Low-frequency somatic copy number alterations in normal human lymphocytes revealed by large-scale single-cell whole-genome profiling.
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ABSTRACT:
SUBMITTER: Liu L
PROVIDER: S-EPMC8744674 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:BackgroundCopy number alteration is a main genetic structural variation that plays an important role in tumor initialization and progression. Accurate detection of copy number alterations is necessary for discovering cancer-causing genes. Whole-exome sequencing has become a widely used technology in the last decade for detecting various types of genomic aberrations in cancer genomes. However, there are several major issues encountered in these detection problems, including normal cell contamination, tumor aneuploidy, and intra-tumor heterogeneity. Especially, deciphering the intra-tumor heterogeneity is imperative for identifying clonal and subclonal copy number alterations.ResultsWe introduce CloneCNA, a novel bioinformatics tool for efficiently addressing these issues and automatically detecting clonal and subclonal somatic copy number alterations from heterogeneous tumor samples. CloneCNA fully explores the log ratio of read counts between paired tumor-normal samples and tumor B allele frequency of germline heterozygous SNP positions, further employs efficient statistical models to quantitatively represent copy number status of tumor sample containing multiple clones. We examine CloneCNA on simulated heterogeneous and real tumor samples, and the results demonstrate that CloneCNA has higher power to detect copy number alterations than existing methods.ConclusionsCloneCNA, a novel algorithm is developed to efficiently and accurately identify somatic copy number alterations from heterogeneous tumor samples. We demonstrate the statistical framework of CloneCNA represents a remarkable advance for tumor whole-exome sequencing data. We expect that CloneCNA will promote cancer-focused studies for investigating the role of clonal evolution and elucidating critical events benefiting tumor tumourigenesis and progression.
| S-EPMC4990858 | biostudies-literature
Project description:Breast cancer is a heterogeneous disease described in well-recognized biological subtypes. Particularly, gene expression profiling has revealed 5 intrinsic subtypes of breast cancer characterized by different biological and clinical features. The diversity of the intrinsic subtypes across human population has been limited described, and there is few information about the genomic architecture of breast tumors in Mexican or Hispanic populations. In this study, we performed PAM50 assay, based in Affymetrix microarray profiling of 128 fresh frozen tumors from Mexican Latino Hispanic population, to describe the overall distribution of subtypes, and characterize the relation to clinicopathologic characteristics. As well, we correlated the mRNA expression patterns with specific copy number alterations (CPA), in order to analyze their role in breast tumors. A total of 100 blood-tumor samples were assayed using Affymetrix 6.0 SNP arrays; segmentation analysis and GISTIC were performed to identify focal amplifications or deletions. The distribution of PAM50 intrinsic subtypes in our cohort was computed to be 44% luminal A, 20% luminal B, 12.0% HER2-enriched, 12% basal-like, and 12% normal-like. Study comparison with the literature mainly TCGA and METABRIC (most of the patients came from Caucasian population), as well as LACE (which describe a population study) show a similar distribution of the intrinsic subtypes within Hispanic and Caucasian populations. Interestingly, basal-like subtype is less represented than in African-American race. The sum of sensitivity and specificity between the clinicopathologic and intrinsic subtype categories across 4 groups (excluding normal-like) was 50% and 87.5%, respectively. Differentially expression profiles within the subtypes reveal a set of genes altered in each group with biological relevance to stablish the phenotypical characteristics of each subtype. Our analyses confirmed the already reported copy number data. Importantly, many of the copy number profiles correlated with mRNA subtype. With this analysis we can conclude that breast cancer intrinsic subtypes have been reproduced in Mexican population contributing to the description of the PAM50 subtypes among multiple ethnic groups based on a gene expression assay. Our observation based in the integrative genomic analysis of mRNA expression and CPA allowed us to define gene circuits and phenotypic characteristics that can explain the heterogeneity of breast cancer subtypes.
2018-08-31 | GSE87048 | GEO
Project description:MOTIVATION:Detection of somatic copy number alterations (SCNAs) using high-throughput sequencing has become popular because of rapid developments in sequencing technology. Existing methods do not perform well in calling SCNAs for the unstable tumor genomes. RESULTS:We developed a new method, DEFOR, to detect SCNAs in tumor samples from exome-sequencing data. The evaluation showed that DEFOR has a higher accuracy for SCNA detection from exome sequencing compared with the five existing tools. This advantage is especially apparent in unstable tumor genomes with a large proportion of SCNAs. AVAILABILITY AND IMPLEMENTATION:DEFOR is available at https://github.com/drzh/defor. SUPPLEMENTARY INFORMATION:Supplementary data are available at Bioinformatics online.
| S-EPMC6761943 | biostudies-literature
Project description:As next-generation sequencing technology advances and the cost decreases, whole genome sequencing (WGS) has become the preferred platform for the identification of somatic copy number alteration (CNA) events in cancer genomes. To more effectively decipher these massive sequencing data, we developed a software program named SEG, shortened from the word "segment". SEG utilizes mapped read or fragment density for CNA discovery. To reduce CNA artifacts arisen from sequencing and mapping biases, SEG first normalizes the data by taking the log2-ratio of each tumor density against its matching normal density. SEG then uses dynamic programming to find change-points among a contiguous log2-ratio data series along a chromosome, dividing the chromosome into different segments. SEG finally identifies those segments having CNA. Our analyses with both simulated and real sequencing data indicate that SEG finds more small CNAs than other published software tools.
| S-EPMC6154469 | biostudies-literature
Project description:Multiple large-scale genomic profiling efforts have been undertaken in osteosarcoma to define the genomic drivers of tumorigenesis, therapeutic response, and disease recurrence. The spatial and temporal intratumor heterogeneity could also play a role in promoting tumor growth and treatment resistance. We conducted longitudinal whole-genome sequencing of 37 tumor samples from 8 patients with relapsed or refractory osteosarcoma. Each patient had at least one sample from a primary site and a metastatic or relapse site. Subclonal copy-number alterations were identified in all patients except one. In 5 patients, subclones from the primary tumor emerged and dominated at subsequent relapses. MYC gain/amplification was enriched in the treatment-resistant clones in 6 of 7 patients with multiple clones. Amplifications in other potential driver genes, such as CCNE1, RAD21, VEGFA, and IGF1R, were also observed in the resistant copy-number clones. A chromosomal duplication timing analysis revealed that complex genomic rearrangements typically occurred prior to diagnosis, supporting a macroevolutionary model of evolution, where a large number of genomic aberrations are acquired over a short period of time followed by clonal selection, as opposed to ongoing evolution. A mutational signature analysis of recurrent tumors revealed that homologous repair deficiency (HRD)-related SBS3 increases at each time point in patients with recurrent disease, suggesting that HRD continues to be an active mutagenic process after diagnosis. Overall, by examining the clonal relationships between temporally and spatially separated samples from patients with relapsed/refractory osteosarcoma, this study sheds light on the intratumor heterogeneity and potential drivers of treatment resistance in this disease.SignificanceThe chemoresistant population in recurrent osteosarcoma is subclonal at diagnosis, emerges at the time of primary resection due to selective pressure from neoadjuvant chemotherapy, and is characterized by unique oncogenic amplifications.
| S-EPMC10646480 | biostudies-literature
Project description:Liquid biopsies, i.e. the analysis of circulating tumor cells (CTCs) or circulating tumor DNA (ctDNA), are evolving into promising clinical tools. Indeed, a plethora of liquid biopsy technologies to deduce non-invasively characteristics of the tumor genome from the peripheral blood have been developed over the last few years. For example, liquid biopsies have been used to assess the tumor burden, to monitor the evolution of tumor genomes, to unravel mechanisms of resistance, to establish the tumor heterogeneity, and for the identification of prognostic and predictive markers. In this review we focus on methods to establish genome-wide profiles of somatic copy number alterations (SCNAs) from plasma DNA and show how they provide novel insights into the biology of cancer and their impact on the management of patients.
| S-EPMC5528970 | biostudies-other
Project description:Gastric cancer, a leading worldwide cause of cancer mortality, shows high geographic and ethnic variation in incidence rates, which are highest in East Asia. The anatomic locations and clinical behavior also differ by geography, leading to the controversial idea that Eastern and Western forms of the disease are distinct. In view of these differences, we investigated whether gastric cancers from Eastern and Western patients show distinct genomic profiles. We used high-density profiling of somatic copy-number aberrations to analyze the largest collection to date of gastric adenocarcinomas and utilized genotyping data to rigorously annotate ethnic status. The size of this collection allowed us to accurately identify regions of significant copy-number alteration and separately to evaluate tumors arising in Eastern and Western patients. Among molecular subtypes classified by The Cancer Genome Atlas, the frequency of gastric cancers showing chromosomal instability was modestly higher in Western patients. After accounting for this difference, however, gastric cancers arising in Easterners and Westerners have highly similar somatic copy-number patterns. Only one genomic event, focal deletion of the phosphatase gene PTPRD, was significantly enriched in Western cases, though also detected in Eastern cases. Thus, despite the different risk factors and clinical features, gastric cancer appears to be a fundamentally similar disease in both populations and the divergent clinical outcomes cannot be ascribed to different underlying structural somatic genetic aberrations.
| S-EPMC5398631 | biostudies-literature
Project description:This SuperSeries is composed of the SubSeries listed below. Refer to individual Series
| S-ECPF-GEOD-23056 | biostudies-other
Project description:Whole-exome sequencing (WES) has become a standard method for detecting genetic variants in human diseases. Although the primary use of WES data has been the identification of single nucleotide variations and indels, these data also offer a possibility of detecting copy number variations (CNVs) at high resolution. However, WES data have uneven read coverage along the genome owing to the target capture step, and the development of a robust WES-based CNV tool is challenging. Here, we evaluate six WES somatic CNV detection tools: ADTEx, CONTRA, Control-FREEC, EXCAVATOR, ExomeCNV and Varscan2. Using WES data from 50 kidney chromophobe, 50 bladder urothelial carcinoma, and 50 stomach adenocarcinoma patients from The Cancer Genome Atlas, we compared the CNV calls from the six tools with a reference CNV set that was identified by both single nucleotide polymorphism array 6.0 and whole-genome sequencing data. We found that these algorithms gave highly variable results: visual inspection reveals significant differences between the WES-based segmentation profiles and the reference profile, as well as among the WES-based profiles. Using a 50% overlap criterion, 13-77% of WES CNV calls were covered by CNVs from the reference set, up to 21% of the copy gains were called as losses or vice versa, and dramatic differences in CNV sizes and CNV numbers were observed. Overall, ADTEx and EXCAVATOR had the best performance with relatively high precision and sensitivity. We suggest that the current algorithms for somatic CNV detection from WES data are limited in their performance and that more robust algorithms are needed.
| S-EPMC6283367 | biostudies-literature
Project description:BackgroundEsophageal adenocarcinoma (EA) is among the leading causes of cancer mortality, especially in developed countries. A high level of somatic copy number alterations (CNAs) accumulates over the decades in the progression from Barrett's esophagus, the precursor lesion, to EA. Accurate identification of somatic CNAs is essential to understand cancer development. Many studies have been conducted for the detection of CNA in EA using microarrays. Next-generation sequencing (NGS) technologies are believed to have advantages in sensitivity and accuracy to detect CNA, yet no NGS-based CNA detection in EA has been reported.ResultsIn this study, we analyzed whole-exome (WES) and whole-genome sequencing (WGS) data for detecting CNA from a published large-scale genomic study of EA. Two specific comparisons were conducted. First, the recurrent CNAs based on WGS and WES data from 145 EA samples were compared to those found in five previous microarray-based studies. We found that the majority of the previously identified regions were also detected in this study. Interestingly, some novel amplifications and deletions were discovered using the NGS data. In particular, SKI and PRKCZ detected in a deletion region are involved in transforming growth factor-β pathway, suggesting the potential utility of novel biomarkers for EA. Second, we compared CNAs detected in WGS and WES data from the same 15 EA samples. No large-scale CNA was identified statistically more frequently by WES or WGS, while more focal-scale CNAs were detected by WGS than by WES.ConclusionsOur results suggest that NGS can replace microarrays to detect CNA in EA. WGS is superior to WES in that it can offer finer resolution for the detection, though if the interest is on recurrent CNAs, WES can be preferable to WGS for its cost-effectiveness.
| S-EPMC4570720 | biostudies-literature