scholarly journals Phased Mutations and Complex Rearrangements in Human Prostate Cancer Cell Lines through Linked-Read Whole Genome Sequencing

2021 ◽  
Author(s):  
Minh-Tam Nguyen Pham ◽  
Harshath Gupta ◽  
Anuj Gupta ◽  
Ajay Vaghasia ◽  
Alyza Skaist ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Whole Genome Sequencing ◽  
Cell Lines ◽  
Genome Sequencing ◽  
Whole Genome ◽  
Genomic Alterations ◽  
Gene Level ◽  
Somatic Genome ◽  
Single Allele ◽  
Castrate Resistant

A limited number of cell lines have fueled the majority of preclinical Prostate cancer (PCa) research. Despite tremendous effort in characterizing their molecular profiles, comprehensive whole genome sequencing with allelic phasing of somatic genome alterations has not been undertaken to date. Here, we utilized whole genome Linked-read sequencing to obtain haplotype information from the seven most commonly used PCa cell lines (PC3, LNCaP, DU145, CWR22Rv1, VCaP, LAPC4, MDA-PCa-2b), four castrate resistant (CR) subclones (LNCaP_Abl, LNCaP_C42b, VCaP-CR, LAPC4-CR), and an immortalized prostate epithelial line RWPE-1. Phasing of mutations allowed derivation of Gene-level Haplotype to assess whether a gene harbored heterozygous mutations in one or both alleles, providing a comprehensive catalogue of mono or bi-allelically inactivated genes. Phased structural variant analysis allowed identification of complex rearrangement chains consistent with chromothripsis and chromoplexy, with breakpoints occurred across a single allele, providing further evidence that complex SVs occurred in a concerted event, rather than through accumulation of multiple independent rearrangements. Additionally, comparison of parental and CR subclones revealed previously known and novel genomic alterations associated with the CR clones. This study therefore comprehensively characterized phased genomic alterations in the commonly used PCa cell lines and provided a useful resource for future cancer research.

scholarly journals Deep whole genome sequencing identifies recurrent genomic alterations in commonly-used breast cancer cell lines and patient derived xenograft models

2021 ◽  
Author(s):  
Niantao Deng ◽  
Andre Minoche ◽  
Kate Harvey ◽  
Andrei Goga ◽  
Alex Swarbrick
Keyword(s):  
Breast Cancer ◽  
Whole Genome Sequencing ◽  
Cell Lines ◽  
Cancer Cell ◽  
Genome Sequencing ◽  
Cancer Cell Lines ◽  
Whole Genome ◽  
Breast Cancers ◽  
Genomic Alterations ◽  
Pdx Models

Abstract BackgroundBreast cancer cell lines (BCCLs) and patient-derived xenografts (PDX) are the most frequently used models in breast cancer research. Despite their widespread usage, genome sequencing of these models is incomplete, with previous studies only focusing on targeted gene panels, whole exome or shallow whole genome sequencing. Deep whole genome sequencing is the most sensitive and accurate method to detect single nucleotide variants and indels, gene copy number and structural events such as gene fusions. ResultsHere we describe deep whole genome sequencing (WGS) of commonly used BCCL and PDX models using the Illumina X10 platform with an average ~ 60x coverage. We identify novel genomic alterations, including point mutations and genomic rearrangements at base-pair resolution, compared to previously available sequencing data. Through integrative analysis with publicly available functional screening data, we annotate new genomic features likely to be of biological significance. CSMD1 , previously identified as a tumor suppressor gene in various cancer types, including head and neck, lung and breast cancers, has been identified with deletion in 50% of our PDX models, suggesting an important role in aggressive breast cancers. ConclusionsOur WGS data provides a comprehensive genome sequencing resource of these models.

scholarly journals Whole-genome sequencing of recurrent neuroblastoma reveals somatic mutations that affect key players in cancer progression and telomere maintenance

2020 ◽  
Vol 10 (1) ◽  
Author(s):  
Susanne Fransson ◽  
Angela Martinez-Monleon ◽  
Mathias Johansson ◽  
Rose-Marie Sjöberg ◽  
Caroline Björklund ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Whole Genome Sequencing ◽  
Genome Sequencing ◽  
Cancer Progression ◽  
Cell Cycle Progression ◽  
Mapk Signaling ◽  
Telomere Maintenance ◽  
Whole Genome ◽  
Genomic Alterations ◽  
Cycle Progression

AbstractNeuroblastoma is the most common and deadly childhood tumor. Relapsed or refractory neuroblastoma has a very poor prognosis despite recent treatment advances. To investigate genomic alterations associated with relapse and therapy resistance, whole-genome sequencing was performed on diagnostic and relapsed lesions together with constitutional DNA from seven children. Sequencing of relapsed tumors indicates somatic alterations in diverse genes, including those involved in RAS-MAPK signaling, promoting cell cycle progression or function in telomere maintenance and immortalization. Among recurrent alterations, CCND1-gain, TERT-rearrangements, and point mutations in POLR2A, CDK5RAP, and MUC16 were shown in ≥ 2 individuals. Our cohort contained examples of converging genomic alterations in primary-relapse tumor pairs, indicating dependencies related to specific genetic lesions. We also detected rare genetic germline variants in DNA repair genes (e.g., BARD1, BRCA2, CHEK2, and WRN) that might cooperate with somatically acquired variants in these patients with highly aggressive recurrent neuroblastoma. Our data indicate the importance of monitoring recurrent neuroblastoma through sequential genomic characterization and that new therapeutic approaches combining the targeting of MAPK signaling, cell cycle progression, and telomere activity are required for this challenging patient group.

scholarly journals Deep Whole Genome Sequencing Identifies Recurrent Genomic Alterations in Commonly-Used Breast Cancer Cell Lines and Patient Derived Xenograft Models

2021 ◽  
Author(s):  
Niantao Deng ◽  
Andre Minoche ◽  
Kate Harvey ◽  
Meng Li ◽  
Juliane Winkler ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Whole Genome Sequencing ◽  
Cell Lines ◽  
Cancer Cell ◽  
Genome Sequencing ◽  
Breast Cancer Cell ◽  
Breast Cancer Cell Lines ◽  
Whole Genome ◽  
Breast Cancers ◽  
Pdx Models

Abstract Background: Breast cancer cell lines (BCCLs) and patient-derived xenografts (PDX) are the most frequently used models in breast cancer research. Despite their widespread usage, genome sequencing of these models is incomplete, with previous studies only focusing on targeted gene panels, whole exome or shallow whole genome sequencing. Deep whole genome sequencing is the most sensitive and accurate method to detect single nucleotide variants and indels, gene copy number and structural events such as gene fusions.Results: Here we describe deep whole genome sequencing (WGS) of commonly used BCCL and PDX models using the Illumina X10 platform with an average ~ 60x coverage. We identify novel genomic alterations, including point mutations and genomic rearrangements at base-pair resolution, compared to previously available sequencing data. Through integrative analysis with publicly available functional screening data, we annotate new genomic features likely to be of biological significance. CSMD1, previously identified as a tumor suppressor gene in various cancer types, including head and neck, lung and breast cancers, has been identified with deletion in 50% of our PDX models, suggesting an important role in aggressive breast cancers. Conclusions: Our WGS data provides a comprehensive genome sequencing resource of these models.

Using whole-genome sequencing to implicate the androgen receptor as the predominant driver of DNA breakpoints and fusion events in prostate cancer.

2014 ◽  
Vol 32 (4_suppl) ◽  
pp. 67-67 ◽  
Author(s):  
Niall Corcoran ◽  
Geoff Macintyre ◽  
Matthew Hong ◽  
Clare Slogget ◽  
Haroon Naeem ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Androgen Receptor ◽  
Whole Genome Sequencing ◽  
Genome Sequencing ◽  
Receptor Binding ◽  
Binding Sites ◽  
Whole Genome ◽  
Structural Rearrangements ◽  
Novel Gene ◽  
Close Proximity

67 Background: Structural rearrangements in cancers genomes have the potential to disrupt normal gene function and result in a selective growth advantage, either by inactivating tumour suppressors or creating novel gene fusions with oncogenic gain-of-function. Specific fusion genes identified to date are found in particular tumor types rather than being present in all cancers suggesting there are tissue-specific mechanisms underlying these events. The most well-known fusion event in prostate cancer is TMPRSS2-ERG. Recent studies have suggested that androgen receptor may play a role in the formation of TMPRSS2-ERG fusions, bringing the two loci in close proximity in the nucleus and facilitating DNA strand break and repair along with AR associated enzymes. Methods: To explore this mechanism more comprehensively, we performed whole-genome sequencing of 14 prostate cancers from seven patients as well as paired whole blood controls. Results: Across the cancer genomes we identified approximately 4,500 high confidence DNA breakpoints and found that a large proportion of these breakpoints were in close proximity to curated androgen receptor binding sites. Furthermore, when we examined breakpoints in 11 other cancers from the TCGA and ICGC projects, we identified a similar association with androgen (and estrogen) receptor binding sites specifically in hormone-dependent tumour types, suggesting a role for steroid hormone receptors in the formation of cancer driving structural rearrangements. In addition, in at least one patient, the formation of a novel gene fusion contributed directly to the lethal evolution of his tumour. Conclusions: These data suggest that the androgen receptor drives genome wide breakpoints and novel fusion events in prostate cancer.

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