Utility of TERT Promoter Mutations for Cutaneous Primary Melanoma Diagnosis

Thomas, Nancy E.; Edmiston, Sharon N.; Tsai, Yi-Hsuan; Parker, Joel S.; Busam, Klaus J.; Scott, Glynis; Zedek, Daniel C.; Parrish, Eloise; Hao, Honglin; Slater, Nathaniel A.; Pearlstein, Michelle V.; Frank, Jill S.; Kuan, Pei Fen; Ollila, David W.; Conway, Kathleen

doi:10.1097/dad.0000000000001259

Cited by 32 publications

(36 citation statements)

References 33 publications

(57 reference statements)

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“…87 In different melanocytic neoplasms, the TERT promoter mutations serve as ancillary tools for ambiguous histological tumors because of their high specificity for melanoma and absence in melanocytic nevi and melanocytes adjacent to the tumors. 64,[108][109][110][111] In bladder cancer, besides being associated with an increased disease recurrence and poor patient outcome, the specificity of the TERT promoter mutations distinguishes histologically deceptive cancers from benign mimics. 88,112 The TERT promoter mutations associated with high disease grades and the worst patient survival in gliomas and together with other markers follow histological classification into subgroups with distinct outcomes.…”

Section: Impact Of Tert Promoter Mutationsmentioning

confidence: 99%

“…A study to measure the effect of individual TERT promoter alterations showed that the less frequent −138/−139CC>TT tandem mutation had the worst impact on disease‐free and melanoma‐specific survival in stage I and II patients 87 . In different melanocytic neoplasms, the TERT promoter mutations serve as ancillary tools for ambiguous histological tumors because of their high specificity for melanoma and absence in melanocytic nevi and melanocytes adjacent to the tumors 64,108‐111 . In bladder cancer, besides being associated with an increased disease recurrence and poor patient outcome, the specificity of the TERT promoter mutations distinguishes histologically deceptive cancers from benign mimics 88,112 .…”

Section: Impact Of Tert Promoter Mutationsmentioning

confidence: 99%

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Occurrence, functionality and abundance of the TERT promoter mutations

Rachakonda

Hoheisel

Kumar

2021

Intl Journal of Cancer

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Telomere shortening at chromosomal ends due to the constraints of the DNA replication process acts as a tumor suppressor by restricting the replicative potential in primary cells. Cancers evade that limitation primarily through the reactivation of telomerase via different mechanisms. Mutations within the promoter of the telomerase reverse transcriptase (TERT) gene represent a definite mechanism for the ribonucleic enzyme regeneration predominantly in cancers that arise from tissues with low rates of self-renewal. The promoter mutations cause a moderate increase in TERT transcription and consequent telomerase upregulation to the levels sufficient to delay replicative senescence but not prevent bulk telomere shortening and genomic instability. Since the discovery, a staggering number of studies have resolved the discrete aspects, effects and clinical relevance of the TERT promoter mutations. The promoter mutations link transcription of TERT with oncogenic pathways, associate with markers of poor outcome and define patients with reduced survivals in several cancers. In this review, we discuss the occurrence and impact of the promoter mutations and highlight the mechanism of TERT activation. We further deliberate on the foundational question of the abundance of the TERT promoter mutations and a general dearth of functional mutations within noncoding sequences, as evident from pan-cancer analysis of the whole-genomes. We posit that the favorable genomic constellation within the TERT promoter may be less than a common occurrence in other noncoding functional elements. Besides, the evolutionary constraints limit the functional fraction within the human genome, hence the lack of abundant mutations outside the coding sequences.

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Section: Impact Of Tert Promoter Mutationsmentioning

confidence: 99%

Section: Impact Of Tert Promoter Mutationsmentioning

confidence: 99%

Occurrence, functionality and abundance of the TERT promoter mutations

Rachakonda

Hoheisel

Kumar

2021

Intl Journal of Cancer

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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%

“…It is worth noting that noncoding mutations in only the promoters of TERT and DPH3 were previously analyzed in BCC [27,135,136]; TERT and DPH3 are known to be mutated in many cancers, including melanoma [109,110]. However, as our WES design generally did not cover promoter regions, we did not look for or detect these mutations.…”

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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“…In different melanocytic neoplasms, the TERT promoter mutations serve as ancillary tools for ambiguous histological tumors because of their high specificity for melanoma and absence in melanocytic nevi and melanocytes adjacent to the tumors 64,[108][109][110][111] . In bladder cancer, besides being associated with an increased disease recurrence and poor patient outcome, the specificity of the TERT promoter mutations distinguishes histologically deceptive cancers from benign mimics 88,112 .…”

Section: Impact Of Tert Promoter Mutationsmentioning

confidence: 99%

Occurrence, functionality, and abundance of theTERTpromoter mutations

Rachakonda

Hoheisel

Kumar

2021

Preprint

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Telomere shortening at chromosomal ends due to the constraints of the DNA replication process acts as a tumor suppressor by restricting the replicative potential in primary cells. Cancers evade that limitation primarily through rejuvenation of telomerase via different mechanisms. Mutations within the promoter of the telomerase reverse transcriptase (TERT) gene define a definite method for the ribonucleic enzyme regeneration predominantly in cancers that arise from tissues with low rates of self-renewal. The promoter mutations cause a moderate surge in TERT transcription and telomerase rejuvenation to the levels sufficient to delay replicative senescence but not prevent bulk telomere shortening and genomic instability. Since the discovery, a staggering number of studies and publications have resolved the discrete aspects, effects, and clinical relevance of the TERT promoter mutations. Those noncoding alterations link the TERT transcription with oncogenic pathways, associate with markers of poor outcome, and define patients with reduced survivals in several cancers. In this review, we discuss the occurrence and impact of the promoter mutations and highlight the mechanism of TERT activation. We further deliberate on the foundational question of the abundance of the TERT promoter mutations and a general dearth of functional mutations within noncoding sequences as evident from pan-cancer analysis of the whole-genomes. We posit that the favorable genomic constellation within the TERT promoter may be less than a common occurrence in other noncoding functional elements and the evolutionary constraints limit the functional fraction within the human genome, hence the lack of abundant mutations outside the coding sequences.

show abstract

Utility of TERT Promoter Mutations for Cutaneous Primary Melanoma Diagnosis

Cited by 32 publications

References 33 publications

Occurrence, functionality and abundance of the TERT promoter mutations

Occurrence, functionality and abundance of the TERT promoter mutations

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

Occurrence, functionality, and abundance of theTERTpromoter mutations

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