scholarly journals Pan-Cancer Analysis Reveals Differential Susceptibility of Bidirectional Gene Promoters to DNA Methylation, Somatic Mutations, and Copy Number Alterations

2018 ◽  
Vol 19 (8) ◽  
pp. 2296 ◽  
Author(s):  
Jeffrey Thompson ◽  
Brock Christensen ◽  
Carmen Marsit
Keyword(s):  
Dna Methylation ◽  
Logistic Regression ◽  
Somatic Mutation ◽  
Copy Number ◽  
Copy Number Alteration ◽  
Somatic Mutations ◽  
Gene Promoters ◽  
Bidirectional Promoters ◽  
Somatic Alteration ◽  
Cancer Types

Bidirectional gene promoters affect the transcription of two genes, leading to the hypothesis that they should exhibit protection against genetic or epigenetic changes in cancer. Therefore, they provide an excellent opportunity to learn about promoter susceptibility to somatic alteration in tumors. We tested this hypothesis using data from genome-scale DNA methylation (14 cancer types), simple somatic mutation (10 cancer types), and copy number variation profiling (14 cancer types). For DNA methylation, the difference in rank differential methylation between tumor and tumor-adjacent normal matched samples based on promoter type was tested by the Wilcoxon rank sum test. Logistic regression was used to compare differences in simple somatic mutations. For copy number alteration, a mixed effects logistic regression model was used. The change in methylation between non-diseased tissues and their tumor counterparts was significantly greater in single compared to bidirectional promoters across all 14 cancer types examined. Similarly, the extent of copy number alteration was greater in single gene compared to bidirectional promoters for all 14 cancer types. Furthermore, among 10 cancer types with available simple somatic mutation data, bidirectional promoters were slightly more susceptible. These results suggest that selective pressures related with specific functional impacts during carcinogenesis drive the susceptibility of promoter regions to somatic alteration.

scholarly journals Pan-Cancer Analysis Reveals Differential Susceptibility of Bidirectional Gene Promoters to DNA Methylation, Somatic Mutations, and Copy Number Alterations

2018 ◽  
Author(s):  
Jeffrey A. Thompson ◽  
Brock C. Christensen ◽  
Carmen J. Marsit
Keyword(s):  
Dna Methylation ◽  
Logistic Regression ◽  
Somatic Mutation ◽  
Copy Number ◽  
Copy Number Alteration ◽  
Somatic Mutations ◽  
Gene Promoters ◽  
Bidirectional Promoters ◽  
Somatic Alteration ◽  
Cancer Types

Bidirectional gene promoters affect the transcription of two genes, leading to the hypothesis that they should exhibit protection against genetic or epigenetic changes in cancer. Therefore, they provide an excellent opportunity to learn about promoter susceptibility to somatic alteration in tumors. We tested this hypothesis using data from genome-scale DNA methylation (14 cancer types), simple somatic mutation (10 cancer types), and copy number variation profiling (14 cancer types). For DNA methylation, the difference in rank differential methylation between tumor and tumor-adjacent normal matched samples based on promoter type was tested by Wilcoxon rank sum test. Logistic regression was used to compare differences in simple somatic mutations. For copy number alteration, a mixed effects logistic regression model was used. The change in methylation between non-diseased tissues and their tumor counterparts was significantly greater in single compared to bidirectional promoters across all 14 cancer types examined. Similarly, the extent of copy number alteration was greater in single gene compared to bidirectional promoters for all 14 cancer types. Furthermore, among 10 cancer types with available simple somatic mutation data, bidirectional promoters were slightly more susceptible. These results suggest that selective pressures related with specific functional impacts during carcinogenesis drive the susceptibility of promoter regions to somatic alteration.

Novel Germline Genetic Variants Associated with Familial Chronic Lymphocytic Leukemia (CLL)

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 465-465
Author(s):  
Jennifer R Brown ◽  
Michael S Lawrence ◽  
Megan Hanna ◽  
Bethany Tesar ◽  
Petar Stojanov ◽  
...  
Keyword(s):  
Tumor Suppressor ◽  
Somatic Mutation ◽  
Cell Biology ◽  
Copy Number ◽  
Somatic Mutations ◽  
Risk Allele ◽  
Conflicts Of Interest ◽  
Similar Distribution ◽  
Mirna Cluster ◽  
Depth Analysis

Abstract Abstract 465 CLL is among the most heritable of all cancers. To understand the genetic basis of this heritability, we have undertaken a comprehensive genomic analysis of familial CLLs including copy number analysis, gene expression profiling (GEP) and whole exome sequencing (WES). First, we examined whether familial and sporadic cases differ in the spectrum of acquired somatic mutations by WES of tumor and germline DNA of 36 familial CLLs (from 31 affected families). Compared to 55 sporadic CLLs, we observed that the somatic mutation rate in the familial CLLs was similar (mean 0.89 mutations/Mb (range 0.29–3.06) for the sporadics vs mean 0.97/Mb (range 0.11–3.78) for the familials, p=0.40). We also examined the spectrum of somatic mutations by testing for enrichment of 9 recently identified putative tumor drivers in our large CLL sequencing study (reported elsewhere in this meeting). We observed a similar distribution of these recurrent CLL mutations among the 36 familial CLLs as the 55 sporadic CLLs. These results were further confirmed by genotyping of the CLL driver mutations in an additional 32 familial and 67 sporadic CLLs. Collectively, these studies suggest that while the predisposing germline events may differ between familial and sporadic CLL, the spectrum of mutations and pattern of mutagenesis appear similar in the established CLL tumors. We therefore proceeded to examine the genetic characterization of germline DNA to identify predisposing loci, which we hypothesized might be enriched in a familial disease context. We first examined germline copy number variations (CNVs), which have not been previously characterized in this disease. We used high resolution Affymetrix 6.0 SNP arrays to study both tumor and germline DNA of 58 individuals representing 44 different families with CLL and lymphoproliferative disorders (LPDs). We identified two families (A and B) with autosomal dominant inheritance of CLL who carried distinct germline CNVs that affect genes previously implicated in CLL. Members of Family A carried a 525 kb germline deletion targeting DLEU7 at 13q14, but not affecting DLEU2, miR-15a, or miR-16–1. Importantly, by examining the tumor genome from these family members, we observed a uniform loss of the second allele of DLEU7 in 2/2 available CLLs from this family, suggesting an acquired “second hit” of a tumor suppressor gene. These findings underline the complexity of the most common somatically acquired copy number aberration (CNA) in CLL, 13q14 deletion, by demonstrating the role of additional regions other than the heavily investigated miRNA cluster. Members of Family B carried a 720 kb germline gain of 6p25 affecting the IRF4 gene, previously implicated in CLL through the identification of a GWAS risk allele located in the 3' UTR of IRF4, as well as the recent description of a recurrent somatic mutation affecting 1.5% of CLL cases. In Family B, the coding regions of the four genes located in this 6p gain, namely IRF4, DUSP22, EXOC2 and HUS1B, were sequenced, and no somatic mutations or novel SNPs were identified. However, the 6p gain in Family B represents an allele-specific enrichment of the haplotype carrying the GWAS risk SNP and, as previously described for that allele, results in lower expression of IRF4 in the two CLLs tested in this family. GEP further identified a signature associated with 6p gain that preserved low expression of IRF4 and showed high expression of KLF6. These results demonstrate that germline CNVs may facilitate the “path to cancer” by providing either an allelic deletion of a tumor suppressor or an amplification of a risk allele. As most familial CLL cases have not been accounted for by known SNPs or germline CNVs, we have initiated an in depth analysis of the WES germline results from familial cases compared to both sporadic CLL patients and normal individuals. Candidate variants have been filtered to exclude all SNPs described in the 1000 Genomes project and to focus on highly conserved sites. Thus far we have found that rare germline variants in patients with familial CLL contain a rich source of loci with relevance to B cell biology. Studies in progress are focused on further analysis of informative families and functional analyses of candidate variants. These comprehensive genomic analyses are expected to identify multiple cooperating genetic mechanisms that contribute to CLL pathogenesis, including CNVs and somatic and germline mutations. Disclosures: No relevant conflicts of interest to declare.

scholarly journals Pan-cancer analysis of RNA binding proteins (RBPs) reveals the involvement of the core pre-mRNA splicing and translation machinery in tumorigenesis

2018 ◽  
Author(s):  
Bin Zhang ◽  
Kamesh R. Babu ◽  
Chun You Lim ◽  
Zhi Hao Kwok ◽  
Jia Li ◽  
...  
Keyword(s):  
Dna Methylation ◽  
Copy Number ◽  
Rna Binding ◽  
Rna Binding Proteins ◽  
Human Cancer ◽  
Mrna Splicing ◽  
Regulatory Mechanisms ◽  
Translation Machinery ◽  
The Core ◽  
Cancer Types

AbstractRNA binding proteins (RBPs) are key regulators of posttranscriptional processes such as RNA maturation, transport, localization, turnover and translation. Despite their dysregulation in various diseases including cancer, the landscape of RBP expression and regulatory mechanisms in human cancer has not been well characterized. Here, we analyzed mRNA expression of 1487 RBPs in ~6700 clinical samples across 16 human cancer types and found that there were significantly more upregulated RBPs than downregulated ones in tumors when compared to their adjacent normal tissues. Across almost all of the 16 cancer types, 109 RBPs were consistently upregulated (cuRBPs) while only 41 RBPs were consistently downregulated (cdRBPs). Integrating expression with the copy number and DNA methylation data, we found that the overexpression of cuRBPs is largely associated with the amplification of copy number, whereas the downregulation of cdRBPs may be a result of epigenetic silencing mediated by DNA methylation. Furthermore, our results indicated that cuRBPs could work together to promote cancer progression potentially through the involvement of splicing and translation machinery, while cdRBPs might function independently to suppress tumorigenesis. Additionally, we focused on colon cancer and identified several novel potential oncogenic RBPs, such as PABPC1L which might promote cancer development via regulating the core splicing machinery. In summary, we showed distinct expression landscapes, regulatory mechanisms and characteristics of cuRBPs and cdRBPs and implicated several novel RBPs in cancer pathogenesis. Moreover, our results suggest that the involvement of the core pre-mRNA splicing and translation machinery could be critical in tumorigenesis.

scholarly journals Clinical Implications of Copy Number Alteration Detection Using Panel-Based Next-Generation Sequencing Data in Myelodysplastic Syndrome

2020 ◽  
Author(s):  
Yoo-Jin Kim ◽  
SeungHyun Jung ◽  
Eun-Hye Hur ◽  
Eun-Ji Choi ◽  
Kyoo-Hyung Lee ◽  
...  
Keyword(s):  
Next Generation Sequencing ◽  
Myelodysplastic Syndrome ◽  
Somatic Mutation ◽  
Copy Number ◽  
Somatic Mutations ◽  
Clinical Implications ◽  
Next Generation ◽  
Clinical Variables ◽  
Ngs Data ◽  
Generation Sequencing

Abstract Background: Recent advancements in next-generation sequencing (NGS) technologies allow the simultaneous identification of targeted copy number alterations (CNAs) as well as somatic mutations using the same panel-based NGS data. We investigated whether CNAs detected by the targeted NGS data provided additional clinical implications, over somatic mutations, in myelodysplastic syndrome (MDS). Methods: Targeted deep sequencing of 28 well-known MDS-related genes was performed for 266 patients with MDS. Results: Overall, 215 (80.8%) patients were found to have at least one somatic mutation; 67 (25.2%) had at least one CNA; 227 (85.3%) had either a somatic mutation or CNA; 160 had somatic mutations without CNA; and 12 had CNA without somatic mutations. Considering the clinical variables and somatic mutations alone, multivariate analysis demonstrated that sex, revised International Prognostic Scoring System (IPSS-R) and NRAS and TP53 mutations were independent prognostic factors for overall survival. For AML-free survival, these factors were sex, IPSS-R, and mutations in NRAS, DNMT3A, and complex karyotype/TP53 mutations. When we consider clinical variables along with somatic mutations and CNAs, genetic alterations in TET2, LAMB4, U2AF1, and CBL showed additional significant impact on the survivals. Conclusions: Our study suggests that the concurrent detection of somatic mutations and targeted CNAs may provide clinically useful information for the prognosis of MDS patients.

Comprehensive Genetic Characterization of 17p Deleted CLL Identifies Predictors of Overall Survival

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 2907-2907
Author(s):  
Lijian Yu ◽  
Haesook T. Kim ◽  
Siddha Kasar ◽  
Parul Benien ◽  
Wei Du ◽  
...  
Keyword(s):  
Overall Survival ◽  
Somatic Mutation ◽  
Copy Number ◽  
Somatic Mutations ◽  
Snp Array ◽  
Genetic Profile ◽  
Complex Karyotype ◽  
Tp53 Mutations ◽  
Total Length ◽  
Treatment Naïve

Abstract Many studies have shown that deletion at chromosome 17p targeting the TP53 gene, or del(17p), is associated with poor prognosis in chronic lymphocytic leukemia (CLL). Despite this, not all del(17p) CLL progresses rapidly to treatment and has short survival. We hypothesized that other coexisting genetic aberrations may contribute to the poor clinical outcome and heterogeneity of del(17p) cases. To assess this, we analyzed copy number alterations (CNAs) using Affymetrix SNP array data from 200 CLL patients (55 with del(17p)), and somatic mutation profile by whole exome sequencing (WES; Illumina) in 168 patients (53 with del(17p)). Ninety-nine patients were studied with both SNP arrays and WES, 39 of whom had del(17p). Analysis of copy number showed that del(17p) CLL had a median of 11 CNA events, mostly copy number losses, compared to 2 events in WT CLL (p=1.1E-12). Both the number of CNA events (p=7.9E-10) and the total length of copy number gain (p=1.6E-4) or loss (p=1.3E-8) were associated with shorter overall survival (OS), even when controlling for co-existing del(17p). Using GISTIC analysis, we discovered three significantly deleted regions specific to del(17p), namely large chromosomal deletions at 3p, 4p, and 9p. These novel recurrent deletions were rarely seen in wild type CLL and the presence of any of these deletions with del(17p) was strongly associated with shorter OS compared to del(17p) alone. We were able to evaluate complex karyotype (CKT) determined by stimulated metaphase cytogenetics in a subset of the cohort, and found that 17/27 (63%) evaluable del(17p) CLLs had CKT, while only 13/58 (22%) WT CLLs did (p=0.0005). Analysis of OS showed that del(17p) and CKT together had worse OS than either individually, although individually they each conferred OS worse than WT (p<0.0001). Next we tested whether the number and size of CNAs predicts progression to treatment in 138 patients who were treatment naïve at sampling (n=23 for del(17p)), 65 of whom progressed to treatment after sampling (n=16 for del(17p)). We found that increasing number of CNA events (p=9E-6), total length of losses (p=4E-4), and total length of gains (p=2E-4) were all predictive of need for future treatment in WT as well as del(17p) CLL. Those treatment naive del(17p) patients who remained untreated had a median of 4 CNAs (n=7), compared to 12.5 for those who went on to treatment (p=0.013). Turning our attention to somatic mutation analysis, del(17p) CLLs had higher numbers of total somatic mutations (21 vs 18, p=0.0046), and nonsynonymous mutations (16 vs 13, p=0.0059) than WT CLL, with no difference in subclonal mutations (12 vs 10, p=0.34). Increasing number of total mutations (p=0.0017) and nonsynonymous mutations (p=0.0003) were both associated with shorter OS, even when controlling for 17p deletion. No significant correlation was observed between number of CNAs and number of somatic mutations in a given CLL, suggesting different mechanisms involved in their causation. In the del(17p) CLLs, as expected, TP53 was the most commonly mutated gene, seen in 43/53 (81%) patients. Interestingly, most TP53 mutations (78%) were clonal, suggesting they occurred early in CLL development, while SF3b1 assessed for comparison was most commonly subclonal (68%). Patients with subclonal TP53 mutations had longer OS than patients with clonal TP53 mutations (p=0.041). We also explored the outcome of patients with loss of both TP53 alleles via 17p deletion and TP53 mutation. We found that biallelic loss was associated with more CNAs (median = 15 vs 9) and longer total length of CNAs than monoallelic loss. Patients with biallelic loss of TP53 showed a trend towards worse OS than the limited cohort with monoallelic loss (p=0.07). In addition to TP53 and other previously reported CLL drivers such as NOTCH1 (n=8, q=8E-5) and DDX3X (n=4, q=0.03), we report RPS15 (n=6, q=6E-5) and GPS2 (n=3, q=0.03) as novel significantly mutated genes in del(17p) CLL but not in WT CLL. All RPS15 mutations were clustered in a 15-amino acid region in the far carboxyl terminus of the gene, suggesting conserved functions. RNA sequencing (n=2) confirmed that the mutant alleles of RPS15 were expressed in the CLLs. We conclude that the genetic profile of del(17p) CLL differs significantly from WT CLL and show that worse OS in del(17p) CLL is associated with complex karyotype and biallelic inactivation of TP53 as well as increasing number of somatic mutations and novel CNAs. Disclosures No relevant conflicts of interest to declare.

Development of a breast and lung cancer research panel to target therapeutically relevant copy number and gene fusion variants from blood.

2017 ◽  
Vol 35 (15_suppl) ◽  
pp. e12518-e12518
Author(s):  
Varun Bagai ◽  
Jeoffrey Schageman ◽  
Dumitru Brinza ◽  
Yanchun Li ◽  
Jian Gu ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Somatic Mutation ◽  
Copy Number ◽  
Gene Fusion ◽  
Somatic Mutations ◽  
Limit Of Detection ◽  
Negative Impact ◽  
Detection Sensitivity ◽  
Gene Fusions ◽  
Blood Samples

e12518 Background: With recent advances in next-generation sequencing (NGS) technologies, it is now possible to detect somatic mutations with allele frequencies in blood samples as low as 0.1% from circulating tumor DNA. A natural extension to this achievement is adding the ability to simultaneously detect copy number variants and gene fusions. A panel such as this addresses a full repertoire of variant classes found to be linked with certain tumors and would enable researchers additional tools to profile cancer samples more dynamically thus enriching current diagnostic tool sets. Here, we present progress on such an approach and apply current NGS technology to achieve our goals. Methods: Samples were sequecned using the Ion S5™ system. Results: Using control samples, we can reproducibly demonstrate detection of ERBB2 (HER2/neu) gene amplifications with high statistical significance and as low as a 2 fold difference versus non-amplified loci in titration experiments. In addition, this ERBB2 gene amplification was detected in the context of a validated breast cancer somatic mutation panel in which no negative impact was exhibited and mutation detection specificity and sensitivity were both greater than 90%. Lastly, we developed an additional panel to detect gene fusions relevant to lung cancer. Using the titration approach above, the EML4-ALK fusion variant was shown to have a limit of detection near 1% with no negative impact on detection sensitivity and specificity when combined with the validated lung cfDNA somatic mutation panel. Conclusions: From the outcomes of these experiments, we have shown the ability to reproducibly and simultaneously detect copy number and gene fusion variants as well as somatic mutations at very low limits of detection in a cell free DNA background derived from blood samples.

scholarly journals MutEx: a multifaceted gateway for exploring integrative pan-cancer genomic data

2019 ◽  
Vol 21 (4) ◽  
pp. 1479-1486 ◽  
Author(s):  
Jie Ping ◽  
Olufunmilola Oyebamiji ◽  
Hui Yu ◽  
Scott Ness ◽  
Jeremy Chien ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Gene Expression ◽  
Somatic Mutation ◽  
Survival Data ◽  
Somatic Mutations ◽  
Genomic Data ◽  
Mismatch Repair Gene ◽  
Survival Difference ◽  
Cancer Types ◽  
Pan Cancer

Abstract Somatic mutation and gene expression dysregulation are considered two major tumorigenesis factors. While independent investigations of either factor pervade, studies of associations between somatic mutations and gene expression changes have been sporadic and nonsystematic. Utilizing genomic data collected from 11 315 subjects of 33 distinct cancer types, we constructed MutEx, a pan-cancer integrative genomic database. This database records the relationships among gene expression, somatic mutation and survival data for cancer patients. MutEx can be used to swiftly explore the relationship between these genomic/clinic features within and across cancer types and, more importantly, search for corroborating evidence for hypothesis inception. Our database also incorporated Gene Ontology and several pathway databases to enhance functional annotation, and elastic net and a gene expression composite score to aid in survival analysis. To demonstrate the usability of MutEx, we provide several application examples, including top somatic mutations associated with the most extensive expression dysregulation in breast cancer, differential mutational burden downstream of DNA mismatch repair gene mutations and composite gene expression score-based survival difference in breast cancer. MutEx can be accessed at http://www.innovebioinfo.com/Databases/Mutationdb_About.php.

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