Identification of interactive networks of gene expression associated with osteosarcoma oncogenesis by integrated molecular profiling

Sadiković, Bekim; Yoshimoto, Maisa; Chilton‐MacNeill, Susan; Thorner, Paul; Squire, Jeremy A.; Zieleńska, Maria

doi:10.1093/hmg/ddp117

Cited by 121 publications

(119 citation statements)

References 38 publications

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“…HDAC9 gain has been described in squamous cell cervical carcinomas (47), and higher HDAC9 expression has been associated with poor prognosis in childhood acute lymphatic leukemias (48). DOCK5, which maps to 8p21.2-p21.3, encodes the dedicator of cytokinesis 5 protein and is recurrently deleted and underexpressed in osteosarcoma (49,50). All of these candidate genes should be further analyzed to explore their potential and specific contributions to PCNSL pathogenesis.…”

Section: Discussionmentioning

confidence: 99%

Recurrent Mutations of MYD88 and TBL1XR1 in Primary Central Nervous System Lymphomas

González-Aguilar

Idbaïh

Boisselier

et al. 2012

Clinical Cancer Research

222

171

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Purpose: Our objective was to identify the genetic changes involved in primary central nervous system lymphoma (PCNSL) oncogenesis and evaluate their clinical relevance.Experimental Design: We investigated a series of 29 newly diagnosed, HIV-negative, PCNSL patients using high-resolution single-nucleotide polymorphism (SNP) arrays (n ¼ 29) and whole-exome sequencing (n ¼ 4) approaches. Recurrent homozygous deletions and somatic gene mutations found were validated by quantitative real-time PCR and Sanger sequencing, respectively. Molecular results were correlated with prognosis.Results: All PCNSLs were diffuse large B-cell lymphomas, and the patients received chemotherapy without radiotherapy as initial treatment. The SNP analysis revealed recurrent large and focal chromosome imbalances that target candidate genes in PCNSL oncogenesis. The most frequent genomic abnormalities were (i) 6p21.32 loss (HLA locus), (ii) 6q loss, (iii) CDKN2A homozygous deletions, (iv) 12q12-q22, and (v) chromosome 7q21 and 7q31 gains. Homozygous deletions of PRMD1, TOX, and DOCK5 and the amplification of HDAC9 were also detected. Sequencing of matched tumor and blood DNA samples identified novel somatic mutations in MYD88 and TBL1XR1 in 38% and 14% of the cases, respectively. The correlation of genetic abnormalities with clinical outcomes using multivariate analysis showed that 6q22 loss (P ¼ 0.006 and P ¼ 0.01) and CDKN2A homozygous deletion (P ¼ 0.02 and P ¼ 0.01) were significantly associated with shorter progression-free survival and overall survival.Conclusions: Our study provides new insights into the molecular tumorigenesis of PCNSL and identifies novel genetic alterations in this disease, especially MYD88 and TBL1XR1 mutations activating the NF-kB signaling pathway, which may be promising targets for future therapeutic strategies.

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Section: Discussionmentioning

confidence: 99%

Recurrent Mutations of MYD88 and TBL1XR1 in Primary Central Nervous System Lymphomas

González-Aguilar

Idbaïh

Boisselier

et al. 2012

Clinical Cancer Research

222

171

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“…GOLPH3L is located at 1q21.3. It has been reported that 1q21 is amplified in several human malignancies, including rhabdomyosarcoma (16)(17)(18)(19)(20)(21)(22)(23)(24). An amplification of 5p13 has not yet been reported in rhabdomyosarcoma.…”

Section: Discussionmentioning

confidence: 99%

Role of GOLPH3 and GOLPH3L in the proliferation of human rhabdomyosarcoma

Kunigou

Nagao²,

Kawabata³

et al. 2011

Oncol Rep

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Abstract. GOLPH3 was originally identified by proteomic analyses of Golgi proteins localized in the trans-Golgi network. Recently, it was reported that GOLPH3 is up-regulated in various types of malignancies, including melanoma, colon cancer and lung cancer. However, the mechanism through which GOLPH3 is involved in the pathogenesis of rhabdomyosarcoma remains unidentified. In order to explore the function of GOLPH3 and its isoform, GOLPH3L, in the pathogenesis of rhabdomyosarcoma, we investigated the expression and knockdown effects of GOLPH3 and GOLPH3L in human rhabdomyosarcoma. Western blot analysis and real-time PCR revealed that human rhabdomyosarcoma cell lines and biopsy specimens exhibited an increased expression of GOLPH3 and GOLPH3L. GOLPH3 and GOLPH3L knockdown by siRNA prevented the proliferation of human rhabdomyosarcoma cell lines. In addition, double-knockdown of GOLPH3 and GOLPH3L also prevented the proliferation of rhabdomyosarcoma cell lines. Our findings improve the understanding of rhabdomyosarcoma pathogenesis and suggest that the knockdown of GOLPH3 or GOLPH3L may be an effective treatment for rhabdomyosarcoma. IntroductionRhabdomyosarcoma, which is the most common soft-tissue sarcoma in children, includes two major subtypes, alveolar rhabdomyosarcoma and embryonal rhabdomyosarcoma. Approximately 70% of rhabdomyosarcoma patients without metastatic tumors are cured, but the prognosis of patients with metastasis or relapse remains dismal. Although numerous clinical trials have been performed, little improvement has been made for high-risk rhabdomyosarcoma patients, who have a 3-year overall survival of approximately 30% (1,2). Thus, improvements in outcome and in the understanding of the molecular pathways of rhabdomyosarcoma pathogenesis are a priority.GOLPH3 (also known as GOPP1, GPP34, MIDAS or FLJ90675) was originally identified by proteomic analyses of Golgi proteins localized to the trans-Golgi network (3,4). It has been reported that GOLPH3 is dynamically associated with the trans-Golgi matrix, as it rapidly moves from the transGolgi network to the cytosol and localizes in endosomes and at the plasma membrane (5). Recently, it has been reported that GOLPH3 modulates solid tumors through mTOR signaling (6).GOLPH3L (also known as GPP34R, GMx33β or FLJ10687) is an isoform of GOLPH3; these proteins are very homologous to each other and are similarly localized (4). Although the two isoforms are highly homologous in their amino acid sequences, the function of GOLPH3L has not yet been examined.In the present study, we investigated the involvement of GOLPH3 and GOLPH3L in the pathogenesis of human rhabdomyosarcoma. We assessed the expression of GOLPH3 and GOLPH3L in rhabdomyosarcoma and the effect of GOLPH3 or GOLPH3L inhibition on the growth of rhabdomyosarcoma cells. We found that the knockdown of GOLPH3 or GOLPH3L inhibited human rhabdomyosarcoma cell proliferation. Materials and methodsCell culture. The human rhabdomyosarcoma cell lines, KYM-1 and RD, were provided by the Health Science R...

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“…Recent studies have demonstrated that these histone clusters genes are overexpressed in several types of malignancies. Sadikovic and colleagues performed integrative whole-genome analysis of DNA copy numbers, promoter methylation, and gene expression using 10 osteosarcomas and identified significant changes, including the hypomethylation, gain, and overexpression of histone cluster 2 genes on chromosome 1q21.1-q21.3 (19). Moreover, Perez-Margan and colleagues identified candidate genes related to meningioma recurrence by differential gene expression profiling analyses of 33 original and 7 recurrent meningiomas.…”

Section: Discussionmentioning

confidence: 99%

Contrasting Expression Patterns of Histone mRNA and microRNA 760 in Patients with Gastric Cancer

Iwaya

Fukagawa

Suzuki

et al. 2013

Clinical Cancer Research

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Purpose: Recent studies revealed that both disseminated tumor cells and noncancerous cells contributed to cancer progression cooperatively in the bone marrow. Here, RNA-seq analysis of bone marrow from gastric cancer patients was performed to identify prognostic markers for gastric cancer.Experimental Design: Bone marrow samples from eight gastric cancer patients (stages I and IV: n ¼ 4 each) were used for RNA-seq analysis. Results were validated through quantitative real-time PCR (qRT-PCR) analysis of HIST1H3D expression in 175 bone marrow, 92 peripheral blood, and 115 primary tumor samples from gastric cancer patients. miR-760 expression was assayed using qRT-PCR in 105 bone marrow and 96 primary tumor samples. Luciferase reporter assays were performed to confirm whether histone mRNAs were direct targets of miR-760. miR-760 expression was also evaluated in noncancerous cells from gastric cancer patients.

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Identification of interactive networks of gene expression associated with osteosarcoma oncogenesis by integrated molecular profiling

Cited by 121 publications

References 38 publications

Recurrent Mutations of MYD88 and TBL1XR1 in Primary Central Nervous System Lymphomas

Recurrent Mutations of MYD88 and TBL1XR1 in Primary Central Nervous System Lymphomas

Role of GOLPH3 and GOLPH3L in the proliferation of human rhabdomyosarcoma

Contrasting Expression Patterns of Histone mRNA and microRNA 760 in Patients with Gastric Cancer

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