BRIP1 protein, human OR C000618935 Dotaz Zobrazit nápovědu
Spindle cell hemangioma is a benign vascular tumor typically occurring in the dermis or subcutis of distal extremities as red-brown lesions that can grow in both size and number over time. They can be very painful and potentially disabling. A family history of cancer or previous history may be relevant and must be taken into consideration. Juxtaglomerular cell tumor (reninoma) is an extremely rare cause of secondary hypertension diagnosed mostly among adolescents and young adults. Excessive renin secretion results in secondary hyperaldosteronism. Subsequent hypokalemia and metabolic alkalosis, together with high blood pressure, are clues for clinical diagnosis. Histological examination of the excised tumor leads to a definitive diagnosis. Reninoma is found in subcapsular localization, in most cases as a solitary mass, in imaging studies of kidneys. Exceptionally, it can be located in another part of a kidney. Both spindle cell hemangioma and reninoma are extremely rare tumors in children and adolescents. Herein, the authors present a case report of a patient with hereditary BRCA1 interacting protein C-terminal helicase 1 (BRIP1) mutation, spindle cell hemangioma, and secondary hypertension caused by atypically localized reninoma.
- Klíčová slova
- children, hypertension, juxtaglomerular cell tumor, kidney, reninoma, spindle cell hemangioendothelioma,
- MeSH
- genetická predispozice k nemoci * MeSH
- hemangiom diagnóza genetika patologie MeSH
- juxtaglomerulární aparát patologie MeSH
- ledviny metabolismus patologie MeSH
- lidé MeSH
- proteiny FANC genetika MeSH
- RNA-helikasy genetika MeSH
- zárodečné mutace genetika MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
- kazuistiky MeSH
- práce podpořená grantem MeSH
- Názvy látek
- BRIP1 protein, human MeSH Prohlížeč
- proteiny FANC MeSH
- RNA-helikasy MeSH
The presence of breast cancer in any first-degree female relative in general nearly doubles the risk for a proband and the risk gradually increases with the number of affected relatives. Current advances in molecular oncology and oncogenetics may enable the identification of high-risk individuals with breast-cancer predisposition. The best-known forms of hereditary breast cancer (HBC) are caused by mutations in the high-penetrance genes BRCA1 and BRCA2. Other genes, including PTEN, TP53, STK11/LKB1, CDH1, PALB2, CHEK2, ATM, MRE11, RAD50, NBS1, BRIP1, FANCA, FANCC, FANCM, RAD51, RAD51B, RAD51C, RAD51D, and XRCC2 have been described as high- or moderate-penetrance breast cancer-susceptibility genes. The majority of breast cancer-susceptibility genes code for tumor suppressor proteins that are involved in critical processes of DNA repair pathways. This is of particular importance for those women who, due to their increased risk of breast cancer, may be subjected to more frequent screening but due to their repair deficiency might be at the risk of developing radiation-induced malignancies. It has been proven that cancers arising from the most frequent BRCA1 gene mutation carriers differ significantly from the sporadic disease of age-matched controls in their histopathological appearances and molecular characteristics. The increased depth of mutation detection brought by next-generation sequencing and a better understanding of the mechanisms through which these mutations cause the disease will bring novel insights in terms of oncological prevention, diagnostics, and therapeutic options for HBC patients.
- Klíčová slova
- Breast cancer, Breast cancer risk, Hereditary breast cancer,
- MeSH
- ATM protein genetika MeSH
- biologické markery MeSH
- CD antigeny MeSH
- checkpoint kinasa 2 genetika MeSH
- fosfohydroláza PTEN genetika MeSH
- genetická predispozice k nemoci * MeSH
- geny BRCA1 MeSH
- geny BRCA2 MeSH
- jaderné proteiny genetika MeSH
- kadheriny genetika MeSH
- kinasy AMP aktivovaných proteinkinas MeSH
- lidé MeSH
- mutace MeSH
- nádorové supresorové proteiny genetika MeSH
- nádorový supresorový protein p53 genetika MeSH
- nádory prsu genetika patologie MeSH
- penetrance MeSH
- protein FANCN MeSH
- protein-serin-threoninkinasy genetika MeSH
- rizikové faktory MeSH
- Check Tag
- lidé MeSH
- ženské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
- přehledy MeSH
- Názvy látek
- ATM protein, human MeSH Prohlížeč
- ATM protein MeSH
- biologické markery MeSH
- CD antigeny MeSH
- CDH1 protein, human MeSH Prohlížeč
- checkpoint kinasa 2 MeSH
- CHEK2 protein, human MeSH Prohlížeč
- fosfohydroláza PTEN MeSH
- jaderné proteiny MeSH
- kadheriny MeSH
- kinasy AMP aktivovaných proteinkinas MeSH
- nádorové supresorové proteiny MeSH
- nádorový supresorový protein p53 MeSH
- PALB2 protein, human MeSH Prohlížeč
- protein FANCN MeSH
- protein-serin-threoninkinasy MeSH
- PTEN protein, human MeSH Prohlížeč
- STK11 protein, human MeSH Prohlížeč
Ovarian cancer (OC) is one of the leading causes of cancer-related deaths in women. Most patients are diagnosed with advanced epithelial OC in their late 60s, and early-onset adult OC diagnosed ≤30 years is rare, accounting for less than 5% of all OC cases. The most significant risk factor for OC development are germline pathogenic/likely pathogenic variants (GPVs) in OC predisposition genes (including BRCA1, BRCA2, BRIP1, RAD51C, RAD51D, Lynch syndrome genes, or BRIP1), which contribute to the development of over 20% of all OC cases. GPVs in BRCA1/BRCA2 are the most prevalent. The presence of a GPV directs tailored cancer risk-reducing strategies for OC patients and their relatives. Identification of OC patients with GPVs can also have therapeutic consequences. Despite the general assumption that early cancer onset indicates higher involvement of hereditary cancer predisposition, the presence of GPVs in early-onset OC is rare (<10% of patients), and their heritability is uncertain. This review summarizes the current knowledge on the genetic predisposition to early-onset OC, with a special focus on epithelial OC, and suggests other alternative genetic factors (digenic, oligogenic, polygenic heritability, genetic mosaicism, imprinting, etc.) that may influence the development of early-onset OC in adult women lacking GPVs in known OC predisposition genes.
- Klíčová slova
- early-onset, genetic predisposition, germline pathogenic variant, ovarian cancer,
- MeSH
- dospělí MeSH
- epiteliální ovariální karcinom genetika MeSH
- genetická predispozice k nemoci * MeSH
- geny BRCA2 MeSH
- lidé MeSH
- nádory vaječníků * patologie MeSH
- protein BRCA1 genetika MeSH
- protein BRCA2 genetika MeSH
- rizikové faktory MeSH
- zárodečné mutace MeSH
- Check Tag
- dospělí MeSH
- lidé MeSH
- ženské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
- přehledy MeSH
- Názvy látek
- protein BRCA1 MeSH
- protein BRCA2 MeSH
BACKGROUND: Monoallelic germline pathogenic variants (GPVs) in five Fanconi anemia (FA) genes (BRCA1/FANCS, BRCA2/FANCD1, PALB2/FANCN, BRIP1/FANCJ, and RAD51C/FANCO) confer an increased risk of breast (BC) and/or ovarian (OC) cancer, but the role of GPVs in 17 other FA genes remains unclear. METHODS: Here, we investigated the association of germline variants in FANCG/XRCC9 with BC and OC risk. RESULTS: The frequency of truncating GPVs in FANCG did not differ between BC (20/10,204; 0.20%) and OC (8/2966; 0.27%) patients compared to controls (6/3250; 0.18%). In addition, only one out of five tumor samples showed loss-of-heterozygosity of the wild-type FANCG allele. Finally, none of the nine functionally tested rare recurrent missense FANCG variants impaired DNA repair activities (FANCD2 monoubiquitination and FANCD2 foci formation) upon DNA damage, in contrast to all tested FANCG truncations. CONCLUSION: Our study suggests that heterozygous germline FANCG variants are unlikely to contribute to the development of BC or OC.
- Klíčová slova
- Fanconi anemia complementation group G, breast cancer, functional analysis, germline genetic testing, hereditary tumors, ovarian cancer,
- MeSH
- dospělí MeSH
- genetická predispozice k nemoci * MeSH
- lidé středního věku MeSH
- lidé MeSH
- nádory prsu * genetika MeSH
- nádory vaječníků * genetika MeSH
- oprava DNA genetika MeSH
- protein FANCG * genetika MeSH
- senioři MeSH
- studie případů a kontrol MeSH
- zárodečné mutace * MeSH
- Check Tag
- dospělí MeSH
- lidé středního věku MeSH
- lidé MeSH
- senioři MeSH
- ženské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
- Názvy látek
- FANCG protein, human MeSH Prohlížeč
- protein FANCG * MeSH
BACKGROUND: Ovarian cancer is a disease with high mortality. Approximately 1,000 women are diagnosed with ovarian cancer in the Czech Republic annually. Women harboring a mutation in cancer-predisposing genes face an increased risk of tumor development. Mutations in BRCA1, BRCA2, BRIP1, and Lynch syndrome genes (RAD51C, RAD51D, and STK11) are associated with a high risk of ovarian cancer, and mutations in ATM, CHEK2, NBN, PALB2, and BARD1 appear to increase the risk. Our aim was to examine the frequency of mutations in cancer-predisposing genes in the Czech Republic. MATERIALS AND METHODS: We analyzed 1,057 individuals including ovarian cancer patients and 617 non-cancer controls using CZECANCA panel next-generation sequencing on the Illumina platform. Pathogenic mutations in high-risk genes, including CNVs, were detected in 30.6% of patients. The mutation frequency reached 25.0% and 18.2% in subgroups of unselected ovarian cancer patients and patients with a negative family cancer history, respectively. The most frequently mutated genes were BRCA1 and BRCA2. The overall frequency of mutations in non-BRCA genes was comparable to that in BRCA2. The mutation frequency in ovarian cancer patients aged >70 years was three times higher than that in patients diagnosed before the age of 30. CONCLUSION: Ovarian cancer is a heterogeneous disease with a high proportion of hereditary cases. The lack of efficient screening for early diagnosis emphasizes the importance of identifying carriers of mutations in ovarian cancer-predisposing genes; this is because proper follow-up and prevention strategies can reduce overall ovarian cancer-related mortality. This work was supported by grants AZV 15-27695A, SVV2019/260367, PROGRES Q28/LF1. 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: 7. 3. 2019 Accepted: 24. 4. 2019.
- Klíčová slova
- cancer genes, gene panel, massively-parallel sequencing, mutation, next generation sequencing, ovarian neoplasms,
- MeSH
- genetická predispozice k nemoci * MeSH
- lidé MeSH
- mutace MeSH
- nádory vaječníků genetika MeSH
- protein BRCA1 genetika MeSH
- protein BRCA2 genetika MeSH
- vysoce účinné nukleotidové sekvenování MeSH
- Check Tag
- lidé MeSH
- ženské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
- Geografické názvy
- Česká republika MeSH
- Názvy látek
- BRCA1 protein, human MeSH Prohlížeč
- BRCA2 protein, human MeSH Prohlížeč
- protein BRCA1 MeSH
- protein BRCA2 MeSH
Only one class of targeted agents (anti-GD2 antibodies) has been incorporated into front-line therapy for neuroblastoma since the 1980s. The Neuroblastoma New Drug Development Strategy (NDDS) initiative commenced in 2012 to accelerate the development of new drugs for neuroblastoma. Advances have occurred, with eight of nine high-priority targets being evaluated in paediatric trials including anaplastic lymphoma kinase inhibitors being investigated in front-line, but significant challenges remain. This article reports the conclusions of the second NDDS forum, which expanded across the Atlantic to further develop the initiative. Pre-clinical and clinical data for 40 genetic targets and mechanisms of action were prioritised and drugs were identified for early-phase trials. Strategies to develop drugs targeting TERT, telomere maintenance, ATRX, alternative lengthening of telomeres (ALT), BRIP1 and RRM2 as well as direct targeting of MYCN are high priority and should be championed for drug discovery. Promising pre-clinical data suggest that targeting of ALT by ATM or PARP inhibition may be potential strategies. Drugs targeting CDK2/9, CDK7, ATR and telomere maintenance should enter paediatric clinical development rapidly. Optimising the response to anti-GD2 by combinations with chemotherapy, targeted agents and other immunological targets are crucial. Delivering this strategy in the face of small patient cohorts, genomically defined subpopulations and a large number of permutations of combination trials, demands even greater international collaboration. In conclusion, the NDDS provides an internationally agreed, biologically driven selection of prioritised genetic targets and drugs. Improvements in the strategy for conducting trials in neuroblastoma will accelerate bringing these new drugs more rapidly to front-line therapy.
- Klíčová slova
- Clinical trials, Drug development, Epigenetics, MYCN, Neuroblastoma, Phase I, Preclinical testing,
- MeSH
- antitumorózní látky izolace a purifikace terapeutické užití MeSH
- cílená molekulární terapie metody trendy MeSH
- dítě MeSH
- experimentální terapie metody trendy MeSH
- inhibitory proteinkinas izolace a purifikace terapeutické užití MeSH
- kongresy jako téma MeSH
- lékařská onkologie metody organizace a řízení trendy MeSH
- lidé MeSH
- nádory mozku farmakoterapie patologie MeSH
- neuroblastom farmakoterapie patologie MeSH
- objevování léků metody organizace a řízení trendy MeSH
- pediatrie metody organizace a řízení trendy MeSH
- vyvíjení léků * metody organizace a řízení trendy MeSH
- Check Tag
- dítě MeSH
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
- přehledy MeSH
- Geografické názvy
- Evropa MeSH
- Názvy látek
- antitumorózní látky MeSH
- inhibitory proteinkinas MeSH
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.
