Downregulation of OGDHL expression is associated with promoter hypermethylation in colorectal cancer

Fedorova, Maria S.; Kudryavtseva, Anna V.; Lakunina, V. A.; Snezhkina, Anastasiya V.; Волченко, Н. Н.; Slavnova, E. N.; Данилова, Т. В.; Садритдинова, А. Ф.; Melnikova, N. V.; Белова, А. А.; Klimina, Ksenia M.; Сидоров, Д. В.; Alekseev, B. Ya.; Каприн, А. Д.; Dmitriev, Alexey A.; Krasnov, George S.

doi:10.1134/s0026893315040044

Cited by 37 publications

(28 citation statements)

References 50 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Tumor development is closely associated with the accumulation of somatic mutations, which may be due to various processes such as endogenous and exogenous DNA damage, defective mechanisms of DNA replication, modification, and repair [2,3]. These cause the changes in expression profiles of many genes, including activation of oncogenes and inactivation of tumor suppressor genes that lead to alterations in signaling pathways, cellular metabolism, and proliferation [4][5][6][7][8][9][10][11][12][13][14]. Distinct combinations of mutation types ("mutational signatures") depend on different mutation processes; multiple mutation processes generate jumbled composite signatures.…”

Section: Introductionmentioning

confidence: 99%

Mutational load in carotid body tumor

et al. 2019

View full text Add to dashboard Cite

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.

show abstract

Section: Introductionmentioning

confidence: 99%

Mutational load in carotid body tumor

et al. 2019

View full text Add to dashboard Cite

show abstract

“…In our study, we provide evidence that a newly identified gene OGDHL was associated with breast cancer risk in Chinese populations. The OGDHL gene, encoding a component of the multienzyme OGDH complex (OGDHC), has been suggested to be a putative tumor suppressor by previous studies . Hypermethylation at CpG sites in the promoter region of the OGDHL gene were observed in multiple cancer types, including breast cancer .…”

Section: Discussionmentioning

confidence: 99%

“…The OGDHL gene, encoding a component of the multienzyme OGDH complex (OGDHC), has been suggested to be a putative tumor suppressor by previous studies. [35][36][37][38] Hypermethylation at CpG sites in the promoter region of the OGDHL gene were observed in multiple cancer types, including breast cancer. 35,36 These in vitro findings provided additionally biological evidence of OGDHL being a putative breast cancer susceptibility gene.…”

Section: Discussionmentioning

confidence: 99%

Discovery of rare coding variants in OGDHL and BRCA2 in relation to breast cancer risk in Chinese women

Guo

Long

Chen

et al. 2019

Intl Journal of Cancer

View full text Add to dashboard Cite

The missing heritability of breast cancer could be partially attributed to rare variants (MAF < 0.5%). To identify breast cancer‐associated rare coding variants, we conducted whole‐exome sequencing (~50×) in genomic DNA samples obtained from 831 breast cancer cases and 839 controls of Chinese females. Using burden tests for each gene that included rare missense or predicted deleterious variants, we identified 29 genes showing promising associations with breast cancer risk. We replicated the association for two genes, OGDHL and BRCA2, at a Bonferroni‐corrected p < 0.05, by genotyping an independent set of samples from 1,628 breast cancer cases and 1,943 controls. The association for OGDHL was primarily driven by three predicted deleterious variants (p.Val827Met, p.Pro839Leu, p.Phe836Ser; p < 0.01 for all). For BRCA2, we characterized a total of 27 disruptive variants, including 18 nonsense, six frameshift and three splicing variants, whereas they were only detected in cases, but none of the controls. All of these variants were either very rare (AF < 0.1%) or not detected in >4,500 East Asian women from the genome Aggregation database (gnomAD), providing additional support to our findings. Our study revealed a potential novel gene and multiple disruptive variants of BRCA2 for breast cancer risk, which may identify high‐risk women in Chinese populations.

show abstract

“…Oncogenic mutations reduce the enzyme activity of NADP+-dependent isocitrate dehydrogenases isoforms 1 and 2 (IDH1/2) resulting in increased 2-hydroxyglutarate levels and decreased concentrations of the OGDHC substrate 2-oxoglutarate [54, 55]. In a previous study, we showed that OGDHL , encoding one more component of the OGDHC, is down-regulated by promoter hypermethylation in CRC [56]. The promoter hypermethylation in OGDHL gene was also observed in breast, cervix, lung, oesophagus, and pancreas cancers [57, 58].…”

Section: Discussionmentioning

confidence: 99%

Differential expression of alternatively spliced transcripts related to energy metabolism in colorectal cancer

et al. 2016

View full text Add to dashboard Cite

BackgroundColorectal cancer (CRC) is one of the most common malignant tumors worldwide. CRC molecular pathogenesis is heterogeneous and may be followed by mutations in oncogenes and tumor suppressor genes, chromosomal and microsatellite instability, alternative splicing alterations, hypermethylation of CpG islands, oxidative stress, impairment of different signaling pathways and energy metabolism. In the present work, we have studied the alterations of alternative splicing patterns of genes related to energy metabolism in CRC.ResultsUsing CrossHub software, we analyzed The Cancer Genome Atlas (TCGA) RNA-Seq datasets derived from colon tumor and matched normal tissues. The expression of 1014 alternative mRNA isoforms involved in cell energy metabolism was examined. We found 7 genes with differentially expressed alternative transcripts whereas overall expression of these genes was not significantly altered in CRC. A set of 8 differentially expressed transcripts of interest has been validated by qPCR. These eight isoforms encoded by OGDH, COL6A3, ICAM1, PHPT1, PPP2R5D, SLC29A1, and TRIB3 genes were up-regulated in colorectal tumors, and this is in concordance with the bioinformatics data. The alternative transcript NM_057167 of COL6A3 was also strongly up-regulated in breast, lung, prostate, and kidney tumors. Alternative transcript of SLC29A1 (NM_001078177) was up-regulated only in CRC samples, but not in the other tested tumor types.ConclusionsWe identified tumor-specific expression of alternative spliced transcripts of seven genes involved in energy metabolism in CRC. Our results bring new knowledge on alternative splicing in colorectal cancer and suggest a set of mRNA isoforms that could be used for cancer diagnosis and development of treatment methods.Electronic supplementary materialThe online version of this article (doi:10.1186/s12864-016-3351-5) contains supplementary material, which is available to authorized users.

show abstract

Downregulation of OGDHL expression is associated with promoter hypermethylation in colorectal cancer

Cited by 37 publications

References 50 publications

Mutational load in carotid body tumor

Mutational load in carotid body tumor

Discovery of rare coding variants in OGDHL and BRCA2 in relation to breast cancer risk in Chinese women

Differential expression of alternatively spliced transcripts related to energy metabolism in colorectal cancer

Contact Info

Product

Resources

About