scholarly journals Profiling diverse sequence tandem repeats in colorectal cancer reveals co-occurrence of microsatellite and chromosomal instability involving Chromosome 8

2020 ◽  
Author(s):  
GiWon Shin ◽  
Stephanie U. Greer ◽  
Erik Hopmans ◽  
Susan M. Grimes ◽  
HoJoon Lee ◽  
...  
Keyword(s):  
Mismatch Repair ◽  
Genomic Instability ◽  
Copy Number ◽  
Chromosomal Instability ◽  
Tandem Repeats ◽  
Chromosome 8 ◽  
Molecular Testing ◽  
Cancer Genes ◽  
Copy Number Alterations ◽  
High Coverage

ABSTRACTColorectal carcinomas (CRCs) which have lost DNA mismatch repair display hypermutability evident in a molecular phenotype called microsatellite instability (MSI). These mismatch repair deficient tumors are thought to lack widespread genomic instability features, such as copy number changes and rearrangements. To identify MSI for clinical diagnosis, current molecular testing looks for changes in mononucleotide or dinucleotide repeats. However, microsatellites have other types of sequence tandem repeats such as tri- and tetranucleotide motifs. These additional classes of microsatellites are generally not examined for MSI but are known to be unstable in a phenotype known as elevated microsatellite alterations at selected tetranucleotide repeats, or EMAST. We developed a sequencing approach that provides ultra-high coverage (>2500X) of microsatellite targets and cancer genes for profiling genomic instability. We assessed the diverse repeat motifs across 200 microsatellites. Our approach provides highly sensitive detection of MSI with high specificity, evaluates copy number alterations with high accuracy, delineates chromosomal instability (CIN) classification and deconvolutes subclonal architecture. By examining both MSI and CIN, we discovered mutations and copy number alterations that defined mixed genomic instability states of CIN and MSI, which are normally considered exclusive. An increase in copy number of chromosome arm 8q was prevalent among MSI tumors. Moreover, we identified an inter-chromosomal translocation event from a CRC with co-occurrence of MSI. Subclonal analysis demonstrated that mutations which are typically considered to be exclusive in MSI, shows mutual occurrence in MSI tumors with more sensitive characterization. Our approach revealed that MSH3 mutations are a potential source of mixed genomic instability features. Overall, our study demonstrates that some colorectal cancers have features of both microsatellite and chromosomal instability. This result may have implications for immunotherapy treatment.

scholarly journals Profiling diverse sequence tandem repeats in colorectal cancer reveals co-occurrence of microsatellite and chromosomal instability involving Chromosome 8

2021 ◽  
Vol 13 (1) ◽  
Author(s):  
GiWon Shin ◽  
Stephanie U. Greer ◽  
Erik Hopmans ◽  
Susan M. Grimes ◽  
HoJoon Lee ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Microsatellite Instability ◽  
Copy Number ◽  
Chromosomal Instability ◽  
Tandem Repeats ◽  
Chromosome 8 ◽  
Driver Mutations ◽  
Colorectal Carcinomas ◽  
Mixed States ◽  
Chromosome Arm

AbstractWe developed a sensitive sequencing approach that simultaneously profiles microsatellite instability, chromosomal instability, and subclonal structure in cancer. We assessed diverse repeat motifs across 225 microsatellites on colorectal carcinomas. Our study identified elevated alterations at both selected tetranucleotide and conventional mononucleotide repeats. Many colorectal carcinomas had a mix of genomic instability states that are normally considered exclusive. An MSH3 mutation may have contributed to the mixed states. Increased copy number of chromosome arm 8q was most prevalent among tumors with microsatellite instability, including a case of translocation involving 8q. Subclonal analysis identified co-occurring driver mutations previously known to be exclusive.

Abstract 1304: Whole-exome analysis of 1,135 melanomas reveals new significantly mutated cancer genes and copy number alterations

2018 ◽  
Author(s):  
Jake R. Conway ◽  
David Liu ◽  
Stephanie Wankowicz ◽  
Amaro Taylor-Weiner ◽  
Felix Dietlein ◽  
...  
Keyword(s):  
Copy Number ◽  
Cancer Genes ◽  
Copy Number Alterations ◽  
Whole Exome ◽  
Exome Analysis

Exposure to arsenic and intra-chromosomal instability in blood

Metallomics ◽  
2014 ◽  
Vol 6 (8) ◽  
pp. 1387-1389
Author(s):  
Tomasz K. Wojdacz ◽  
Matteo Bottai ◽  
Marie Vahter ◽  
Karin Broberg
Keyword(s):  
Data Processing ◽  
Copy Number ◽  
Chromosomal Instability ◽  
Processing Algorithm ◽  
Copy Number Alterations ◽  
Data Processing Algorithm ◽  
Infinium Humanmethylation450 Beadchip ◽  
Illumina Infinium Humanmethylation450 Beadchip ◽  
Chip Analysis

The 450k Chip Analysis Methylation Pipeline (ChAMP) is a novel Illumina Infinium HumanMethylation450 BeadChip data processing algorithm that allows the analysis of copy number alterations (CNAs).

scholarly journals Identifying Key Somatic Copy Number Alterations Driving Dysregulation of Cancer Hallmarks in Lower-Grade Glioma

2021 ◽  
Vol 12 ◽  
Author(s):  
Yao Zhou ◽  
Shuai Wang ◽  
Haoteng Yan ◽  
Bo Pang ◽  
Xinxin Zhang ◽  
...  
Keyword(s):  
Copy Number ◽  
Lower Grade ◽  
Cancer Genes ◽  
Copy Number Alterations ◽  
Driver Genes ◽  
Functional Roles ◽  
Active Gene ◽  
Gene Sets ◽  
Lower Grade Glioma ◽  
Somatic Copy Number Alterations

Somatic copy-number alterations (SCNAs) are major contributors to cancer development that are pervasive and highly heterogeneous in human cancers. However, the driver roles of SCNAs in cancer are insufficiently characterized. We combined network propagation and linear regression models to design an integrative strategy to identify driver SCNAs and dissect the functional roles of SCNAs by integrating profiles of copy number and gene expression in lower-grade glioma (LGG). We applied our strategy to 511 LGG patients and identified 98 driver genes that dysregulated 29 cancer hallmark signatures, forming 143 active gene-hallmark pairs. We found that these active gene-hallmark pairs could stratify LGG patients into four subtypes with significantly different survival times. The two new subtypes with similar poorest prognoses were driven by two different gene sets (one including EGFR, CDKN2A, CDKN2B, INFA8, and INFA5, and the other including CDK4, AVIL, and DTX3), respectively. The SCNAs of the two gene sets could disorder the same cancer hallmark signature in a mutually exclusive manner (including E2F_TARGETS and G2M_CHECKPOINT). Compared with previous methods, our strategy could not only capture the known cancer genes and directly dissect the functional roles of their SCNAs in LGG, but also discover the functions of new driver genes in LGG, such as IFNA5, IFNA8, and DTX3. Additionally, our method can be applied to a variety of cancer types to explore the pathogenesis of driver SCNAs and improve the treatment and diagnosis of cancer.

Integrative Analysis of Genomic Aberration and Gene Expression Suggests That MPD with Loss of Heterozygosity or Gain of Chromosome 9 Represents a Distinct Entity

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 3735-3735
Author(s):  
Weijia Zhang ◽  
Benjamin L. Ebert ◽  
Windy Berkofsky-Fessler ◽  
Monica Buzzai ◽  
Yezhou Sun ◽  
...  
Keyword(s):  
Gene Expression ◽  
Genomic Instability ◽  
Loss Of Heterozygosity ◽  
Copy Number ◽  
Expression Profiles ◽  
Gene Expression Profiles ◽  
Chromosome 8 ◽  
Chromosome 9 ◽  
Chromosomal Anomalies ◽  
Multiple Testing Correction

Abstract Polycythemia vera (PV), essential thrombocythemia (ET) and idiopathic myelofibrosis (IMF) can all be associated with the JAK2V617F gain of function mutation. MPDs are also associated with gross cytogenetic anomalies including genomic gain/loss or loss of heterozygosity (LOH) due to mitotic homologous recombination. To determine whether genomic anomalies may be associated with JAK mutation status/disease phenotype we subjected genomic DNA from the granulocytes of 87 patients with PV, ET or IMF to analysis using high resolution Affymetrix 250K Nsp SNP arrays with an average probe spacing of 12Kb. Firstly this analysis precisely mapped previously identified anomalies in MPD patients such as gain of chromosome 1q chromosome 9 (Chr9), chromosome 8, and deletion of 20q and 13q indicating the robustness of the technique. By removing genomic Copy Number Polymorphisms (CNPs) ascertained from 90 normal individuals from the HapMap dataset, we further detected a number of novel alterations such as frequent gain of Chr9p33–34 harboring among other genes, Notch1. MPD patients heterozygous for the JAK V617F mutation exhibited higher genomic instability than JAK2 V617 homozygous or wild type patients. IMF patients had overall more aberrations than PV or ET patients but unsupervised hierarchical clustering of chromosomal anomalies could not distinguish patients with PV, ET or IMF. Whole chromosomal gain or loss was equally frequent among the three diseases, however IMF patients had more frequent alteration of 10Mb or greater when compared to ET or PV (p<0.01) and ET and IMF patients both more frequently exhibited changes ranging from 1–10Mb in size than PV patients (p<0.01). Correlation of gene expression profiles from the granulocytes of 38 MPD patients with copy number profiles from DNA of the patients indicated that gene expression in regions of copy number gain or loss correlated with gene dosages in general. From 2493 genes residing in regions of copy number change region, 259 genes exhibited a positive correlation between copy number and gene expression. By calculating the t–statistics of expression values between samples with and without chromosomal aberrations we further identified 28 genes that showed a change of at least 1.5 fold (p<0.05), 27 of which were located on chromosome 9. Among these were Smarca2, NOTCH1 JAK2 itself. JAK2V617F expression was highly elevated by gain of Chr9 or Chr9p LOH. LOH on chr9p was detected in 16 patients, the majority of whom were confirmed as homozygous for JAK2V617F. To investigate how the over-expression of JAK2V617F might affect the expression of other genes and pathways, gene expression profiles of patients with Chr9 abnormality including Chr9 gain or Chr9p LOH were compared to samples with a normal copy number for Chr9. We identified 493 genes including 210 up-regulated and 283 down-regulated genes by at least 1.5 fold at a p value of 0.05 after multiple-testing correction. As a control gene expression patterns in JAK2-wildtype MPD granulocytes were compared to expression in normal granulocytes. This analysis identified an almost completely different set of genes; 441/493 (89%) of genes differentially expressed in Chr9 abnormal cases versus Chr9 normal cases were not found in the Chr9 normal versus normal control dataset. Up-regulated genes in Chr9 abnormal cases included CD177, CDK5RAP2, BIRC1, STAT5, TLR4 and down-regulated genes include KLRB1, Myc, RUNX3, P53CSV, Pathway analysis of dysregulated genes in Chr9 gain/LOH cases showed that genes involved in p38/MAP kinase, Toll-like receptor and Fc epsilon RI signaling were up-regulated and the genes involved in pathways of protein synthesis/translation and T cell receptor signaling were down-regulated. Collectively these findings suggest that MPD associated with Chr9 gain or 9pLOH and increased expression of JAK2V617F represents a distinct subset of MPD, characterized by less genomic instability than other cases. Furthermore, increased JAK2 and STAT5 expression and activity in these cases may induce distinct downstream pathways and alterations in gene expression.

Overlapping high-resolution copy number alterations in cancer genomes identified putative cancer genes in hepatocellular carcinoma

Hepatology ◽  
2010 ◽  
Vol 52 (5) ◽  
pp. 1690-1701 ◽  
Author(s):  
Chian-Feng Chen ◽  
En-Chi Hsu ◽  
Kuen-Tyng Lin ◽  
Pang-Hsien Tu ◽  
Hung-Wei Chang ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
High Resolution ◽  
Copy Number ◽  
Cancer Genes ◽  
Copy Number Alterations ◽  
Cancer Genomes

scholarly journals Whole-genome sequencing of follicular thyroid carcinomas reveal recurrent mutations in microRNA processing subunit DGCR8

2021 ◽  
Author(s):  
Johan O Paulsson ◽  
Nima Rafati ◽  
Sebastian DiLorenzo ◽  
Yi Chen ◽  
Felix Haglund ◽  
...  
Keyword(s):  
Copy Number ◽  
Somatic Mutations ◽  
Whole Genome ◽  
Cancer Genes ◽  
Copy Number Alterations ◽  
Thyroid Carcinomas ◽  
Future Studies ◽  
Recurrent Mutations ◽  
Microrna Processing ◽  
Widely Invasive

Abstract Background The genomic and transcriptomic landscape of widely invasive follicular thyroid carcinomas (wiFTCs) and Hürthle cell carcinoma (HCC) are poorly characterized and subsets of these tumors lack information on genetic driver events. The aim of this study was to bridge this gap. Methods We performed whole-genome and RNA sequencing and subsequent bioinformatic analyses of 11 wiFTCs and 2 HCCs with a particularly poor prognosis, and matched normal tissue. Results All wiFTCs exhibited one or several mutations in established thyroid cancer genes, including TERT (n=4), NRAS (n=3), HRAS, KRAS, AKT, PTEN, PIK3CA, MUTYH, TSHR and MEN1 (n=1 each). MutSig2CV analysis revealed recurrent somatic mutations in FAM72D (n=3, in two wiFTCs and in a single HCC), TP53 (n=3, in two wiFTCs and a single HCC) and EIF1AX (n=3), with DGCR8 (n=2) as borderline significant. The DGCR8 mutations were recurrent p.E518K missense alterations, known to cause familial multinodular goiter via disruption of microRNA processing. Expression analyses showed reduced DGCR8 mRNA expression in FTCs in general, and the two DGCR8 mutants displayed a distinct miRNA profile compared to DGCR8 wildtypes. Copy number analyses revealed recurrent gains on chromosomes 4, 6 and 10, and fusiongene analyses revealed 27 high-quality events. Both HCCs displayed hyperploidy, which was fairly unusual in the FTC cohort. Based on the transcriptome data tumors amassed in two principal clusters. Conclusion We describe the genomic and transcriptomic landscape in wiFTCs and HCCs and identify novel recurrent mutations and copy number alterations with possible driver properties and lay the foundation for future studies.

scholarly journals Chromosomal Instability and Copy Number Alterations in Barrett's Esophagus and Esophageal Adenocarcinoma

2009 ◽  
Vol 15 (10) ◽  
pp. 3305-3314 ◽  
Author(s):  
Thomas G. Paulson ◽  
Carlo C. Maley ◽  
Xiaohong Li ◽  
Hongzhe Li ◽  
Carissa A. Sanchez ◽  
...  
Keyword(s):  
Barrett’S Esophagus ◽  
Esophageal Adenocarcinoma ◽  
Copy Number ◽  
Barrett's Esophagus ◽  
Chromosomal Instability ◽  
Copy Number Alterations

Distinct genomic instability landscape of lung adenocarcinoma associated with treatment and metastasis.

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. 9534-9534
Author(s):  
Chuanxin Wu ◽  
Jing Zhang ◽  
Hua Bao ◽  
Ao Wang ◽  
Zhuang Luo ◽  
...  
Keyword(s):  
Lung Adenocarcinoma ◽  
Genomic Instability ◽  
Copy Number ◽  
Targeted Sequencing ◽  
Early Event ◽  
Copy Number Alterations ◽  
Term Survival ◽  
Tissue Samples ◽  
Primary Tumors ◽  
Increased Risk

9534 Background: Lung adenocarcinoma (LUAD) is the most common subtype of non-small cell lung cancer (NSCLC). Genomic instability, defined as genome-wide copy number alterations, is a key pathogenic signature which occurs at the early stage of most cancers and is associated with an increased risk of recurrence or death. We examined the pattern of genomic instability in primary and metastatic LUAD. Methods: We performed deep targeted sequencing (425 genes) of 3395 tissue samples and whole exome sequencing (WES) of 60 tissue samples from LUAD patients. Whole-genome doubling (WGD) and arm level aneuploidy were analyzed to uncover correlation with clinical phenotypes and other genomic alterations including driver mutations, tumor mutation burden (TMB), and microsatellite instability (MSI). Results: Overall, targeted sequencing revealed that WGD occurred in 64.33% LUAD samples, which was comparable with WES results. Compared to primary site, metastasis exhibited higher proportion of WGD (1.14 fold). Specifically, liver metastasis has the highest WGD percentage among metastasis sites (~87.5%; 1.40 fold increase compared to primary). Interestingly, patients who received tyrosine kinase inhibitors (TKI) had higher frequency of WGD than patients without TKI treatment. In addition, TMB was higher in WGD+ patients but MSI status was not significantly different between groups. Arm-level aneuploidy was prevalent in this cohort. The most common amplification events were 7p gain (62%), 5p gain (54%), and 8q gain (53%); top deletion events were 19p loss (47%), 15q loss (42%), and 10 q loss (41%). Patients with EGFR or TP53 mutation were more likely to have aneuploidy compared to wildtypes. Subgroup analysis showed distinct patterns of aneuploidy among metastasis sites, suggesting organ-specific alterations. Evolution analysis showed 7p gain was an early event common in primary tumor whereas metastatic tumor had multiple distinct evolutionary trajectories following 7p gain. Several copy number signatures were associated with specific TKI and chemotherapies. For example, TKI-naïve tumors lacked 7p gain but had 19p loss as the most common alteration. Conclusions: The genomic landscape of LUAD was characterized by widespread large-scale copy number alterations including WGD and chromosomal aneuploidy. Metastasis had elevated level of aneuploidy compared to primary tumors which were specific to metastatic site. Copy number signature associated with different treatments may contribute to distinct long-term survival and side effects among patients.

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