Classifying Melanoma by TERT Promoter Mutational Status

Shaughnessy, Michael F.; Njauw, Ching‐Ni Jenny; Artomov, Mykyta; Hensin, Tsao

doi:10.1016/j.jid.2019.06.149

Cited by 24 publications

(35 citation statements)

References 16 publications

(16 reference statements)

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“…When we investigated the role of the rs2853669 polymorphism at −245 bp, which reportedly counteracts the activating effect of the above-mentioned TERTprom mutations [25] and modulates their negative effect on melanoma survival [4], we found that the SNP did not interfere with the effect of the two hotspots on treatment outcome and was not associated with telomere length, as opposed to what was observed in melanoma cell lines [26].…”

Section: Discussionmentioning

confidence: 90%

TERT Promoter Mutations Differently Correlate with the Clinical Outcome of MAPK Inhibitor-Treated Melanoma Patients

Bianco

Stagni

Giunco

et al. 2020

Cancers

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Resistance is a major challenge in the management of mitogen-activated protein kinase inhibitor (MAPKi)-treated metastatic melanoma. Tumor genetic alterations can cause MAPK pathway reactivation, leading to lack of response and poor outcome. Characterization of the mutational profile in patients with melanoma might be crucial for patient-tailored treatment choices. Mutations in the promoter region of the telomerase reverse transcriptase gene (TERTprom) lead to increased TERT expression and telomerase activity and are frequent in BRAFV600 mutant melanoma. Reportedly, TERTprom, and BRAFV600 mutations cooperate in driving cancer progression and aggressiveness. We evaluated the effect of the TERTprom status on the clinical outcome in 97 MAPKi-treated melanoma patients. We observed that patients with the c.-146C > T mutation showed a significantly worse progression-free survival (PFS) compared to those carrying the c.-124C > T mutation and a two-fold increased risk of progression (median 5.4 vs. 9.5 months; hazard ratio (HR) 1.9; 95% confidence interval (CI) 1.2–3.2; p = 0.013). This trend was also observed for the overall survival (OS); melanoma patients with the c.-146C > T mutation showed a poorer prognosis compared to those with the c.-124C > T mutation (median 13.3 vs. 25.5 months; HR 1.9, 95% CI 1.1–3.3, p = 0.023). Our results disclose a different correlation of the two TERTprom mutations with MAPKi-treated melanoma patient outcome, highlighting a different impact of the pathway blockade.

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Section: Discussionmentioning

confidence: 90%

TERT Promoter Mutations Differently Correlate with the Clinical Outcome of MAPK Inhibitor-Treated Melanoma Patients

Bianco

Stagni

Giunco

et al. 2020

Cancers

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“…Many of the identified noncoding hotspots were located in sequences of genes functionally related to cancer or more specifically to UV radiation-related skin cancers. Some of them were reported before in melanoma or identified by us in melanoma TCGA samples, the cancer type most intensively studied in terms of mutations in noncoding regions [109,110]. Below, we briefly describe the cancer-related role of the three most interesting genes with hotspot mutations in noncoding regions, i.e., BAD , DHODH , and CHCHD2 .…”

Section: Discussionmentioning

confidence: 99%

Profile of basal cell carcinoma mutations and copy number alterations - focus on gene-associated noncoding variants

Nawrocka

Galka-Marciniak

Urbanek-Trzeciak

et al. 2021

Preprint

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Basal cell carcinoma (BCC) of the skin is the most common cancer in humans, characterized by the highest mutation rate among cancers, and is mostly driven by mutations in genes involved in the hedgehog pathway. To date, almost all BCC genetic studies have focused exclusively on protein-coding sequences; therefore, the impact of noncoding variants on the BCC genome is unrecognized. In this study, with the use of whole-exome sequencing of 27 tumor/normal pairs of BCC samples, we performed an analysis of somatic mutations in both protein-coding sequences and gene-associated noncoding regions, including 5’UTRs, 3’UTRs, and exon-adjacent intron sequences. Separately, in each region, we performed hotspot identification, mutation enrichment analysis, and cancer driver identification with OncodriveFML. Additionally, we performed a whole-genome copy number alteration analysis with GISTIC2. Of the >80,000 identified mutations, ∼50% were localized in noncoding regions. The results of the analysis generally corroborated the previous findings regarding genes mutated in coding sequences, including PTCH1, TP53, and MYCN, but more importantly showed that mutations were also clustered in specific noncoding regions, including hotspots. Some of the genes specifically mutated in noncoding regions were identified as highly potent cancer drivers, of which BAD had a mutation hotspot in the 3’UTR, DHODH had a mutation hotspot in the Kozak sequence in the 5’UTR, and CHCHD2 frequently showed mutations in the 5’UTR. All of these genes are functionally implicated in cancer-related processes (e.g., apoptosis, mitochondrial metabolism, and de novo pyrimidine synthesis) or the pathogenesis of UV radiation-induced cancers. We also found that the identified BAD and CHCHD2 mutations frequently occur in melanoma but not in other cancers via The Cancer Genome Atlas analysis. Finally, we identified frequent deletion of chr9q, encompassing PTCH1, and unreported frequent copy number gain of chr9p, encompassing the genes encoding the immune checkpoint ligands PD-L1 and PD-L2. In conclusion, this study is the first systematic analysis of coding and noncoding mutations in BCC and provides a strong basis for further analyses of the variants in BCC and cancer in general.Author summaryThe study is the first systematic analysis of both coding and noncoding mutations in basal cell carcinoma (BCC), the most common and the most highly mutated human cancer. Noncoding mutations accounted for ∼50% (∼40K mutations) of all mutations detected by the standard WES approach. Among the genes frequently mutated in noncoding regions are: BAD with a hotspot in the 3’UTR, DHODH with a hotspot in the Kozak sequence, and CHCHD2 with mutations in 5’UTR, all genes functionally related to cell metabolism and apoptosis. Analysis of copy number alterations showed frequent chr9q deletion, encompassing PTCH1 (the key BCC tumor suppressor), and frequent copy number gain of chr9p, encompassing the genes of the immune checkpoint proteins PD-L1 and PD-L2.

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“…Previous studies have reported that TERT mutations could lead to overexpression of TERT in several cancers. For example, transcriptional activity of TERT with c.-124C > T, c.-146C > T or c.-57A > C was higher than wild type in melanoma [23,30]; Cao et al [31] reported that ampli cation of TERT increase the expression of TERT; Bayard et al [32] reported that rearrangement of TERT could induce overexpression of TERT. In survival analysis, we found that TERT mutations correlated with shorter TTP and OS of HCC patients underwent hepatectomy.…”

Section: Discussionmentioning

confidence: 99%

TERT Mutations Correlated With the Prognosis of Patients With Hepatitis B-Related Hepatocellular Carcinoma Underwent Curative Hepatectomy

Song¹,

Huo²,

He³

et al. 2021

Preprint

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Background To explore the value of TERT mutations in predicting the early recurrence and prognosis of hepatitis B-related hepatocellular carcinoma (HCC) patients underwent curative hepatectomy.Methods A total of 81 patients with hepatitis B-related HCC were enrolled and all patients underwent curative hepatectomy. Associations were sought between TERT mutations and recurrence rate within 2 years after hepatectomy, time to progress (TTP) and overall survival (OS).Results TERT mutations (HR: 2.985, 95%CI: 1.158-7.692, p=0.024) and Barcelona clinic liver (BCLC) stage B (HR: 3.326, 95%CI: 1.019-10.856, p=0.046) were independent risk factors for recurrence within 2 years after hepatectomy. Patients with a TERT mutation had poor TTP (p=0.003) and OS (p=0.013) than others. TERT mutations (HR: 2.245, 95%CI: 1.185-4.252, p=0.013) and BCLC stage B (HR: 2.132, 95%CI: 1.082-4.198, p=0.029) were independent risk factors for poor TTP after curative hepatectomy. A predictive model based on TERT mutations and BCLC stage had better ability to predict early recurrence after hepatectomy of HCC patients than any single factor (AUC: 0.688 vs. 0.639, 0.688 vs. 0.607, respectively). Patients with both TERT mutations and BCLC stage B had poorer TTP and OS than others (p=0.001, p<0.001, respectively).Conclusion TERT mutations had ability to predict early recurrence and poor prognosis for hepatitis B-related HCC patients underwent curative hepatectomy.

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Classifying Melanoma by TERT Promoter Mutational Status

Cited by 24 publications

References 16 publications

TERT Promoter Mutations Differently Correlate with the Clinical Outcome of MAPK Inhibitor-Treated Melanoma Patients

TERT Promoter Mutations Differently Correlate with the Clinical Outcome of MAPK Inhibitor-Treated Melanoma Patients

Profile of basal cell carcinoma mutations and copy number alterations - focus on gene-associated noncoding variants

TERT Mutations Correlated With the Prognosis of Patients With Hepatitis B-Related Hepatocellular Carcinoma Underwent Curative Hepatectomy

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