Familial inheritance in non-medullary thyroid cancer (NMTC) is an area that has yet to be adequately explored. Despite evidence suggesting strong familial clustering of non-syndromic NMTC, known variants still account for a very small percentage of the genetic burden. In a recent whole genome sequencing (WGS) study of five families with several NMTCs, we shortlisted promising variants with the help of our in-house developed Familial Cancer Variant Prioritization Pipeline (FCVPPv2). Here, we report potentially disease-causing variants in checkpoint kinase 2 (CHEK2), Ewing sarcoma breakpoint region 1 (EWSR1) and T-lymphoma invasion and metastasis-inducing protein 1 (TIAM1) in one family. Performing WGS on three cases, one probable case and one healthy individual in a family with familial NMTC left us with 112254 variants with a minor allele frequency of less than 0.1%, which was reduced by pedigree-based filtering to 6368. Application of the pipeline led to the prioritization of seven coding and nine non-coding variants from this family. The variant identified in CHEK2, a known tumor suppressor gene involved in DNA damage-induced DNA repair, cell cycle arrest, and apoptosis, has been previously identified as a germline variant in breast and prostate cancer and has been functionally validated by Roeb et al. in a yeast-based assay to have an intermediate effect on protein function. We thus hypothesized that this family may harbor additional disease-causing variants in other functionally related genes. We evaluated two further variants in EWSR1 and TIAM1 with promising in silico results and reported interaction in the DNA-damage repair pathway. Hence, we propose a polygenic mode of inheritance in this family. As familial NMTC is considered to be more aggressive than its sporadic counterpart, it is important to identify such susceptibility genes and their associated pathways. In this way, the advancement of personalized medicine in NMTC patients can be fostered. We also wish to reopen the discussion on monogenic vs polygenic inheritance in NMTC and instigate further development in this area of research.

• MeSH
• checkpoint kinasa 2 chemie   genetika   metabolismus   MeSH
• frekvence genu MeSH
• genetická predispozice k nemoci * MeSH
• genom lidský MeSH
• lidé MeSH
• papilární karcinom štítné žlázy genetika   metabolismus   MeSH
• protein EWS vázající RNA chemie   genetika   metabolismus   MeSH
• protein TIAM1 chemie   genetika   metabolismus   MeSH
• rodokmen MeSH
• sekvence aminokyselin MeSH
• sekvenční seřazení MeSH
• sekvenování celého genomu MeSH
• Check Tag
• lidé MeSH
• mužské pohlaví MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Geografické názvy
• Itálie MeSH

Non-medullary thyroid cancer (NMTC) is a common endocrine malignancy with a genetic basis that has yet to be unequivocally established. In a recent whole-genome sequencing study of five families with occurrence of NMTCs, we shortlisted promising variants with the help of bioinformatics tools. Here, we report in silico analyses and in vitro experiments on a novel germline variant (p.V29L) in the highly conserved oligonucleotide/oligosaccharide binding domain of the Protection of Telomeres 1 (POT1) gene in one of the families. The results showed a reduction in telomere-bound POT1 levels in the mutant protein as compared to its wild-type counterpart. HEK293T cells carrying POT1 p.V29L showed increased telomere length in comparison to wild-type cells, suggesting that the mutation causes telomere dysfunction and may play a role in predisposition to NMTC in this family. While one germline mutation in POT1 has already been reported in a melanoma-prone family with prevalence of thyroid cancers, we report the first of such mutations in a family affected solely by NMTCs, thus expanding current knowledge on shelterin complex-associated cancers.

• Publikační typ
• časopisecké články MeSH

Hirschsprung's disease (HD) can be associated with the development of neuroendocrine tumours such as medullary thyroid carcinoma (MTC). The RET proto-oncogene is the major gene responsible for both HD and MTC. Mutations in exon 10 (codons 609, 611, 618, 620) were found in patients with co-occurrence of HD and MTC. The aim of the study was to screen the MTC risk in patients with HD. The prospective and retrospective genetic analyses comprised 56 HD patients (41 males, 15 females, aged 0-47). The prospective subgroup of patients consisted of 34 patients (25 boys, 9 girls) operated on between June 2003 and December 2005. The retrospective subgroup comprised 22 patients (16 boys, 6 girls) of 194 patients who were operated on between December 1979 and May 2003, non-systematically chosen preferably for total colonic aganglionosis (TCA). DNAs were isolated from blood and resected segments of aganglionic bowel. The HD patients and nine available family members (2 HD) were tested for RET mutations in exons 10, 11, 13, 14, 15 and 16. Direct double-stranded fluorescent sequencing revealed typical germline heterozygous MTC risk RET mutations in 3/56 (5.4%) female HD patients: Cys609Tyr, Cys620Arg (both exon 10) and Tyr791Phe (exon 13). Two of these patients had TCA and one patient had classical type of HD. One TCA patient developed clinical stage of MTC and underwent total thyroidectomy (TTE). The other two RET positive HD patients (aged 7 and 25 years) are screened for calcitonin level and they are without TTE till now. Two family members (mothers of TCA patients) with detected RET mutation underwent prophylactic TTE with MTC finding. Results showed the benefit of systematic RET mutation screening in HD patients in order to identify the risk of MTC in preclinical stage of the disease in patients with HD and their family members. We recommend to investigate not only exon 10 but also exon 13.

• MeSH
• dítě MeSH
• dospělí MeSH
• Hirschsprungova nemoc epidemiologie   genetika   MeSH
• kojenec MeSH
• komorbidita MeSH
• lidé středního věku MeSH
• lidé MeSH
• medulární karcinom epidemiologie   chemicky indukované   MeSH
• mladiství MeSH
• nádory štítné žlázy epidemiologie   genetika   MeSH
• předškolní dítě MeSH
• protoonkogenní proteiny c-ret genetika   MeSH
• riziko MeSH
• zárodečné mutace MeSH
• Check Tag
• dítě MeSH
• dospělí MeSH
• kojenec MeSH
• lidé středního věku MeSH
• lidé MeSH
• mladiství MeSH
• mužské pohlaví MeSH
• předškolní dítě MeSH
• ženské pohlaví MeSH
• Publikační typ
• práce podpořená grantem MeSH

Syndromy mnohočetné endokrinní neoplazie (MEN syndromy) jsou vzácná autozomálně dominantně dědičná onemocnění s přítomností nádorů dvou a více endokrinních žláz s možnou manifestací v časném dětském věku. Pozdní diagnóza MEN syndromu může být pro jedince fatální. Časná identifikace rizikových jedinců je proto klíčová pro prevenci a léčbu potenciálně život ohrožujících endokrinních a neendokrinních neoplazií. Z MEN syndromů má nejzávažnější prognózu MEN 2B syndrom, a to vzhledem k vysoce agresivnímu medulárnímu karcinomu štítné žlázy s časným postnatálním vývojem a vysokému zastoupení de novo mutací. Znalost neendokrinních projevů u tohoto syndromu proto může vést k časné diagnóze před rozvojem pokročilého maligního onemocnění. Popisujeme nejnovější poznatky o MEN syndromech se zaměřením na klinické symptomy, genetické pozadí, korelaci genotyp–fenotyp u MEN 2 syndromů, guidelines Americké tyreoidologické asociace pro screening vývoje nádorů a jejich léčbu u dětí.

Multiple endocrine neoplasia syndromes (MEN syndromes) are rare autosomal dominantly inherited diseases with the occurence of tumors of two or more endocrine glands, with possible manifestation in early childhood. A late diagnosis of MEN syndrome can be fatal for an individual. Early identification of at-risk individuals is therefore crucial for the prevention and treatment of potentially life-threatening endocrine and non-endocrine neoplasias. MEN 2B syndrome has the most serious prognosis due to highly aggressive medullary thyroid carcinoma with early postnatal development and a high prevalence of de novo mutations. Knowledge of the non-endocrine features of this syndrome may lead to early diagnosis before the development of advanced malignant disease. We describe the latest knowledge about MEN syndromes with a focus on clinical symptoms, genetic background, genotype-phenotype correlation in MEN 2 syndromes, American Thyroid Association guidelines for screening of tumors and their treatment in children.

• MeSH
• časná detekce nádoru MeSH
• dítě MeSH
• lidé MeSH
• mnohočetné endokrinní neoplazie * genetika   klasifikace   MeSH
• mutace MeSH
• věkové faktory MeSH
• Check Tag
• dítě MeSH
• lidé MeSH
• Publikační typ
• přehledy MeSH

Hirschsprungova choroba (HSCR) je vrozené vývojové onemocnění enterického nervového systému. Příčinou je chybějící intramurální inervace určitého úseku střeva. Postižený střevní úsek je trvale stažen a zdravé střevo nad ním se postupně dilatuje a vytváří megakolon. Rozlišuje se několik variant HSCR podle délky postiženého úseku střeva. HSCR se vyskytuje izolovaně nebo syndromicky, sporadicky (80 %) nebo familiárně (20 %). Genetická podstata HSCR je komplexní, je známo 12 příčinných genů zapojených v různých signalizačních kaskádách. Majoritním genem je RET proto-onkogen, kde se nalézají příčinné inaktivující mutace nebo predispoziční varianty v kódující i nekódující části genu. Dalšími geny jsou geny zapojené do RET/GDNF kaskády nebo EDNRB/ENT3 kaskády a s nimi spojené transkripční faktory modulující aktivitu těchto drah. Tyto dráhy a faktory spolu souvisejí a vzájemně se ovlivňují. Kromě příčinných genů je známa řada modifikujících genů, které mohou ovlivňovat fenotyp HSCR. Poznáním genetické podstaty HSCR je možné odhalit příčinu vzniku HSCR, zjistit dědičnost a penetranci jednotlivých mutací. Protože RET proto-onkogen je také příčinou vzniku medulárního karcinomu štítné žlázy (MTC), jsou pacienti s HSCR ve zvýšeném riziku MTC a všichni pacienti by měli být doporučeni ke genetickému screeningu.

Hirschsprung´s disease (HSCR) is a congenital developmental disease of enteric nervous system. The cause is the congenital primary loss of intramural innervation of certain bowel segment. The affected part of bowel is permanently contracted and the healthy bowel above is dilatated and it leads to the development of megacolon. Several variants of HSCR are distinguished by different length of affected colon. It is occurred alone or syndromic, sporadic (80%) or familial form (20%) of HSCR. Genetic cause of HSCR is complex, 12 causative genes are known to be involved in different signal cascades. The major gene is the RET proto-oncogene, where causative inactivating mutations or predisposing variants in coding or non-coding part of gene are found. The other genes are involved in RET/GDNF or EDNRB/ENT3 cascades and transcription factors modulating activities of these cascades. These cascades and factors are in connection and influence themselves. Beside causative genes several modifying genes are known that can influence phenotype of HSCR. Due to the recognition of genetic cause of HSCR it is possible to find the cause of development of HSCR, distinguish the inheritance and the penetrance of each mutation. Because mutations in the RET proto-oncogene are known to be the cause of development of medullary thyroid carcinoma (MTC), patients with HSCR are in higher risk of MTC and all patients should be recommended to genetic screening.

• MeSH
• chromozomální aberace MeSH
• endotelin-3 genetika   MeSH
• fenotyp MeSH
• fyziologie buňky MeSH
• genetické nemoci vrozené MeSH
• genetické testování MeSH
• haplotypy MeSH
• Hirschsprungova nemoc * genetika   MeSH
• lidé MeSH
• medulární karcinom MeSH
• mutace MeSH
• nádory štítné žlázy MeSH
• protoonkogeny MeSH
• signální transdukce MeSH
• transkripční faktory SOXE MeSH
• transkripční faktory MeSH
• zinkové prsty MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• práce podpořená grantem MeSH
• přehledy MeSH

PURPOSE OF THE REPORT: Cases of synchronous non-Hodgkin lymphoma (NHL) and second primary carcinoma in previously untreated immunocompetent patients are relatively rare. The aim of this part of our prospective study was to a revealed 2-F-18 fluoro-2-deoxy-D-glucose (F-18 FDG) positron emission tomography (PET)-positive lesion in an extranodal organ suggestive of second primary neoplasm in newly diagnosed NHL patients. MATERIALS AND METHODS: A total of 209 patients with NHL underwent initial staging F-18 FDG PET/computed tomography (CT). The finding was assessed by a radiologist, nuclear medicine physician, and hematologist. In 6 suspicious cases (2.9%) of second neoplasm, the decision was made to perform further investigations before lymphoma therapy. RESULTS: Two patients were diagnosed with colorectal carcinoma, 1 with esophageal adenocarcinoma, 1 with invasive ductal breast carcinoma, 1 with medullary thyroid carcinoma, and 1 with squamous cell lung carcinoma. In 5 of the 6 patients, the second solid tumor was completely asymptomatic and revealed only by F-18 FDG PET/CT examination. CONCLUSIONS: We conclude that in patients with NHL, appropriate imaging, clinical, and histologic analysis of organ lesions detected by F-18 FDG PET/CT will occasionally demonstrate significant synchronous neoplasms.

• MeSH
• fluorodeoxyglukosa F18 diagnostické užití   MeSH
• lidé středního věku MeSH
• lidé MeSH
• nehodgkinský lymfom patologie   radiografie   MeSH
• počítačová rentgenová tomografie MeSH
• pozitronová emisní tomografie MeSH
• sekundární malignity radiografie   MeSH
• senioři MeSH
• staging nádorů MeSH
• Check Tag
• lidé středního věku MeSH
• lidé MeSH
• mužské pohlaví MeSH
• senioři MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• kazuistiky MeSH
• práce podpořená grantem MeSH