Loss of heterozygosity on chromosome 10q in glioblastomas, and its association with other genetic alterations and survival in Indian patients

Kakkar, Aanchal; Suri, Vaishali; Jha, Prerana; Srivastava, Arti; Sharma, Vikas; Pathak, Pankaj; Sharma, Mehar Chand; Sharma, Manish; Kale, Shashank S.; Chosdol, Kunzang; Phalak, Manoj; Sarkar, Chitra

doi:10.4103/0028-3886.79139

Cited by 17 publications

(2 citation statements)

References 25 publications

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“…Lower losses on chromosome 10 are seen in anaplastic astrocytoma indicating that loss of heterozygosity on chromosome 10 is a terminal genetic event associated with GBM [30]. Loss of heterozygosity on chromosome 10q has been found to be associated with reduced survival of GBM patients [9] and in a study of 25 cases of GBM in Indian patients was seen more frequently in older patients [31]. The loss of heterozygosity profile may thus have prognostic implications but to date has not guided treatment options.…”

Section: Molecular and Metabolic Alterations In Gbm And Their Potementioning

confidence: 99%

Emerging Biomarkers in Glioblastoma

McNamara

Sahebjam

Mason

2013

Cancers

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Glioblastoma, the most common primary brain tumor, has few available therapies providing significant improvement in survival. Molecular signatures associated with tumor aggressiveness as well as with disease progression and their relation to differences in signaling pathways implicated in gliomagenesis have recently been described. A number of biomarkers which have potential in diagnosis, prognosis and prediction of response to therapy have been identified and along with imaging modalities could contribute to the clinical management of GBM. Molecular biomarkers including O(6)-methlyguanine-DNA-methyltransferase (MGMT) promoter and deoxyribonucleic acid (DNA) methylation, loss of heterozygosity (LOH) of chromosomes 1p and 19q, loss of heterozygosity 10q, isocitrate dehydrogenase (IDH) mutations, epidermal growth factor receptor (EGFR), epidermal growth factor, latrophilin, and 7 transmembrane domain-containing protein 1 on chromosome 1 (ELTD1), vascular endothelial growth factor (VEGF), tumor suppressor protein p53, phosphatase and tensin homolog (PTEN), p16INK4a gene, cytochrome c oxidase (CcO), phospholipid metabolites, telomerase messenger expression (hTERT messenger ribonucleic acid [mRNA]), microRNAs (miRNAs), cancer stem cell markers and imaging modalities as potential biomarkers are discussed. Inclusion of emerging biomarkers in prospective clinical trials is warranted in an effort for more effective personalized therapy in the future.

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Section: Molecular and Metabolic Alterations In Gbm And Their Potementioning

confidence: 99%

Emerging Biomarkers in Glioblastoma

McNamara

Sahebjam

Mason

2013

Cancers

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“…The assessment of LOH10q genotype is not included in the recent WHO classification for gliomas (WHO 2016), as it is believed that the assessment of both chromosome 7+/10q− and TERTp mutations is perhaps more informative than assessing EGFR amplification for the diagnosis of GBM (7). Moreover, most studies to date have identified LOH of 10q as a poor prognostic marker for high-grade gliomas (8)(9)(10). Allelic deletion on chromosome 10q has also been observed in various advanced human malignancies (11)(12)(13)(14).…”

Section: Introductionmentioning

confidence: 99%

ADD3 Deletion in Glioblastoma Predicts Disease Status and Survival

2021

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Loss of heterozygosity (LOH) on chromosome 10 frequently occurs in gliomas. Whereas genetic loci with allelic deletion often implicate tumor suppressor genes, a putative tumor suppressor Adducin3 (ADD3) mapped to chromosome 10q25.2 was found to be preferentially downregulated in high-grade gliomas compared with low-grade lesions. In this study, we unveil how the assessment of ADD3 deletion provides clinical significance in glioblastoma (GBM). By deletion mapping, we assessed the frequency of LOH in forty-three glioma specimens using five microsatellite markers spanning chromosome 10q23-10qter. Data were validated in The Cancer Genome Atlas (TCGA) cohort with 203 GBM patients. We found that allelic loss in both D10S173 (ADD3/MXI1 locus) and D10S1137 (MGMT locus) were positively associated with tumor grading and proliferative index (MIB-1). However, LOH events at only the ADD3/MXI1 locus provided prognostic significance with a marked reduction in patient survival and appeared to have diagnostic potential in differentiating high-grade gliomas from low-grade ones. Furthermore, we showed progressive loss of ADD3 in six out of seven patient-paired gliomas with malignant progression, as well as in recurrent GBMs. These findings suggest the significance of ADD3/MXI1 locus as a promising marker that can be used to refine the LOH10q assessment. Data further suggest the role of ADD3 as a novel tumor suppressor, whereby the loss of ADD3 is indicative of a progressive disease that may at least partially account for rapid disease progression in GBM. This study revealed for the first time the downregulation of ADD3 on the genetic level resulting from copy number deletion.

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Impact of Genetic Targets on Primary Brain Tumor Therapy: What’s Ready for Prime Time?

Zalatimo

Zoccoli

Patel

et al. 2012

Advances in Experimental Medicine and Biology

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Primary brain tumors constitute a substantial public health problem with 66,290 cases diagnosed in the US in 2012, and 13,700 deaths recorded. With discovery of genetic factors associated with specific brain tumor subtypes, the goal of therapy is changing from treating a class of tumors to developing individualized therapies catering to the molecular composition of the actual tumor. For oligodendrogliomas, the loss of 1p/19q due to an unbalanced translocation improves both survival and the response to therapy, and is thus both a prognostic and a predictive marker. Several additional genetic alterations such as EGFR amplification, MGMT methylation, PDGFR activation, and 9p and 10q loss, have improved our understanding of the characteristics of these tumors and may help guide therapy in the future. For astrocytic tumors, MGMT is associated with a better prognosis and an improved response to temozolomide, and for all glial tumors, mutations in the IDH1 gene are possibly the most potent of good prognostic markers. Three of these markers - 1p/19q deletions, MGMT methylation status, and mutations in the IDH1 gene - are so potent that a new brain tumor subtype, the "triple negative" glioma (1p/19q intact, MGMT unmethylated, IDH1 non-mutated) has entered common parlance. Newer markers, such as CD 133, require additional investigation to determine their prognostic and predictive utility. In medulloblastomas, markers of WNT activation, MYCC/MCYN amplification, and TrkC expression levels are reliable prognostic indicators, but do not yet drive specific treatment selection. Many other proposed markers, such as 17q gain, TP53 mutations, and hMOF protein expression show promise, but are not yet ready for prime time. In this chapter, we focus on the markers that have shown convincing prognostic, predictive, and diagnostic value, and discuss potential markers that are being currently being intensively investigated. We also discuss serum profiling of tumors in an effort to discover additional potential markers.

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Loss of heterozygosity on chromosome 10q in glioblastomas, and its association with other genetic alterations and survival in Indian patients

Cited by 17 publications

References 25 publications

Emerging Biomarkers in Glioblastoma

Emerging Biomarkers in Glioblastoma

ADD3 Deletion in Glioblastoma Predicts Disease Status and Survival

Impact of Genetic Targets on Primary Brain Tumor Therapy: What’s Ready for Prime Time?

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