Exome analysis of carotid body tumor

Snezhkina, Anastasiya V.; Lukyanova, E. N.; Kalinin, D. V.; Pokrovsky, Anatoly V.; Dmitriev, Alexey A.; Koroban, N. V.; Pudova, Elena A.; Fedorova, Maria S.; Волченко, Н. Н.; Степанов, О. А.; Zhevelyuk, Ekaterina A.; Kharitonov, Sergey L.; Lipatova, Anastasiya V.; Абрамов, И. С.; Golovyuk, Alexander L.; Yegorov, Yegor E.; Vishnyakova, Khava S.; Moskalev, Alexey; Krasnov, George S.; Melnikova, Nataliya V.; Shcherbo, Dmitry S.; Kiseleva, Marina V.; Каприн, А. Д.; Alekseev, Boris; Zaretsky, Andrew R.; Kudryavtseva, Anna V.

doi:10.1186/s12920-018-0327-0

Cited by 25 publications

(30 citation statements)

References 85 publications

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“…We analyzed germline variants in 42 genes (VHL, SDHA, SDHB, SDHC, SDHD, NF1, RET, HRAS, KRAS, EPAS1 (HIF2A), ATRX, CSDE1, BRAF, FGFR1, FGFR2, FGFR3, FGFR4, FGFRL1, SETD2, ARNT, TP53, TP53BP1, TP53BP2, TP53I13, KMT2D, BAP1, IDH1, IDH2, SDHAF1, SDHAP2, FH, EGLN1, MDH2, TMEM127, MAX, KIF1B, MEN1, GDNF, GNAS, CDKN2A, BRCA1, and BRCA2) reported previously to be involved in the development of paragangliomas/pheochromocytomas [34,52]. Three pathogenic and two likely pathogenic germline variants were found across six patients with CBT according to the predicted algorithms and public databases ( variants were characterized by high conservation scores (PhastCons) and had an allele frequency less than 0.01% in 1000 Genomes Project, ESP 6500, and ExAC databases.…”

Section: Pathogenic and Likely Pathogenic Germline Variants In Causatmentioning

confidence: 99%

Mutational load in carotid body tumor

et al. 2019

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Background: Carotid body tumor (CBT) is a rare neoplasm arising from paraganglion located near the bifurcation of the carotid artery. There is great intra-tumor heterogeneity, and CBT development could be associated with both germline and somatic allelic variants. Studies on the molecular genetics of CBT are limited, and the molecular mechanisms of its pathogenesis are not fully understood. This work is focused on the estimation of mutational load (ML) in CBT. Methods: Using the NextSeq 500 platform, we performed exome sequencing of tumors with matched lymph node tissues and peripheral blood obtained from six patients with CBT. To obtain reliable results in tumors with low ML, we developed and successfully applied a complex approach for the analysis of sequencing data. ML was evaluated as the number of somatic variants per megabase (Mb) of the target regions covered by the Illumina TruSeq Exome Library Prep Kit. Results: The ML in CBT varied in the range of 0.09-0.28/Mb. Additionally, we identified several pathogenic/likely pathogenic somatic and germline allelic variants across six patients studied (including TP53 variants). Conclusions: Using the developed approach, we estimated the ML in CBT, which is much lower than in common malignant tumors. Identified variants in known paraganglioma/pheochromocytoma-causative genes and novel genes could be associated with the pathogenesis of CBT. The obtained results expand our knowledge of the mutation process in CBT as well as the biology of tumor development.

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Section: Pathogenic and Likely Pathogenic Germline Variants In Causatmentioning

confidence: 99%

Mutational load in carotid body tumor

et al. 2019

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“…The average coverage for each sample was at least 300×. In this study, we used exome data of CPGL samples that were previously sequenced; raw sequence reads for Pat02–Pat51 are available at NCBI Sequence Read Archive (SRA) BioProject PRJNA411769 [ 56 ], and sequence data for Pat100–Pat104 are available at SRA BioProject PRJNA476932 [ 57 ]. Raw sequence data from an expanded set of CPGL samples (Pat53–Pat71) were added to the NCBI SRA BioProject PRJNA411769.…”

Section: Methodsmentioning

confidence: 99%

Immunohistochemistry and Mutation Analysis of SDHx Genes in Carotid Paragangliomas

Snezhkina

Kalinin

Pavlov

et al. 2020

IJMS

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Carotid paragangliomas (CPGLs) are rare neuroendocrine tumors often associated with mutations in SDHx genes. The immunohistochemistry of succinate dehydrogenase (SDH) subunits has been considered a useful instrument for the prediction of SDHx mutations in paragangliomas/pheochromocytomas. We compared the mutation status of SDHx genes with the immunohistochemical (IHC) staining of SDH subunits in CPGLs. To identify pathogenic/likely pathogenic variants in SDHx genes, exome sequencing data analysis among 42 CPGL patients was performed. IHC staining of SDH subunits was carried out for all CPGLs studied. We encountered SDHx variants in 38% (16/42) of the cases in SDHx genes. IHC showed negative (5/15) or weak diffuse (10/15) SDHB staining in most tumors with variants in any of SDHx (94%, 15/16). In SDHA-mutated CPGL, SDHA expression was completely absent and weak diffuse SDHB staining was detected. Positive immunoreactivity for all SDH subunits was found in one case with a variant in SDHD. Notably, CPGL samples without variants in SDHx also demonstrated negative (2/11) or weak diffuse (9/11) SDHB staining (42%, 11/26). Obtained results indicate that SDH immunohistochemistry does not fully reflect the presence of mutations in the genes; diagnostic effectiveness of this method was 71%. However, given the high sensitivity of SDHB immunohistochemistry, it could be used for initial identifications of patients potentially carrying SDHx mutations for recommendation of genetic testing.

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“…В работе использованы результаты секвенирования эк зома 52 архивных образцов каротидных параганглиом (Snezhkina et al, 2018…”

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“…Ранее в единственной работе, посвященной оценке му тационной нагрузки при КПГ, нами показано, что в не скольких генах обнаруживается существенно повышен ное количество мутаций (в пересчете на одну мегабазу кодирующего региона генома) по сравнению с другими генами (Snezhkina et al, 2018 Для всех четырех выявленных генов ранее показана во влеченность в образование опухолей. Ген CDC27 кодирует белок цикла клеточного деления 27.…”

Section: потенциально патогенные мутации в генах Cdc27 Ctbp2 Hydin unclassified

“…Исследование уровня мутационной нагрузки при раз личных опухолях является как фундаментальной, так и актуальной прикладной задачей. Ранее нами на основании анализа секвенирования экзома 52 образцов опухолей была впервые проведена оценка мутационной нагрузки при КПГ (Snezhkina et al, 2018). Выявлено, что несколько генов характеризуются существенно повышенным ко личеством потенциально соматических «вредных» (при водящих к изменению структуры белка) мутаций по сравнению с другими генами.…”

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Analysis of mutations in CDC27, CTBP2, HYDIN and KMT5A genes in carotid paragangliomas

et al. 2018

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Carotid paragangliomas (CPGLs) are rare neuroendocrine tumors that arise from paraganglionic tissue of the carotid body localizing at the bifurcation of carotid artery. These tumors are slowly growing, but occasionally they become aggressive and metastatic. Surgical treatment remains high-risk and extremely challenging; radiation and chemotherapy are poorly effective. The study of molecular pathogenesis of CPGLs will allow developing novel therapeutic approaches and revealing biomarkers. Previously, we performed the exome sequencing of 52 CPGLs and estimated mutational load (ML). Paired histologically normal tissues or blood were unavailable, so potentially germline mutations were excluded from the analysis with strong filtering conditions using 1000 Genomes Project and ExAC databases. In this work, ten genes (ZNF717, CDC27, FRG2C, FAM104B, CTBP2, HLA-DRB1, HYDIN, KMT5A, MUC3A, and PRSS3) characterized by the highest level of mutational load were analyzed. Using several prediction algorithms (SIFT, PolyPhen-2, MutationTaster, and LRT), potentially pathogenic mutations were identified in four genes (CDC27, CTBP2, HYDIN, and KMT5A). Many of these mutations occurred in the majority of cases, and their mutation type was checked using exome sequencing data of blood prepared with the same exome enrichment kit that was used for preparation of exome libraries from CPGLs. The majority of the mutations were germline that can apparently be associated with annotation errors in 1000 Genomes Pro ject and ExAC. However, part of the mutations identified in CDC27, CTBP2, HYDIN, and KMT5A remain potentially pathogenic, and there is a large body of data on the involvement of these genes in the formation and progression of other tumors. This allows considering CDC27, CTBP2, HYDIN, and KMT5A genes as potentially associated with CPGL pathogenesis and requires taking them into account in further investigations. Thus, there is a necessity to improve the methods for identification of cancer-asso ciated genes as well as pathogenic mutations.

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Exome analysis of carotid body tumor

Cited by 25 publications

References 85 publications

Mutational load in carotid body tumor

Mutational load in carotid body tumor

Immunohistochemistry and Mutation Analysis of SDHx Genes in Carotid Paragangliomas

Analysis of mutations in CDC27, CTBP2, HYDIN and KMT5A genes in carotid paragangliomas

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