Dataset Information

Molecular Genetics of Conjunctival Melanoma and Prognostic Value of TERT Promoter Mutation Analysis.

ABSTRACT: The aim of this study was exploration of the genetic background of conjunctival melanoma (CM) and correlation with recurrent and metastatic disease. Twenty-eight CM from the Rotterdam Ocular Melanoma Study group were collected and DNA was isolated from the formalin-fixed paraffin embedded tissue. Targeted next-generation sequencing was performed using a panel covering GNAQ, GNA11, EIF1AX, BAP1, BRAF, NRAS, c-KIT, PTEN, SF3B1, and TERT genes. Recurrences and metastasis were present in eight (29%) and nine (32%) CM cases, respectively. TERT promoter mutations were most common (54%), but BRAF (46%), NRAS (21%), BAP1 (18%), PTEN (14%), c-KIT (7%), and SF3B1 (4%) mutations were also observed. No mutations in GNAQ, GNA11, and EIF1AX were found. None of the mutations was significantly associated with recurrent disease. Presence of a TERT promoter mutation was associated with metastatic disease (p-value = 0.008). Based on our molecular findings, CM comprises a separate entity within melanoma, although there are overlapping molecular features with uveal melanoma, such as the presence of BAP1 and SF3B1 mutations. This warrants careful interpretation of molecular data, in the light of clinical findings. About three quarter of CM contain drug-targetable mutations, and TERT promoter mutations are correlated to metastatic disease in CM.

SUBMITTER: van Poppelen NM

PROVIDER: S-EPMC8198138 | biostudies-literature | 2021 May

REPOSITORIES: biostudies-literature

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Molecular Genetics of Conjunctival Melanoma and Prognostic Value of TERT Promoter Mutation Analysis.

van Poppelen Natasha M NM van Ipenburg Jolique A JA van den Bosch Quincy Q Vaarwater Jolanda J Brands Tom T Eussen Bert B Magielsen Frank F Dubbink Hendrikus J HJ Paridaens Dion D Brosens Erwin E Naus Nicole N de Klein Annelies A Kiliç Emine E Verdijk Robert M RM

International journal of molecular sciences 20210528 11

The aim of this study was exploration of the genetic background of conjunctival melanoma (CM) and correlation with recurrent and metastatic disease. Twenty-eight CM from the Rotterdam Ocular Melanoma Study group were collected and DNA was isolated from the formalin-fixed paraffin embedded tissue. Targeted next-generation sequencing was performed using a panel covering GNAQ, GNA11, EIF1AX, BAP1, BRAF, NRAS, c-KIT, PTEN, SF3B1, and ...[more]

PMID: 34071371

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Project description:PurposeMelanoma is the most aggressive form of skin cancer. Circulating tumor DNA (ctDNA) is a diagnostic and prognostic marker of melanoma. However, whether ctDNA mutations can independently predict survival remains controversial. This meta-analysis assessed the prognostic value of the presence or change in ctDNA mutations in melanoma patients.MethodsWe identified studies from the PubMed, EMBASE, Web of Science, and Cochrane databases. We estimated the combined hazard ratios (HRs) for overall survival (OS) and progression-free survival (PFS) using either fixed-effect or random-effect models based on heterogeneity.ResultsSixteen studies including 1,781 patients were included. Both baseline and posttreatment detectable ctDNA were associated with poor OS (baseline detectable vs. undetectable, pooled HR = 1.97, 95% CI = 1.64-2.36, P < 0.00001; baseline undetectable vs. detectable, pooled HR = 0.19, 95% CI = 0.11-0.36, P < 0.00001; posttreatment detectable vs. undetectable, pooled HR = 2.36, 95% CI = 1.30-4.28, P=0.005). For PFS, baseline detectable ctDNA may be associated with adverse PFS (baseline detectable vs. undetectable, pooled HR = 1.41, 95% CI = 0.84-2.37, P=0.19; baseline undetectable vs. detectable, pooled HR = 0.43, 95% CI = 0.19-0.95, P=0.04) and baseline high ctDNA and increased ctDNA were significantly associated with adverse PFS (baseline high vs. low/undetectable, pooled HR = 3.29, 95% CI = 1.73-6.25, P=0.0003; increase vs. decrease, pooled HR = 4.48, 95% CI = 2.45-8.17, P < 0.00001). The baseline BRAFV600 ctDNA mutation-positive group was significantly associated with adverse OS compared with the baseline ctDNA-negative group (pooled HR = 1.90, 95% CI = 1.58-2.29, P < 0.00001). There were no significant differences in PFS between the baseline BRAFV600 ctDNA mutation-detectable group and the undetectable group (pooled HR = 1.02, 95% CI = 0.72-1.44, P=0.92).ConclusionThe presence or elevation of ctDNA mutation or BRAFV600 ctDNA mutation was significantly associated with worse prognosis in melanoma patients.

Project description:Mutations in the telomerase reverse transcriptase gene promoter (TERTp) are common in glioblastomas (GBMs) and oligodendrogliomas (ODGs), and therefore, have a key role in tumorigenesis and may be of prognostic value. However, the extent of their prognostic importance in various gliomas is controversial. We studied 168 patients separated into five groups: Group 1: 65 patients with ODG carrying an IDH1 or IDH2 mutation (IDH-mutant) and 1p/19q-codeletion, Group 2: 23 patients with anaplastic astrocytoma (AA), IDH-mutant, Group 3: 13 patients with GBM, IDH-mutant, Group 4: 15 patients with AA, IDH-wildtype (WT), and Group 5: 52 patients with GBM, IDH-WT. TERTp mutations were found in 96.9%, 4.4%, 76.9%, 20.0%, and 84.6% of patients in Groups 1, 2, 3, 4, and 5, respectively. The R132H mutation in IDH1 was found in 60.5% (23/38) of patients in the AA cohort (Groups 2 and 4) and 20.0% (13/65) of patients from our GBM cohort (Groups 3 and 5), whereas all patients with ODG (Group 1) had a mutation either in IDH1 (n = 62) or IDH2 (n = 3). Using Kaplan Meier survival analysis, we found that the TERTp mutation was correlated with poor overall survival (OS) in Groups 2 and 4 combined (P = 0.001) and in Group 4 (P = 0.113), and in multivariate analysis, the TERTp mutant group was associated with significantly poor survival in Group 5 (P = 0.045). However, IDH mutation, MGMT methylation, and younger patient age (<55 years old) were significantly correlated with favorable OS (all P < 0.05) in our cohort of astrocytic and ODGs. In patients with ODG (Group 1), mutant IDH and TERTp did not have prognostic value because these mutations were universally present. Based on the revised 2016 WHO classification of gliomas, we found that TERTp mutation was frequently present in patients with GBM or ODG and because it was strongly correlated with poor survival outcome in patients with IDH-WT GBM in multivariate analysis, it may be of prognostic value in this subgroup of patients with gliomas.

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Project description:Multifocal occurrence is a main characteristic of urothelial bladder cancer (UBC). Whether urothelial transformation is caused by monoclonal events within the urothelium, or by polyclonal unrelated events resulting in several tumor clones is still under debate. TERT promoter mutations are the most common somatic alteration identified in UBC. In this study, we analyzed different histological tissues from whole-organ mapping bladder cancer specimens to reveal TERT mutational status, as well as to discern how tumors develop. Up to 23 tissues from nine whole-organ mapping bladder tumor specimens, were tested for TERT promoter mutations including tumor associated normal urothelium, non-invasive urothelial lesions (hyperplasia, dysplasia, metaplasia), carcinoma in situ (CIS) and different areas of muscle invasive bladder cancers (MIBC). The mutational DNA hotspot region within the TERT promoter was analyzed by SNaPshot analysis including three hot spot regions (-57, -124 or -146). Telomere length was measured by the Relative Human Telomere Length Quantification qPCR Assay Kit. TERT promoter mutations were identified in tumor associated normal urothelium as well as non-invasive urothelial lesions, CIS and MIBC. Analysis of separate regions of the MIBC showed 100% concordance of TERT promoter mutations within a respective whole-organ bladder specimen. Polyclonal events were observed in five out of nine whole-organ mapping bladder cancers housing tumor associated normal urothelium, non-invasive urothelial lesions and CIS where different TERT promoter mutations were found compared to MIBC. The remaining four whole-organ mapping bladders were monoclonal for TERT mutations. No significant differences of telomere length were observed. Examining multiple whole-organ mapping bladders we conclude that TERT promoter mutations may be an early step in bladder cancer carcinogenesis as supported by TERT mutations detected in tumor associated normal urothelium as well as non-invasive urothelial lesions. Since mutated TERT promoter regions within non-invasive urothelial lesions are not sufficient alone for the establishment of cancerous growth, this points to the contribution of other gene mutations as a requirement for tumor development.

Dataset Information

Molecular Genetics of Conjunctival Melanoma and Prognostic Value of TERT Promoter Mutation Analysis.

Publications

Molecular Genetics of Conjunctival Melanoma and Prognostic Value of <i>TERT</i> Promoter Mutation Analysis.

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