Humans MeSH
• Mutation * MeSH
• DNA Mutational Analysis methods   MeSH
• Pilot Projects MeSH
• Predictive Value of Tests MeSH
• Reproducibility of Results MeSH
• Risk Factors MeSH
• Aged, 80 and over MeSH
• Aged MeSH
• Gene Expression Profiling methods   MeSH
• Transcriptome * MeSH
• Computational Biology MeSH
• High-Throughput Nucleotide Sequencing * MeSH
• Check Tag
• Adult MeSH
• Middle Aged MeSH
• Humans MeSH
• Male MeSH
• Aged, 80 and over MeSH
• Aged MeSH
• Female MeSH
• Publication type
• Journal Article MeSH
• Geographicals
• Czech Republic MeSH

Non-syndromic autosomal recessive hearing loss is an extremely heterogeneous disease caused by mutations in more than 80 genes. We examined Czech patients with early/prelingual non-syndromic, presumably genetic hearing loss (NSHL) without known cause after GJB2 gene testing. Four hundred and twenty-one unrelated patients were examined for STRC gene deletions with quantitative comparative fluorescent PCR (QCF PCR), 197 unrelated patients with next-generation sequencing by custom-designed NSHL gene panels and 19 patients with whole-exome sequencing (WES). Combining all methods, we discovered the cause of the disease in 54 patients. The most frequent type of NSHL was DFNB16 (STRC), which was detected in 22 patients, almost half of the clarified patients. Other biallelic pathogenic mutations were detected in the genes: MYO15A, LOXHD1, TMPRSS3 (each gene was responsible for five clarified patients, CDH23 (four clarified patients), OTOG and OTOF (each gene was responsible for two clarified patients). Other genes (AIFM1, CABP2, DIAPH1, PTPRQ, RDX, SLC26A4, TBC1D24, TECTA, TMC1) that explained the cause of hearing impairment were further detected in only one patient for each gene. STRC gene mutations, mainly deletions remain the most frequent NSHL cause after mutations in the GJB2.

• MeSH
• Child MeSH
• Adult MeSH
• Genetic Predisposition to Disease MeSH
• Deafness embryology   genetics   pathology   MeSH
• Cadherins genetics   MeSH
• Connexin 26 genetics   MeSH
• Humans MeSH
• Membrane Glycoproteins genetics   MeSH
• Membrane Proteins genetics   MeSH
• Intercellular Signaling Peptides and Proteins genetics   MeSH
• Adolescent MeSH
• Young Adult MeSH
• Mutation genetics   MeSH
• Myosins genetics   MeSH
• Neoplasm Proteins genetics   MeSH
• Hearing Loss epidemiology   genetics   pathology   MeSH
• Exome Sequencing MeSH
• Serine Endopeptidases genetics   MeSH
• Carrier Proteins genetics   MeSH
• High-Throughput Nucleotide Sequencing MeSH
• Check Tag
• Child MeSH
• Adult MeSH
• Humans MeSH
• Adolescent MeSH
• Young Adult MeSH
• Male MeSH
• Female MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH
• Geographicals
• Czech Republic MeSH

BACKGROUND: Carriers of mutations in hereditary cancer predisposition genes represent a small but clinically important subgroup of oncology patients. The identification of causal germline mutations determines follow-up management, treatment options and genetic counselling in patients' families. Targeted next-generation sequencing-based analyses using cancer-specific panels in high-risk individuals have been rapidly adopted by diagnostic laboratories. While the use of diagnosis-specific panels is straightforward in typical cases, individuals with unusual phenotypes from families with overlapping criteria require multiple panel testing. Moreover, narrow gene panels are limited by our currently incomplete knowledge about possible genetic dispositions. METHODS: We have designed a multi-gene panel called CZECANCA (CZEch CAncer paNel for Clinical Application) for a sequencing analysis of 219 cancer-susceptibility and candidate predisposition genes associated with frequent hereditary cancers. RESULTS: The bioanalytical and bioinformatics pipeline was validated on a set of internal and commercially available DNA controls showing high coverage uniformity, sensitivity, specificity and accuracy. The panel demonstrates a reliable detection of both single nucleotide and copy number variants. Inter-laboratory, intra- and inter-run replicates confirmed the robustness of our approach. CONCLUSION: The objective of CZECANCA is a nationwide consolidation of cancer-predisposition genetic testing across various clinical indications with savings in costs, human labor and turnaround time. Moreover, the unified diagnostics will enable the integration and analysis of genotypes with associated phenotypes in a national database improving the clinical interpretation of variants.

• MeSH
• Neoplastic Syndromes, Hereditary genetics   MeSH
• Genetic Predisposition to Disease MeSH
• Genetic Association Studies MeSH
• Genetic Testing MeSH
• Humans MeSH
• INDEL Mutation MeSH
• Mutation MeSH
• Biomarkers, Tumor * MeSH
• Reproducibility of Results MeSH
• Sensitivity and Specificity MeSH
• DNA Copy Number Variations MeSH
• Computational Biology methods   MeSH
• High-Throughput Nucleotide Sequencing * methods   standards   MeSH
• Check Tag
• Humans MeSH
• Male MeSH
• Female MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH

B-cell neoplasms represent a clinically heterogeneous group of hematologic malignancies with considerably diverse genomic architecture recently endorsed by next-generation sequencing (NGS) studies. Because multiple genetic defects have a potential or confirmed clinical impact, a tendency toward more comprehensive testing of diagnostic, prognostic, and predictive markers is desired. This study introduces the design, validation, and implementation of an integrative, custom-designed, capture-based NGS panel titled LYmphoid NeXt-generation sequencing (LYNX) for the analysis of standard and novel molecular markers in the most common lymphoid neoplasms (chronic lymphocytic leukemia, acute lymphoblastic leukemia, diffuse large B-cell lymphoma, follicular lymphoma, and mantle cell lymphoma). A single LYNX test provides the following: i) accurate detection of mutations in all coding exons and splice sites of 70 lymphoma-related genes with a sensitivity of 5% variant allele frequency, ii) reliable identification of large genome-wide (≥6 Mb) and recurrent chromosomal aberrations (≥300 kb) in at least 20% of the clonal cell fraction, iii) the assessment of immunoglobulin and T-cell receptor gene rearrangements, and iv) lymphoma-specific translocation detection. Dedicated bioinformatic pipelines were designed to detect all markers mentioned above. The LYNX panel represents a comprehensive, up-to-date tool suitable for routine testing of lymphoid neoplasms with research and clinical applicability. It allows a wide adoption of capture-based targeted NGS in clinical practice and personalized management of patients with lymphoproliferative diseases.

• MeSH
• Chromosome Aberrations MeSH
• Molecular Diagnostic Techniques MeSH
• Genetic Predisposition to Disease * MeSH
• Genetic Variation MeSH
• Genomics methods   MeSH
• Humans MeSH
• Leukemia, Lymphoid diagnosis   genetics   MeSH
• Lymphoma diagnosis   genetics   MeSH
• INDEL Mutation MeSH
• Biomarkers, Tumor * MeSH
• Prognosis MeSH
• Translocation, Genetic MeSH
• DNA Copy Number Variations MeSH
• Computational Biology methods   MeSH
• High-Throughput Nucleotide Sequencing * methods   MeSH
• Check Tag
• Humans MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH

BACKGROUND: Epilepsy is a heterogeneous disease with a broad phenotypic spectrum and diverse genotypes. A significant proportion of epilepsies has a genetic aetiology. In our study, a custom designed gene panel with 112 genes known to be associated with epilepsies was used. In total, one hundred and fifty-one patients were tested (86 males / 65 females). RESULTS: In our cohort, the highest probability for the identification of the cause of the disease was for patients with a seizure onset within the first four weeks of life (61.9% clarification rate) - about two times more than other groups. The level of statistical significance was determined using a chi-square analysis. From 112 genes included in the panel, suspicious and rare variants were found in 53 genes (47.3%). Among the 151 probands included in the study we identified pathogenic variants in 39 patients (25.8%), likely pathogenic variants in three patients (2%), variants of uncertain significance in 40 patients (26.5%) and likely benign variants in 69 patients (45.7%). CONCLUSION: Our report shows the utility of diagnostic genetic testing of severe childhood epilepsies in a large cohort of patients with a diagnostic rate of 25.8%. A gene panel can be considered as a method of choice for the detection of pathogenic variants within patients with unknown origin of early onset severe epilepsy.

• MeSH
• Child MeSH
• Epilepsy genetics   MeSH
• Genetic Predisposition to Disease genetics   MeSH
• Infant MeSH
• Spasms, Infantile genetics   MeSH
• Humans MeSH
• Mutation MeSH
• Child, Preschool MeSH
• Chi-Square Distribution MeSH
• Seizures genetics   MeSH
• Check Tag
• Child MeSH
• Infant MeSH
• Humans MeSH
• Male MeSH
• Child, Preschool MeSH
• Female MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH

Východiska: V současné době bylo popsáno již více než 200 nádorových syndromů. Ve většině populací jsou však dostupné pouze informace o mutačním spektru ve vysoce rizikových genech limitované počtem vyšetřených jedinců. Metody: V rámci retrospektivní NGS studie v Masarykově onkologickém ústavu bylo provedeno vyšetření TruSight Cancer panelem zahrnujícím 94 genů u 50 vysoce rizikových jedinců se závažnou osobní i rodinnou anamnézou onkologického onemocnění bez detekované kauzální mutace v genech BRCA1, BRCA2, MLH1, MSH2, MSH6, TP53 nebo APC dle indikace. Všechny patogenní nebo pravděpodobně patogenní mutace detekované pomocí NGS technologie byly potvrzeny Sangerovým sekvenováním. Výsledky: Ztrátové (frame-shift, nonsense) mutace byly detekovány v genech ATM, BAP1, FANCC, FANCI, PMS2, SBDS, ERCC2, RECQL4. Několik patogenních nebo pravděpodobně patogenních mutací (missense, predikované sestřihové mutace, in-frame delece/inzerce) bylo zachyceno v genech ATM, BRIP1, CDH1, CHEK2, ERCC2, ERCC3, ERCC4, FANCA, MC1R, MEN1, MRE11A, MUTYH, PALB2, RAD51C, RET, SDHB, STK11. Nacházejí se ve vysoce konzervovaných funkčních doménách proteinů a ně­kte­ré z nich již byly prokázány jako patogenní mutace pomocí funkčních testů nebo u závažných autozomálně recesivních syndromů (Ataxia telangiectasia, Fanconiho anémie). Většina z detekovaných missense variant v řadě dalších genů je nejasného klinického významu a determinace jejich významnosti zůstává otevřená do budoucna. Závěr: Detekce variant se střední nebo nízkou penetrancí má pouze limitovanou klinickou využitelnost. Panelové testování u vysoce rizikových osob s nádorovým onemocněním může poskytnout důležitou informaci o příčině nádorové predispozice a může pomoci s výběrem optimální léčby a v preventivní personalizované onkologii.

Background: Currently, more than 200 hereditary cancer syndromes have been described, yet, in most countries genetic testing is restricted to a narrow spectrum of genes within a limited group of people tested. Methods: For this retrospective study we used the TruSight cancer panel (Illumina) – NGS panel targeting 94 cancer predisposition genes in order to analyze 50 high-risk cancer patients with significant personal and family history of cancer who did not carry mutations in BRCA1, BRCA2, MLH1, MSH2, MSH6, TP53 or APC genes. All pathogenic and potentially pathogenic mutations detected by NGS technology have been confirmed by Sanger sequencing. Results: There were several deleterious (frame-shift/nonsense) mutations detected in ATM, BAP1, FANCC, FANCI, PMS2, SBDS, ERCC2, RECQL4 genes. Various pathogenic or potentially pathogenic (missense, predicted splice site, in-frame insertion/deletion) mutations were detected in ATM, BRIP1, CDH1, CHEK2, ERCC2, ERCC3, ERCC4, FANCA, MC1R, MEN1, MRE11A, MUTYH, PALB2, RAD51C, RET, SDHB, STK11. These mutations affect highly conserved protein domains and affect their function as proved by the available functional assays. They were confirmed to be pathogenic as an „Parent No2 “ in serious recessive diseases such as Ataxia telangiectasia or Fanconi anemia. The clinical significance of the majority of detected missense variants still remains to be identified. Conclusion: Moderate or low penetrance variants are of limited clinical importance. Panel genetic testing in high-risk individuals with cancer provides important information concerning the cause of the investigated cancer, and may assist in the risk assesment and optimal management of the cancer, as well as in further preventive care. Key words: hereditary cancer syndromes – hereditary breast and ovarian cancer syndrome – hereditary nonpolyposis colorectal cancer – high-throughput DNA sequencing – TruSight cancer panel – MiSeq This work was supported by MH CZ – DRO (MMCI, 00209805) and by the State budget project of CR (OP VaVpI – RECAMO CZ.1.05/2.1.00/03.0101). The authors declare they have no potential conflicts of interest concerning drugs, products, or services used in the study. The Editorial Board declares that the manuscript met the ICMJE recommendation for biomedical papers. Submitted: 20. 8. 2015 Accepted: 22. 9. 2015

• Keywords
• hereditární nádorové syndromy, TruSight cancer panel, sekvenování nové generace, ATM mutace, BAP1, PMS2, FANCI, RAD51C, BRIP1, ztrátové mutace,
• MeSH
• Adenosine Triphosphatases genetics   MeSH
• Medical History Taking MeSH
• Ataxia Telangiectasia Mutated Proteins genetics   MeSH
• Neoplastic Syndromes, Hereditary * diagnosis   genetics   MeSH
• Colorectal Neoplasms, Hereditary Nonpolyposis genetics   MeSH
• Hereditary Breast and Ovarian Cancer Syndrome genetics   MeSH
• DNA-Binding Proteins genetics   MeSH
• Adult MeSH
• DNA Repair Enzymes genetics   MeSH
• Genetic Predisposition to Disease MeSH
• Genetic Testing MeSH
• Risk Assessment MeSH
• Middle Aged MeSH
• Humans MeSH
• Mutation, Missense MeSH
• Adolescent MeSH
• Tumor Suppressor Proteins genetics   MeSH
• Kidney Neoplasms genetics   MeSH
• Breast Neoplasms genetics   MeSH
• Pancreatic Neoplasms genetics   MeSH
• Colonic Neoplasms genetics   MeSH
• Codon, Nonsense MeSH
• Pilot Projects MeSH
• Fanconi Anemia Complementation Group Proteins genetics   MeSH
• Retrospective Studies MeSH
• Rhabdomyosarcoma genetics   MeSH
• RNA Helicases genetics   MeSH
• Pedigree MeSH
• Sequence Analysis, DNA * methods   utilization   MeSH
• Ubiquitin Thiolesterase genetics   MeSH
• Check Tag
• Adult MeSH
• Middle Aged MeSH
• Humans MeSH
• Adolescent MeSH
• Male MeSH
• Female MeSH
• Publication type
• Case Reports MeSH
• Research Support, Non-U.S. Gov't MeSH

Pancreatic ductal adenocarcinoma (PDAC) is the sixth most frequent cancer type in the Czech Republic with a poor prognosis that could be improved by an early detection and subsequent surgical treatment combined with chemotherapy. Genetic factors play an important role in PDAC risk. We previously identified one PDAC patient harboring the Slavic founder deleterious mutation c.657del5 in the NBN gene, using a panel next-generation sequencing (NGS). A subsequent analysis of 241 unselected PDAC patients revealed other mutation carriers. The overall frequency of c.657del5 in unselected PDAC patients (5/241; 2.07%) significantly differed from that in non-cancer controls (2/915; 0.2%; P=0.006). The result indicates that the NBN c.657del5 variant represents a novel PDAC-susceptibility allele increasing PDAC risk (OR=9.7; 95% CI: 1.9 to 50.2). The increased risk of PDAC in follow-up recommendations for NBN mutation carriers should be considered if other studies also confirm an increased frequency of c.657del5 carriers in PDAC patients from other populations.

• MeSH
• Adenocarcinoma genetics   MeSH
• Gene Deletion * MeSH
• Carcinoma, Pancreatic Ductal genetics   MeSH
• Genetic Predisposition to Disease MeSH
• Nuclear Proteins genetics   MeSH
• Middle Aged MeSH
• Humans MeSH
• Pancreatic Neoplasms genetics   MeSH
• Cell Cycle Proteins genetics   MeSH
• Pedigree MeSH
• Check Tag
• Middle Aged MeSH
• Humans MeSH
• Male MeSH
• Female MeSH
• Publication type
• Journal Article MeSH
• Geographicals
• Czechoslovakia MeSH

Východiská: Lynchov syndróm (LS) je autozomálne dominantné dedičné ochorenie, ktoré sa prejavuje zvýšením rizika vzniku nádorových ochorení, a to predovšetkým kolorektálneho a endometriálneho karcinómu. Nedávne štúdie preukázali aj asociáciu medzi LS a nádorovým ochorením prsníka. Cieľom tejto štúdie je poukázať na možný výskyt prítomnosti mutácií v génoch asociovaných s LS u pacientov s rakovinou prsníka a na potrebu zahrnúť vyšetrenie Lynch asociovaných génov u pacientov s familiárnym a opakovaným výskytom rakoviny prsníka ako aj s výskytom ďalších Lynch asociovaných nádorových ochorení. Materiál a metódy: Analyzovali sme vzorky nádorového tkaniva od 78 pacientov s primárnym nádorom prsníka. U pacientov sme analyzovali panel génov asociovaný s rizikom vzniku rakoviny prsníka, pričom sme sa v rámci našej štúdie sústredili primárne na výskyt mutácií v mismatch-repair génoch. DNA izolovaná z nádorového tkaniva bola sekvenovaná pomocou metódy sekvenovania novej generácie (next generation sequencing – NGS) a podrobená analýze pomocou nástroja Ingenuity Variant Analysis. Na potvrdenie zárodočnej mutácie sme vyšetrili krvnú vzorku pacientky pomocou NGS. Výsledky: V rámci našej analýzy sa nám v nádorovom tkanive prsníka podarilo identifikovať variant v géne PMS2 u jednej pacientky. Prítomnosť mutácie naznačuje, že vzniknuté nádorové ochorenie môže byť následkom LS. Z hľadiska patogenity sa jednalo o pravdepodobne patogénny variant, nakoľko sme odhalili deléciu v exónovej oblasti, ktorá viedla k frameshift mutácii. Navyše sme identifikovali aj jednonukleotidové patogénne varianty v génoch TP53 a PIK3CA. Pre definitívne stanovenie diagnózy LS u pacientky sme vyšetrili krvnú vzorku, kde sme tiež identifikovali mutáciu génu PMS2. Záver: LS je u mnohých Lynch asociovaných nádorových ochorení poddiagnostikovaný. V prípade familiárneho výskytu rakoviny prsníka a ďalších Lynch asociovaných génov je však dôležité myslieť aj na možnú diagnózu LS a v prípade, že pacient spĺňa diagnostické kritéria, uskutočniť aj genetické vyšetrenie Lynch asociovaných génov.

Background: Lynch syndrome (LS) is an autosomal dominant inherited disorder which causes an increased risk of cancer, especially colorectal and endometrial carcinomas. Recent studies have shown an association between LS and breast cancer as well. The aim of our study is to highlight the possible presence of mutations in genes associated with LS in patients with breast cancer and the need to include the examination of Lynch-associated genes in patients with a family history of breast cancer as well as in patients with recurrent breast cancer, as well as with the occurrence of other Lynch-associated cancer. Materials and methods: We analyzed tumor tissue samples from 78 patients with primary breast cancer. Our samples were tested with a gene panel associated with the risk of developing breast cancer, while in our study we focused primarily on the occurrence of mutations in mismatch-repair genes. DNA isolated from tumor tissue was sequenced using next generation sequencing (NGS) and analyzed using the Ingenuity Variant Analysis tool. To confirm the germline mutation, we examined the patient‘s blood sample using NGS sequencing. Results: As a result of our analysis, we managed to identify a mutation in the PMS2 gene in one patient‘s breast tumor tissue. The presence of this mutation indicates that the resulting cancer may be a consequence of LS. As for pathogenicity, this was probably a pathogenic variant, as we detected deletions in the exon region, which led to frameshift mutation. Moreover, we also identified single-nucleotide pathogenic variants in the TP53 and PIK3CA genes. To definitively establish the diagnosis of LS in the patient, we examined a blood sample, where we also identified a mutation of the PMS2 gene. Conclusion: LS is underdiagnosed in many Lynch-associated cancers. However, in the case of a familial occurrence of breast cancer and other Lynch-associated genes, it is important to think about a possible diagnosis of LS and, if the patient meets the diagnostic criteria, to carry out a genetic examination of Lynch-associated genes.

• MeSH
• Colorectal Neoplasms, Hereditary Nonpolyposis diagnosis   genetics   pathology   MeSH
• Genetic Predisposition to Disease MeSH
• Humans MeSH
• Mismatch Repair Endonuclease PMS2 genetics   MeSH
• Mutation MeSH
• Breast Neoplasms * genetics   MeSH
• Pilot Projects MeSH
• Germ-Line Mutation MeSH
• Check Tag
• Humans MeSH
• Female MeSH
• Publication type
• Research Support, Non-U.S. Gov't MeSH

Male breast cancer (mBC) is a rare cancer diagnosis that constitutes less than 1 % of all breast cancer cases globally. Genetic factors play an important role in the mBC risk. Germline pathogenic variants (PVs) in cancer predisposition genes could be identified in about 15 % of cases. We performed germline genetic testing in 248 Czech mBC patients and 3,626 non-cancer male controls using next-generation sequencing by the CZECANCA panel (226 genes). We identified 46/248 (18.5 %) carriers of PVs in the established mBC predisposition genes, primarily in BRCA2 (N = 34), less frequently in BRCA1 (N = 7) and PALB2 (N = 5). The presence of a PV in these genes significantly increased the mBC risk (OR 44.04; 5.82; and 8.26, respectively). Additionally, we identified 16 carriers of PVs in candidate mBC genes, but only PVs in CHEK2 were significantly associated with increased mBC risk (OR = 4.98). The significance of 26 germline alterations in 23/192 additionally analysed genes remained uncertain. The carriers of PVs in BRCA1 and CHEK2 were significantly younger (55.8 and 52.6 years, respectively) than non-carriers (64.8 years), and all carriers of PVs in the established genes had more frequently grade G3 tumours and positive family cancer history. Our study underscores the critical role of BRCA2 in mBC predisposition while also highlighting the potential contributions of additional genes that warrant further investigation. Moreover, it supports and justifies universal genetic testing for all mBC patients to generally improve early cancer detection and tailored treatment.

• MeSH
• Checkpoint Kinase 2 genetics   MeSH
• Adult MeSH
• Genetic Predisposition to Disease * MeSH
• Genetic Testing MeSH
• Middle Aged MeSH
• Humans MeSH
• Breast Neoplasms, Male * genetics   MeSH
• BRCA1 Protein genetics   MeSH
• BRCA2 Protein genetics   MeSH
• Aged MeSH
• Germ-Line Mutation genetics   MeSH
• Check Tag
• Adult MeSH
• Middle Aged MeSH
• Humans MeSH
• Male MeSH
• Aged MeSH
• Publication type
• Journal Article MeSH

We performed comprehensive molecular analysis of five cases of metastasizing uveal malignant melanoma (UM) (fresh-frozen samples) with an NGS panel of 73 genes. A likely pathogenic germline TP53 mutation c.760A > G (p.I254V) was found in two tumor samples and matched nontumor tissue. In three cases, pathogenic BAP1 mutation was detected together with germline missense variants of uncertain significance in ATM. All cases carried recurrent activating GNAQ or GNA11 mutation. Moreover, we analyzed samples from another 16 patients with primary UM by direct Sanger sequencing focusing only on TP53 coding region. No other germline TP53 mutation was detected in these samples. Germline TP53 mutation, usually associated with Li-Fraumeni syndrome, is a rare event in UM. To the best of our knowledge, only one family with germline TP53 mutation has previously been described. In our study, we detected TP53 mutation in two patients without known family relationship. The identification of germline aberrations in TP53 or BAP1 is important to identify patients with Li-Fraumeni syndrome or BAP1 cancer syndrome, which is also crucial for proper genetic counseling.

• MeSH
• Ataxia Telangiectasia Mutated Proteins genetics   MeSH
• Adult MeSH
• Genetic Predisposition to Disease MeSH
• Middle Aged MeSH
• Humans MeSH
• Melanoma genetics   pathology   MeSH
• Survival Rate MeSH
• Young Adult MeSH
• DNA Mutational Analysis MeSH
• Tumor Suppressor Proteins genetics   MeSH
• Tumor Suppressor Protein p53 genetics   MeSH
• Liver Neoplasms genetics   secondary   MeSH
• Uveal Neoplasms genetics   pathology   MeSH
• Prognosis MeSH
• Aged MeSH
• Ubiquitin Thiolesterase genetics   MeSH
• Germ-Line Mutation * MeSH
• Check Tag
• Adult MeSH
• Middle Aged MeSH
• Humans MeSH
• Young Adult MeSH
• Male MeSH
• Aged MeSH
• Female MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH