Dataset Information

Telomere Maintenance Associated Mutations in the Genetic Landscape of Gynecological Mucosal Melanoma.

ABSTRACT: Purpose:Gynecological melanomas (GMs) are rare tumors with a poor prognosis. Here, we performed exome sequencing to generate the mutational landscape of GMs. Methods:Next-generation sequencing was carried out on mucosal melanoma samples (n = 35) obtained from gynecological sites. The alternative telomere lengthening (ALT) phenotype was verified by fluorescence in situ hybridization and the C-circle assay. Immunohistochemistry was performed to detect ATRX protein. Copy number variations in TERT were detected by droplet digital polymerase chain reaction. Results:In the 58 formalin-fixed paraffin-embedded samples, we identified 33 (56.9%) ALT-positive cases, with 23 showing loss of ATRX protein. TERT promoter mutation was not detected in GMs (n = 40), but copy number variations in the TERT region were observed in 20% (7/35) of the samples. TERT amplification was mutually exclusive with ALT (P < 0.05). Kaplan-Meier revealed that ALT relative to TERT amplification was associated with longer overall survival in GM patients without metastasis. Conclusion:These findings indicate that telomere maintenance mechanisms play a critical role in the tumorigenesis of GMs and may aid in the prediction of clinical prognosis and the development of targeted therapy for the treatment of GM.

SUBMITTER: Yuan G

PROVIDER: S-EPMC7492295 | biostudies-literature | 2020

REPOSITORIES: biostudies-literature

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Telomere Maintenance Associated Mutations in the Genetic Landscape of Gynecological Mucosal Melanoma.

Yuan Guangwen G Song Jinge J Li Ning N Song Qianqian Q Li Yifei Y Du Yingxi Y Wang Xiaobing X Jiao Yuchen Y Wu Lingying L

Frontiers in oncology 20200902

<h4>Purpose</h4>Gynecological melanomas (GMs) are rare tumors with a poor prognosis. Here, we performed exome sequencing to generate the mutational landscape of GMs.<h4>Methods</h4>Next-generation sequencing was carried out on mucosal melanoma samples (<i>n</i> = 35) obtained from gynecological sites. The alternative telomere lengthening (ALT) phenotype was verified by fluorescence <i>in situ</i> hybridization and the C-circle assay. Immunohistochemistry was performed to detect ATRX protein. Cop ...[more]

PMID: 32984050

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Project description:BackgroundTelomeres at the ends of eukaryotic chromosomes play a critical role in maintaining the integrity and stability of the genome and participate in the initiation of DNA damage/repair responses.MethodsWe performed a case-control study to evaluate the role of three SNPs (TERT-07, TERT-54 and POT1-03) in telomere maintenance genes previously found to be significantly associated with breast cancer risk. We used sister-sets obtained from the New York site of the Breast Cancer Family Registry (BCFR). Among the 313 sister-sets, there were 333 breast cancer cases and 409 unaffected sisters who were evaluated in the current study. We separately applied conditional logistic regression and generalized estimating equations (GEE) models to evaluate associations between the three SNPs and breast cancer risk within sister-sets. We examined the associations between genotype, covariates and telomere length among unaffected sisters using a GEE model.ResultsWe found no significant associations between the three SNPs in telomere maintenance genes and breast cancer risk by both conditional logistic regression and GEE models, nor were these SNPs significantly related to telomere length. Among unaffected sisters, shortened telomeres were statistically significantly correlated with never hormone replacement therapy (HRT) use. Increased duration of HRT use was significantly associated with reduced telomere length. The means of telomere length were 0.77 (SD = 0.35) for never HRT use, 0.67 (SD = 0.29) for HRT use < 5 yrs and 0.59 (SD = 0.24) for HRT use ≥ 5 yrs after adjusting for age of blood donation and race and ethnicity.ConclusionsWe found that exogenous hormonal exposure was inversely associated with telomere length. No significant associations between genetic variants and telomere length or breast cancer risk were observed. These findings provide initial evidence to understand hormonal exposure in the regulation of telomere length and breast cancer risk but need replication in prospective studies.

Dataset Information

Telomere Maintenance Associated Mutations in the Genetic Landscape of Gynecological Mucosal Melanoma.

Publications

Telomere Maintenance Associated Mutations in the Genetic Landscape of Gynecological Mucosal Melanoma.

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