scholarly journals Inherited predisposition to malignant mesothelioma and overall survival following platinum chemotherapy

2019 ◽  
Vol 116 (18) ◽  
pp. 9008-9013 ◽  
Author(s):  
Raffit Hassan ◽  
Betsy Morrow ◽  
Anish Thomas ◽  
Tom Walsh ◽  
Ming K. Lee ◽  
...  
Keyword(s):  
Overall Survival ◽  
Dna Repair ◽  
Tumor Suppressor ◽  
Malignant Mesothelioma ◽  
Tumor Suppressor Genes ◽  
Pleural Mesothelioma ◽  
Loss Of Function ◽  
Suppressor Genes ◽  
Inherited Mutations ◽  
Platinum Chemotherapy

Survival from malignant mesothelioma, particularly pleural mesothelioma, is very poor. For patients with breast, ovarian, or prostate cancers, overall survival is associated with increased sensitivity to platinum chemotherapy due to loss-of-function mutations in DNA repair genes. The goal of this project was to evaluate, in patients with malignant mesothelioma, the relationship between inherited loss-of-function mutations in DNA repair and other tumor suppressor genes and overall survival following platinum chemotherapy. Patients with histologically confirmed malignant mesothelioma were evaluated for inherited mutations in tumor suppressor genes. Survival was evaluated with respect to genotype and site of mesothelioma. Among 385 patients treated with platinum chemotherapy, median overall survival was significantly longer for patients with loss-of-function mutations in any of the targeted genes compared with patients with no such mutation (P = 0.0006). The effect of genotype was highly significant for patients with pleural mesothelioma (median survival 7.9 y versus 2.4 y, P = 0.0012), but not for patients with peritoneal mesothelioma (median survival 8.2 y versus 5.4 y, P = 0.47). Effect of patient genotype on overall survival, measured at 3 y, remained independently significant after adjusting for gender and age at diagnosis, two other known prognostic factors. Patients with pleural mesothelioma with inherited mutations in DNA repair and other tumor suppressor genes appear to particularly benefit from platinum chemotherapy compared with patients without inherited mutations. These patients may also benefit from other DNA repair targeted therapies such as poly-ADP ribose polymerase (PARP) inhibitors.

scholarly journals Transposon Mutagenesis-Guided CRISPR/Cas9 Screening Strongly Implicates Dysregulation of Hippo/YAP Signaling in Malignant Peripheral Nerve Sheath Tumor Development

Cancers ◽  
2021 ◽  
Vol 13 (7) ◽  
pp. 1584
Author(s):  
Germán L. Vélez-Reyes ◽  
Nicholas Koes ◽  
Ji Hae Ryu ◽  
Gabriel Kaufmann ◽  
Mariah Berner ◽  
...  
Keyword(s):  
Tumor Suppressor ◽  
Schwann Cell ◽  
Peripheral Nerve ◽  
Cell Line ◽  
Schwann Cells ◽  
Tumor Suppressor Genes ◽  
Tumor Formation ◽  
Loss Of Function ◽  
Suppressor Genes ◽  
Nerve Sheath

Malignant peripheral nerve sheath tumors (MPNSTs) are highly aggressive, genomically complex, have soft tissue sarcomas, and are derived from the Schwann cell lineage. Patients with neurofibromatosis type 1 syndrome (NF1), an autosomal dominant tumor predisposition syndrome, are at a high risk for MPNSTs, which usually develop from pre-existing benign Schwann cell tumors called plexiform neurofibromas. NF1 is characterized by loss-of-function mutations in the NF1 gene, which encode neurofibromin, a Ras GTPase activating protein (GAP) and negative regulator of RasGTP-dependent signaling. In addition to bi-allelic loss of NF1, other known tumor suppressor genes include TP53, CDKN2A, SUZ12, and EED, all of which are often inactivated in the process of MPNST growth. A sleeping beauty (SB) transposon-based genetic screen for high-grade Schwann cell tumors in mice, and comparative genomics, implicated Wnt/β-catenin, PI3K-AKT-mTOR, and other pathways in MPNST development and progression. We endeavored to more systematically test genes and pathways implicated by our SB screen in mice, i.e., in a human immortalized Schwann cell-based model and a human MPNST cell line, using CRISPR/Cas9 technology. We individually induced loss-of-function mutations in 103 tumor suppressor genes (TSG) and oncogene candidates. We assessed anchorage-independent growth, transwell migration, and for a subset of genes, tumor formation in vivo. When tested in a loss-of-function fashion, about 60% of all TSG candidates resulted in the transformation of immortalized human Schwann cells, whereas 30% of oncogene candidates resulted in growth arrest in a MPNST cell line. Individual loss-of-function mutations in the TAOK1, GDI2, NF1, and APC genes resulted in transformation of immortalized human Schwann cells and tumor formation in a xenograft model. Moreover, the loss of all four of these genes resulted in activation of Hippo/Yes Activated Protein (YAP) signaling. By combining SB transposon mutagenesis and CRISPR/Cas9 screening, we established a useful pipeline for the validation of MPNST pathways and genes. Our results suggest that the functional genetic landscape of human MPNST is complex and implicate the Hippo/YAP pathway in the transformation of neurofibromas. It is thus imperative to functionally validate individual cancer genes and pathways using human cell-based models, to determinate their role in different stages of MPNST development, growth, and/or metastasis.

Progression of colorectal cancer is associated with multiple tumor suppressor gene defects but inhibition of tumorigenicity is accomplished by correction of any single defect via chromosome transfer

1992 ◽  
Vol 12 (3) ◽  
pp. 1387-1395
Author(s):  
M C Goyette ◽  
K Cho ◽  
C L Fasching ◽  
D B Levy ◽  
K W Kinzler ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Tumor Suppressor ◽  
Tumor Suppressor Genes ◽  
Loss Of Function ◽  
Chromosome 18 ◽  
Chromosome 5 ◽  
Suppressor Genes ◽  
Single Defect

Carcinogenesis is a multistage process that has been characterized both by the activation of cellular oncogenes and by the loss of function of tumor suppressor genes. Colorectal cancer has been associated with the activation of ras oncogenes and with the deletion of multiple chromosomal regions including chromosomes 5q, 17p, and 18q. Such chromosome loss is often suggestive of the deletion or loss of function of tumor suppressor genes. The candidate tumor suppressor genes from these regions are, respectively, MCC and/or APC, p53, and DCC. In order to further our understanding of the molecular and genetic mechanisms involved in tumor progression and, thereby, of normal cell growth, it is important to determine whether defects in one or more of these loci contribute functionally in the progression to malignancy in colorectal cancer and whether correction of any of these defects restores normal growth control in vitro and in vivo. To address this question, we have utilized the technique of microcell-mediated chromosome transfer to introduce normal human chromosomes 5, 17, and 18 individually into recipient colorectal cancer cells. Additionally, chromosome 15 was introduced into SW480 cells as an irrelevant control chromosome. While the introduction of chromosome 17 into the tumorigenic colorectal cell line SW480 yielded no viable clones, cell lines were established after the introduction of chromosomes 15, 5, and 18. Hybrids containing chromosome 18 are morphologically similar to the parental line, whereas those containing chromosome 5 are morphologically distinct from the parental cell line, being small, polygonal, and tightly packed. SW480-chromosome 5 hybrids are strongly suppressed for tumorigenicity, while SW480-chromosome 18 hybrids produce slowly growing tumors in some of the animals injected. Hybrids containing the introduced chromosome 18 but was significantly reduced in several of the tumor reconstitute cell lines. Introduction of chromosome 5 had little to no effect on responsiveness, whereas transfer ot chromosome 18 restored responsiveness to some degree. Our findings indicate that while multiple defects in tumor suppressor genes seem to be required for progression to the malignant state in colorectal cancer, correction of only a single defect can have significant effects in vivo and/or in vitro.

scholarly journals GENE-41. UNDERSTANDING THE DIFFERENCES IN ADOLESCENT AND YOUNG ADULT (AYA) GLIOMAS AND OLDER ADULT (OA) GLIOMAS BASED ON FUNCTIONAL MOLECULAR SUBGROUPS

2019 ◽  
Vol 21 (Supplement_6) ◽  
pp. vi106-vi106
Author(s):  
Catherine Bi ◽  
Ashwin Subramaniam ◽  
Joanne Xiu ◽  
Amy Heimberger ◽  
Sharon Michelhaugh ◽  
...  
Keyword(s):  
Dna Repair ◽  
Transcriptional Regulation ◽  
Tumor Suppressor ◽  
Metabolic Pathways ◽  
Tumor Suppressor Genes ◽  
Mutation Frequency ◽  
Pik3ca Mutation ◽  
Low Grade ◽  
Suppressor Genes ◽  
Pathway Gene

Abstract BACKGROUND Gliomas in the AYA population (15–39 years of age) have unique biological characteristics and need to be better characterized. METHODS Glioma tumors in AYA subjects and subjects >65 years of age (OA) were analyzed by next generation sequencing using a 592 gene panel. Pathogenic mutations were classified into five functional groups, viz. metabolic pathways genes (IDH1/2, FH), tumor suppressor genes (TP53, RB1, APC, NF1/2, PTEN, TSC1/2), genes involved in DNA repair (MMR genes, BRCA1/2, POLE, ARID1A, CHEK2, ATM, BLM, BRIP1, WRN, BARD1, POT1, MUTYH), oncogenes (BRAF, NRAS, HRAS, EGFR, PDGFRA, FGFR1, NOTCH1, MYCN), and genes involved in transcriptional regulation (SETD2, H3F3A, KMTD2A/2C/2D, KDM6A, PIK3CA). Mutation frequency in AYA tumors and OA tumors were compared using Chi-squared analysis (Pearson’s score χ2; likelihood ratio LR). RESULTS 720 unique gliomas tumors were analyzed: 118 AYA, 602 OA; 420 males, 300 females. When both groups are considered together, glioblastoma was the most common histology (75%), followed by grade 3 astrocytoma (13%), glioma NOS (3.8%), oligodendrogliomas (3%), low grade gliomas (2.9%) and other (2.3%). AYA tumors harbored more metabolic pathway gene mutations (χ2 137.7, p< 0.0001) driven primarily by IDH1 mutations, while OA tumors had a higher mutation frequency in oncogenes (χ2 9.22, p=0.0024) driven by EGFR mutations (LR 27.567) and tumor suppressor genes (χ2 40.35, p< 0.0001) driven by NF1 (LR 18.147) and PTEN (LR 66.216). No significant differences were noted in mutation frequency in DNA repair or transcriptional regulation genes. However, AYA glioblastoma tumors had a significant increase in mutations in genes involved in chromatin remodeling, (χ2 11.43, p=0.0007) even after excluding H3F3A. CONCLUSIONS Functional genomic classification of AYA tumors may help develop better targeted therapies, especially focused on genes involved in metabolic pathways and transcriptional regulation.

Recurring loss involving chromosomes 1, 3, and 22 in malignant mesothelioma: Possible sites of tumor suppressor genes

1989 ◽  
Vol 1 (2) ◽  
pp. 148-154 ◽  
Author(s):  
Wendy L. Flejter ◽  
Frederick P. Li ◽  
Karen H. Antman ◽  
Joseph R. Testa
Keyword(s):  
Tumor Suppressor ◽  
Malignant Mesothelioma ◽  
Tumor Suppressor Genes ◽  
Suppressor Genes

Prognostic Impact of the Number of Methylated Genes in Myelodysplastic Syndromes and Acute Myeloid Leukemias Treated with 5-Azacytidine

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 1717-1717
Author(s):  
María Abáigar ◽  
Fernando Ramos ◽  
Rocío Benito ◽  
María Díez-Campelo ◽  
Javier Sánchez-del-Real ◽  
...  
Keyword(s):  
Dna Methylation ◽  
Overall Survival ◽  
Tumor Suppressor ◽  
Myelodysplastic Syndromes ◽  
Tumor Suppressor Genes ◽  
Methylation Status ◽  
Prognostic Impact ◽  
Suppressor Genes ◽  
Myeloid Leukemias ◽  
Acute Myeloid

Abstract Abstract 1717 Background: Aberrant DNA methylation of tumor suppressor genes is a common event in myelodysplastic syndromes (MDS) and acute myeloid leukemias (AML). Therefore hypomethylating agents like azacytidine (AZA) and decitabine seem to be a good therapeutic approach for the treatment of these diseases. Clinical experience and recent published data have demonstrated that AZA is effective for the treatment of MDS and AML patients. However, the prognostic impact of the aberrant hypermethylation on response and outcome to AZA treatment remains to be determined. For this reason the influence of the methylation status of a selected set of tumor suppressor genes on the overall survival and clinical response in MDS and AML patients, prior to treatment with AZA was studied. Patients and Methods: A total of 78 patients with MDS or AML who had been treated with AZA were evaluated. Among these, 25 were excluded because they had received less than 4 cycles, AZA was used after allogeneic stem cell transplantation, response was not assessable, or there was not enough quality DNA available. So finally, the study was focused in 53 patients: 36 MDS and 17 AML. Most of the AML included in the study had low blast count (20–30%). Responses were assessed according to the IWG MDS criteria in accordance to Fenaux et.al, and IWG AML criteria following European LeukemiaNet recommendations. DNA methylation status was analyzed using the Methylation Specific Multiplex Ligation Probe Amplification (MS-MLPA), with a panel of 24 different tumor suppressor genes related to cell cycle control, apoptosis regulation, DNA repair, cell adhesion and cell growth. Results: In the study cohort 47% of patients had cytogenetic alterations prior to AZA treatment, 4 with isolated -5/del(5q), 7 with isolated −7/del(7q), 4 with trisomy 8, 4 with not isolated -5/del(5q), 1 with trisomy 14, and 5 with complex cytogenetics. Methylation analysis showed that most patients (74%) had at least one methylated gene, but only 10% of patients displayed more than 3 methylated genes. The most frequently methylated genes were IGSF4 (28.3%), CDKN2B (24.5%), ESR1 (22.6%), CDH13 (17%) and CDKN1B (11.3%). The presence of a high number (≥2) of methylated genes (p=0.02), an adverse cytogenetics (p=0.03) or anemia (p=0.04) were independent prognostic factors associated with shorter overall survival. Moreover, the analysis of those patients displaying “no methylation”, patients with 1 methylated gene, patients with 2 methylated genes and those with more than 3 methylated genes, showed that as the number of methylated genes increases, the survival was shorter. The patients displaying the highest level of methylation (more than 3 genes), had a very short survival (median OS of 9.3 months, p<0.001). Forty-nine per cent of all patients responded to azacytidine. The statistical analysis revealed that the number of methylated genes did not correlate in general with the clinical response to AZA, although four of the five patients with more than 3 genes methylated did not respond. By contrast, cytogenetics was the only factor that independently influenced the response to AZA. Thus 64.7% of patients with favorable cytogenetics responded to AZA, while only 28.6% of those with adverse cytogenetics responded (p=0.03). Interestingly, our study included 3 MDS patients with isolated chromosome 7 alterations, and all of them responded. Conclusion: In summary, these results suggest that the analysis of the methylation status before AZA treatment by a feasible methodology such as MS-MLPA could be used in a clinical setting in order to identify a group of patients with poor survival, in which other alternative therapeutic approaches might be considered. Disclosures: Ramos: Celgene, Novartis, Amgen, Pfizer, and Merck Sharp & Dohme: Honoraria. Hernández:Celgene: Research Funding.

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