Cross-species genomics identifies DLG2 as a tumor suppressor in osteosarcoma

Shao, Yang; Wood, Geoffrey A.; Lu, Jinchang; Tang, Qinglian; Liu, Jonathan; Molyneux, Sam D.; Chen, Yan; Fang, Hui; Adissu, Hibret A.; McKee, Trevor D.; Waterhouse, Paul; Khokha, Rama

doi:10.1038/s41388-018-0444-4

Cited by 72 publications

(70 citation statements)

References 31 publications

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“…Synaptogenesis is a key process in neuronal differentiation, and mutations in genes involved in the formation of synapses have frequently been implicated in NDD (also termed shankopathies) 65 . Furthermore, DLG2 has been recently described as a tumor suppressor in osteosarcoma 46,47 . We propose that the dysregulation of Supplementary Fig.…”

Section: Discussionmentioning

confidence: 99%

“…The SHANK2 gene was found disrupted in 11 HR-NA tumors; 3 samples involved gene fusions that didn't appear in frame. DLG2, a newly described tumor suppressor in osteosarcoma 46,47 , was found disrupted in 10 samples based on SJ-BP and RD-BP analyses from a total of 14 samples, two of which involved gene fusion events. Both SHANK2 and DLG2 are located on chromosome 11q and play a role in the formation of postsynaptic density (PSD) 48 .…”

Section: Identification Of Genes Recurrently Altered By Svs In High-rmentioning

confidence: 99%

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Somatic structural variation targets neurodevelopmental genes and identifies SHANK2 as a tumor suppressor in neuroblastoma

López

Conkrite

Doepner

et al. 2019

Preprint

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Neuroblastoma, like many childhood cancers, exhibits a relative paucity of somatic single nucleotide variants (SNVs). Here, we assess the contribution of structural variation (SV) in neuroblastoma using a combination of whole genome sequencing (WGS; n=135) and single nucleotide polymorphism (SNP) genotyping (n=914) of matched tumor-normal pairs. Our study design provided means for orthogonal validation of SVs as well as validation across genomic platforms. SV frequency, type, and localization varied significantly among high-risk tumors, with MYCN non-amplified tumors harboring an increased SV burden overall (P=1.12x10 -5 ). Genes disrupted by SV breakpoints were enriched in neuronal lineages and autism spectrum disorder. The postsynaptic adapter protein-coding gene SHANK2, located on chromosome 11q13, was disrupted by SVs in 14% and 10% of MYCN non-amplified highrisk tumors based on WGS and SNP array cohorts, respectively. Forced expression of SHANK2 in neuroblastoma cell models resulted in significant growth inhibition (P=2.62x10 -2 to 3.4x10 -5 ) and accelerated neuronal differentiation following treatment with all-trans retinoic acid (P=3.08x10 -13 to 2.38x10 -30 ). These data further define the complex landscape of structural variation in neuroblastoma and suggest that events leading to deregulation of neurodevelopmental processes, such as inactivation of SHANK2, are key mediators of tumorigenesis.Neuroblastoma is a cancer of the developing sympathetic nervous system that most commonly affects children under 5 years of age, with a median age at diagnosis of 17 months 1 . Approximately 50% of cases present with disseminated disease at the time of diagnosis, and despite intense multi-modal therapy, the survival rate for this high-risk subset remains less than 50% 1 . Recent whole genome and exome sequencing studies of neuroblastoma have revealed relatively few recurrent protein-coding somatic mutations including single nucleotide variations (SNVs) and small (<50b) insertion/deletions (indels) 2-5 .Large-scale structural variations (SVs) such as deletions, insertions, inversions, tandem duplications and translocations can arise from mutational processes that alter chromosome structure and evade innate mechanisms of maintaining genomic stability. These diverse SVs are commonly acquired somatically and act as driver mutations 6 .A plethora of approaches have been applied to detect SVs across large cancer datasets 6-9 .First, methods that identify copy number variations (CNVs) can be applied to intensity log R ratios from genotyping and comparative genomic hybridization (CGH) arrays as well as read-depth measures from next generation sequencing. Different segmentation algorithms have been applied to either platform in order to obtain copy number gain and loss calls, which range from a few hundred base-pair size to whole chromosomal alterations. These methods are dosage sensitive, allowing numerical quantification of amplifications and homozygous deletions. Analysis of CNVs in neuroblastoma primary tumor and matched...

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Section: Discussionmentioning

confidence: 99%

Section: Identification Of Genes Recurrently Altered By Svs In High-rmentioning

confidence: 99%

Somatic structural variation targets neurodevelopmental genes and identifies SHANK2 as a tumor suppressor in neuroblastoma

López

Conkrite

Doepner

et al. 2019

Preprint

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“…EGCG was proposed to affect cell proliferation and apoptosis through Hippo signaling pathway in oral cancer [43], but has not been studied in bladder cancer. While the role of DLG2 as a tumor suppressor gene in osteosarcoma [44] and miRNA target in ovarian cancer inhibiting cell migration [45] were reported, its involvement in bladder cancer remains unclear.…”

Section: Discussionmentioning

confidence: 99%

Effects of Epigallocatechin Gallate (EGCG) on Urinary Bladder Urothelial Carcinoma―Next-Generation Sequencing and Bioinformatics Approaches

et al. 2019

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Background and objectives: Bladder urothelial carcinoma is the most common type of genitourinary cancer. Patients with bladder cancer may have limited treatment efficacy related to drug toxicity, resistance or adverse effects, and novel therapeutic strategies to enhance treatment efficacy or increase sensitivity to drugs are of high clinical importance. Epigallocatechin gallate (EGCG) is a polyphenolic compound found in green tea leaves, and a potential anti-cancer agent in various cancer types through modulating and regulating multiple signaling pathways. The current study aimed to explore the role and novel therapeutic targets of EGCG on bladder urothelial carcinoma. Materials and Methods: The BFTC-905 cells, human urinary bladder transitional cell carcinoma (TCC) cell line, were treated with EGCG or water for 24 hours, and the expression profiles of mRNAs and microRNAs were analyzed using next generation sequencing (NGS). The enriched biological functions were determined using different bioinformatics databases. Results: A total of 108 differentially expressed genes in EGCG-treated bladder TCC cells were identified, which were mainly involved in nicotinamide adenine dinucleotide (NAD) biogenesis, inflammatory response and oxidation-reduction metabolism. Moreover, several microRNA-mRNA interactions that potentially participated in the response of bladder TCC to EGCG treatment, including miR-185-3p-ARRB1 (arrestin beta 1), miR-3116-MGAT5B (alpha-1,6-mannosylglycoprotein 6-beta-N-acetylglucosaminyltransferase B), miR-31-5p-TNS1 (tensin 1), miR-642a-5p-TNS1, miR-1226-3p-DLG2 (discs large homolog 2), miR-484-DLG2, and miR-22-3p-PPM1K (protein phosphatase 1K). Conclusions: The current findings provide insights into novel therapeutic targets and underlying mechanisms of action of EGCG treatment in bladder cancer.

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“…One study found that DLG2 copy number loss occurs in 56% of canine osteosarcomas. Deleting the DLG2 gene in a murine model also accelerated the development of canine osteosarcoma [65].…”

Section: Osteosarcomamentioning

confidence: 97%

“…The study found SETD2 mutations in 21% of tumors across all three breeds of predisposed dogs (golden retrievers, Rottweilers and greyhounds). The gene DLG2, important in regulating cell division, migration and tumorigenesis, is also a viable tumor suppressor candidate of osteosarcoma [65]. One study found that DLG2 copy number loss occurs in 56% of canine osteosarcomas.…”

Section: Osteosarcomamentioning

confidence: 99%

Molecular Mechanisms of Canine Cancers

Cao¹,

Kouznetsova²,

Tsigelny³

2019

obm genet

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Cancer is the leading cause of death in dogs, and 50 percent of dogs over the age of 10 develop cancer at some point. The most common cancers in dogs include lymphoma, mast cell tumors, osteosarcoma, mammary gland tumors, and melanoma, and many of them share marked similarities with their human counterparts. Although canines are afflicted with many of the same types of cancers as humans, the genetic basis behind these cancers are not as well understood. Thus, the aim of this study is to elucidate some of the molecular mechanisms behind canine cancers. Canine lymphoma mutation patterns generally vary with the type of lymphoma afflicted-B-cell lymphomas have mutations in the alternative NF-kB pathway including MAP3K14, whereas in T-cell lymphomas the mTOR pathway in boxers and cellular metabolism genes in golden retrievers are affected. Mast cell tumors are largely traced to internal tandem duplications and deletions in the juxtamembrane domain of the proto-oncogene c-KIT. In osteosarcoma, mutations in RB1 and TP53 (especially G: C->A:T transitions in exons 4 and 5), as well as CDK4 inhibitors CDKN2A/B are common. Mammary gland tumors are associated with BRCA2 underexpression due to reading frame shift and mutations in BRC repeat 3. Lastly, deletion or underexpression of p16 and PTEN and altered expression of cell-cell adhesion molecules are common factors in the development of melanoma. The genes identified were then studied to identify more key amino acid mutations that changed protein products and promoted tumorigenesis. Genes that altered expression levels of proteins were analyzed separately. Both sets of candidate genes were then analyzed with the Database for Annotation, Visualization, and Integrated Discovery (DAVID) in order to elucidate the molecular pathways involved in canine cancers and identify more genes possibly involved in tumorigenesis. The proposition of this review is that treatments for both canine and human cancers would be enhanced by comparative genomic studies.

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Cross-species genomics identifies DLG2 as a tumor suppressor in osteosarcoma

Cited by 72 publications

References 31 publications

Somatic structural variation targets neurodevelopmental genes and identifies SHANK2 as a tumor suppressor in neuroblastoma

Somatic structural variation targets neurodevelopmental genes and identifies SHANK2 as a tumor suppressor in neuroblastoma

Effects of Epigallocatechin Gallate (EGCG) on Urinary Bladder Urothelial Carcinoma―Next-Generation Sequencing and Bioinformatics Approaches

Molecular Mechanisms of Canine Cancers

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