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Coding and noncoding drivers of mantle cell lymphoma identified through exome and genome sequencing.

ABSTRACT: Mantle cell lymphoma (MCL) is an uncommon B-cell non-Hodgkin lymphoma (NHL) that is incurable with standard therapies. The genetic drivers of this cancer have not been firmly established, and the features that contribute to differences in clinical course remain limited. To extend our understanding of the biological pathways involved in this malignancy, we performed a large-scale genomic analysis of MCL using data from 51 exomes and 34 genomes alongside previously published exome cohorts. To confirm our findings, we resequenced the genes identified in the exome cohort in 191 MCL tumors, each having clinical follow-up data. We confirmed the prognostic association of TP53 and NOTCH1 mutations. Our sequencing revealed novel recurrent noncoding mutations surrounding a single exon of the HNRNPH1gene. In RNA-seq data from 103 of these cases, MCL tumors with these mutations had a distinct imbalance of HNRNPH1 isoforms. This altered splicing of HNRNPH1 was associated with inferior outcomes in MCL and showed a significant increase in protein expression by immunohistochemistry. We describe a functional role for these recurrent noncoding mutations in disrupting an autoregulatory feedback mechanism, thereby deregulating HNRNPH1 protein expression. Taken together, these data strongly imply a role for aberrant regulation of messenger RNA processing in MCL pathobiology.

SUBMITTER: Pararajalingam P

PROVIDER: S-EPMC7440974 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Coding and non-coding drivers of mantle cell lymphoma identified through exome and genome sequencing

Project description:Mantle cell lymphoma (MCL) is an uncommon B-cell non-Hodgkin lymphoma (NHL) that is incurable with standard therapies. The genetic drivers of this cancer have not been firmly established and the features that contribute to differences in clinical course remain limited. To extend our understanding of the biological pathways involved in this malignancy, we performed a large-scale genomic analysis of MCL using data from 51 exomes and 34 genomes alongside previously published exome cohorts. To confirm our findings, we re-sequenced the genes identified in the exome cohort in 191 MCL tumors, each having clinical follow-up data. We confirmed the prognostic association of TP53 and NOTCH1 mutations. Our sequencing revealed novel recurrent non-coding mutations surrounding a single exon of the HNRNPH1 gene. In RNA-seq data from 103 of these cases, MCL tumors with these mutations had a distinct imbalance of HNRNPH1 isoforms. This altered splicing of HNRNPH1 was associated with inferior outcomes in MCL and showed a significant increase in protein expression by immunohistochemistry. We describe a functional role for these recurrent non-coding mutations in disrupting an auto-regulatory feedback mechanism, thereby deregulating HNRNPH1 protein expression. Taken together, these data strongly implicate a role for aberrant regulation of mRNA processing in MCL pathobiology.

| EGAS00001004289 | EGA

Whole exome sequencing identified sixty-five coding mutations in four neuroblastoma tumors.

Project description:Neuroblastoma is a pediatric tumor characterized by histologic heterogeneity, and accounts for ~15% of childhood deaths from cancer. The five-year survival for patients with high-risk stage 4 disease has not improved in two decades. We used whole exome sequencing (WES) to identify mutations present in three independent high-risk stage 4 neuroblastoma tumors (COA/UAB-3, COA/UAB -6 and COA/UAB -8) and a stage 3 tumor (COA/UAB-14). Among the four tumors WES analysis identified forty-three mutations that had not been reported previously, one of which was present in two of the four tumors. WES analysis also corroborated twenty-two mutations that were reported previously. No single mutation occurred in all four tumors or in all stage 4 tumors. Three of the four tumors harbored genes with CADD scores??20, indicative of mutations associated with human pathologies. The average depth of coverage ranged from 39.68 to 90.27, with?>99% sequences mapping to the genome. In summary, WES identified sixty-five coding mutations including forty-three mutations not reported previously in primary neuroblastoma tumors. The three stage 4 tumors contained mutations in genes encoding protein products that regulate immune function or cell adhesion and tumor cell metastasis.

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Germline Variants Associated with Nasopharyngeal Carcinoma Predisposition Identified through Whole-Exome Sequencing.

Project description:The current understanding of genetic susceptibility factors for nasopharyngeal carcinoma (NPC) is still incomplete. To identify novel germline variants associated with NPC predisposition, we analysed whole-exome sequencing data from 119 NPC patients from Singapore with a family history of NPC and/or with early-onset NPC, together with 1337 Singaporean participants without NPC. Variants were prioritised and filtered by selecting variants with minor allele frequencies of <1% in both local control (n = 1337) and gnomAD non-cancer (EAS) (n = 9626) cohorts and a high pathogenicity prediction (CADD score > 20). Using single-variant testing, we identified 17 rare pathogenic variants in 17 genes that were associated with NPC. Consistent evidence of enrichment in NPC patients was observed for five of these variants (in JAK2, PRDM16, LRP1B, NIN, and NKX2-1) from an independent case-control comparison of 156 NPC patients and 9770 unaffected individuals. In a family with five siblings, a FANCE variant (p. P445S) was detected in two affected members, but not in three unaffected members. Gene-based burden testing recapitulated variants in NKX2-1 and FANCE as being associated with NPC risk. Using pathway analysis, endocytosis and immune-modulating pathways were found to be enriched for mutation burden. This study has identified NPC-predisposing variants and genes which could shed new insights into the genetic predisposition of NPC.

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Burden Testing of Rare Variants Identified through Exome Sequencing via Publicly Available Control Data.

Project description:The genetic causes of many Mendelian disorders remain undefined. Factors such as lack of large multiplex families, locus heterogeneity, and incomplete penetrance hamper these efforts for many disorders. Previous work suggests that gene-based burden testing-where the aggregate burden of rare, protein-altering variants in each gene is compared between case and control subjects-might overcome some of these limitations. The increasing availability of large-scale public sequencing databases such as Genome Aggregation Database (gnomAD) can enable burden testing using these databases as controls, obviating the need for additional control sequencing for each study. However, there exist various challenges with using public databases as controls, including lack of individual-level data, differences in ancestry, and differences in sequencing platforms and data processing. To illustrate the approach of using public data as controls, we analyzed whole-exome sequencing data from 393 individuals with idiopathic hypogonadotropic hypogonadism (IHH), a rare disorder with significant locus heterogeneity and incomplete penetrance against control subjects from gnomAD (n = 123,136). We leveraged presumably benign synonymous variants to calibrate our approach. Through iterative analyses, we systematically addressed and overcame various sources of artifact that can arise when using public control data. In particular, we introduce an approach for highly adaptable variant quality filtering that leads to well-calibrated results. Our approach "re-discovered" genes previously implicated in IHH (FGFR1, TACR3, GNRHR). Furthermore, we identified a significant burden in TYRO3, a gene implicated in hypogonadotropic hypogonadism in mice. Finally, we developed a user-friendly software package TRAPD (Test Rare vAriants with Public Data) for performing gene-based burden testing against public databases.

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Novel Non-coding RNA Analysis in Multiple Myeloma Identified Through High-Throughput Sequencing.

Project description:This study aimed to explore the potential effects of novel non-coding ribose nucleic acids (ncRNAs) in patients with multiple myeloma (MM). The gene expression profile of plasma cells was used for sequence analysis to explore the expression pattern of ncRNAs in MM. The expression patterns of non-coding RNAs in MM were analyzed by RNA sequencing (whole-transcriptome-specific RNA sequencing). Next, the expression of the selected ncRNAs was verified by quantitative real-time polymerase chain reaction. Further, the lncRNA-associated competitive endogenous RNA network in MM was elucidated using deep RNA-seq. Differentially expressed (DE) ncRNAs were significantly regulated in patients with MM. DE target lncRNAs were analyzed by cis and trans targeting prediction. Two new lncRNAs were shown to be related to MM oncogenes. MSTRG.155519 played a carcinogenic role in myeloma by targeting CEACAM1; MSTRG.13132 was related to FAM46C. Finally, the network of lncRNA-mRNA-miRNA in MM was constructed in this study. The expression of non-coding RNAs through sequence and functional analyses might be helpful for further studies on the pathogenesis of MM and the development of new MM-targeted therapy for non-coding RNAs.

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Genome-wide discovery of somatic coding and noncoding mutations in pediatric endemic and sporadic Burkitt lymphoma.

Project description:Although generally curable with intensive chemotherapy in resource-rich settings, Burkitt lymphoma (BL) remains a deadly disease in older patients and in sub-Saharan Africa. Epstein-Barr virus (EBV) positivity is a feature in more than 90% of cases in malaria-endemic regions, and up to 30% elsewhere. However, the molecular features of BL have not been comprehensively evaluated when taking into account tumor EBV status or geographic origin. Through an integrative analysis of whole-genome and transcriptome data, we show a striking genome-wide increase in aberrant somatic hypermutation in EBV-positive tumors, supporting a link between EBV and activation-induced cytidine deaminase (AICDA) activity. In addition to identifying novel candidate BL genes such as SIN3A, USP7, and CHD8, we demonstrate that EBV-positive tumors had significantly fewer driver mutations, especially among genes with roles in apoptosis. We also found immunoglobulin variable region genes that were disproportionally used to encode clonal B-cell receptors (BCRs) in the tumors. These include IGHV4-34, known to produce autoreactive antibodies, and IGKV3-20, a feature described in other B-cell malignancies but not yet in BL. Our results suggest that tumor EBV status defines a specific BL phenotype irrespective of geographic origin, with particular molecular properties and distinct pathogenic mechanisms. The novel mutation patterns identified here imply rational use of DNA-damaging chemotherapy in some patients with BL and targeted agents such as the CDK4/6 inhibitor palbociclib in others, whereas the importance of BCR signaling in BL strengthens the potential benefit of inhibitors for PI3K, Syk, and Src family kinases among these patients.

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Analysis of the coding exome of follicular lymphoma

Project description:Follicular lymphoma (FL) constitutes the second most common non-Hodgkin lymphoma in the Western world. FL carries characteristic recurrent structural genomic aberrations. However, information regarding the coding genome in FL is still evolving. Here, we describe the results of massively parallel exome sequencing and high-resolution SNP 6.0 array profiling of 12 highly purified FL cases and validation of mutations in an expansion cohort of 45 cases. In addition to confirming high-frequency mutations in MLL2, CREBBP and BCL2, we report identification of 18 recurrently mutated genes in FL. These include novel mutations in MCL1, IRF8 and POU2FA/OCT2, and high-frequency mutations in various components of the linker histone HIST1H1. Further, multiple novel mutated genes located within regions of acquired uniparental disomy (aUPD) are identified, providing candidate genes for this common lesion type in FL. In aggregate, these data substantially broaden our understanding of the types and frequency of recurrently mutated genes and pathways in FL

2014-01-17 | GSE50973 | GEO

Comparison of Exome and Genome Sequencing Technologies for the Complete Capture of Protein-Coding Regions.

Project description:For next-generation sequencing technologies, sufficient base-pair coverage is the foremost requirement for the reliable detection of genomic variants. We investigated whether whole-genome sequencing (WGS) platforms offer improved coverage of coding regions compared with whole-exome sequencing (WES) platforms, and compared single-base coverage for a large set of exome and genome samples. We find that WES platforms have improved considerably in the last years, but at comparable sequencing depth, WGS outperforms WES in terms of covered coding regions. At higher sequencing depth (95x-160x), WES successfully captures 95% of the coding regions with a minimal coverage of 20x, compared with 98% for WGS at 87-fold coverage. Three different assessments of sequence coverage bias showed consistent biases for WES but not for WGS. We found no clear differences for the technologies concerning their ability to achieve complete coverage of 2,759 clinically relevant genes. We show that WES performs comparable to WGS in terms of covered bases if sequenced at two to three times higher coverage. This does, however, go at the cost of substantially more sequencing biases in WES approaches. Our findings will guide laboratories to make an informed decision on which sequencing platform and coverage to choose.

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Rare coding mutations identified by sequencing of Alzheimer disease genome-wide association studies loci.

Project description:ObjectiveTo detect rare coding variants underlying loci detected by genome-wide association studies (GWAS) of late onset Alzheimer disease (LOAD).MethodsWe conducted targeted sequencing of ABCA7, BIN1, CD2AP, CLU, CR1, EPHA1, MS4A4A/MS4A6A, and PICALM in 3 independent LOAD cohorts: 176 patients from 124 Caribbean Hispanics families, 120 patients and 33 unaffected individuals from the 129 National Institute on Aging LOAD Family Study; and 263 unrelated Canadian individuals of European ancestry (210 sporadic patients and 53 controls). Rare coding variants found in at least 2 data sets were genotyped in independent groups of ancestry-matched controls. Additionally, the Exome Aggregation Consortium was used as a reference data set for population-based allele frequencies.ResultsOverall we detected a statistically significant 3.1-fold enrichment of the nonsynonymous mutations in the Caucasian LOAD cases compared with controls (p = 0.002) and no difference in synonymous variants. A stop-gain mutation in ABCA7 (E1679X) and missense mutation in CD2AP (K633R) were highly significant in Caucasian LOAD cases, and mutations in EPHA1 (P460L) and BIN1 (K358R) were significant in Caribbean Hispanic families with LOAD. The EPHA1 variant segregated completely in an extended Caribbean Hispanic family and was also nominally significant in the Caucasians. Additionally, BIN1 (K358R) segregated in 2 of the 6 Caribbean Hispanic families where the mutations were discovered.InterpretationTargeted sequencing of confirmed GWAS loci revealed an excess burden of deleterious coding mutations in LOAD, with the greatest burden observed in ABCA7 and BIN1. Identifying coding variants in LOAD will facilitate the creation of tractable models for investigation of disease-related mechanisms and potential therapies.

| S-EPMC4546546 | biostudies-literature

Molecular characterization of PRKN structural variations identified through whole-genome sequencing.

Project description:BackgroundEarly-onset Parkinson's disease (PD) is the most common inherited form of parkinsonism, with the PRKN gene being the most frequently identified mutated. Exon rearrangements, identified in about 43.2% of the reported PD patients and with higher frequency in specific ethnicities, are the most prevalent PRKN mutations reported to date in PD patients.MethodsIn this study, three consanguineous families with early-onset PD were subjected to whole-genome sequencing (WGS) analyses that were followed by Sanger sequencing and droplet digital PCR to validate and confirm the disease segregation of the identified genomic variations and to determine their parental origin.ResultsFive different PRKN structural variations (SVs) were identified. Because the genomic sequences surrounding the break points of the identified SVs might hold important information about their genesis, these were also characterized for the presence of homology and repeated sequences.ConclusionWe concluded that all identified PRKN SVs might originate through retrotransposition events.

| S-EPMC6305656 | biostudies-literature

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