ALT Positivity in Human Cancers: Prevalence and Clinical Insights

MacKenzie, Danny; Watters, Andrea; To, Julie T.; Young, Melody W.; Muratori, Jonathan; Wilkoff, Marni H.; Abraham, Rita G.; Plummer, Maria M.; Zhang, Dong

doi:10.3390/cancers13102384

Cited by 53 publications

(55 citation statements)

References 213 publications

(559 reference statements)

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“…Loss-of-function (LoF) genetic alterations in the chromatin remodeling genes ATRX and DAXX (death domainassociated protein) were associated with ALT in multiple malignancies [30,[73][74][75][76][77]. Moreover, ALT is less commonly associated with mutations in TP53, IDH, H3.3 G34R/V, H3F3A, and SMARCL1 [78][79][80][81][82][83][84]. LoF mutations in ATRX are the most common genetic lesions in NB [24,85].…”

Section: Alt and Atrx Genetic Alterationsmentioning

confidence: 99%

How Do Telomere Abnormalities Regulate the Biology of Neuroblastoma?

Akter

2021

Biomolecules

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Telomere maintenance plays important roles in genome stability and cell proliferation. Tumor cells acquire replicative immortality by activating a telomere-maintenance mechanism (TMM), either telomerase, a reverse transcriptase, or the alternative lengthening of telomeres (ALT) mechanism. Recent advances in the genetic and molecular characterization of TMM revealed that telomerase activation and ALT define distinct neuroblastoma (NB) subgroups with adverse outcomes, and represent promising therapeutic targets in high-risk neuroblastoma (HRNB), an aggressive childhood solid tumor that accounts for 15% of all pediatric-cancer deaths. Patients with HRNB frequently present with widely metastatic disease, with tumors harboring recurrent genetic aberrations (MYCN amplification, TERT rearrangements, and ATRX mutations), which are mutually exclusive and capable of promoting TMM. This review provides recent insights into our understanding of TMM in NB tumors, and highlights emerging therapeutic strategies as potential treatments for telomerase- and ALT-positive tumors.

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Section: Alt and Atrx Genetic Alterationsmentioning

confidence: 99%

How Do Telomere Abnormalities Regulate the Biology of Neuroblastoma?

Akter

2021

Biomolecules

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“…Therefore, we suggest that telomere shortening is typical of ULs and most likely precedes the occurrence of chromosomal aberrations in UL cells. The rejuvenation of telomere length does not appear to be characteristic of ULs either through telomerase activity [ 57 , 58 ] due to the lack of an active telomerase complex [ 59 , 60 ] or through the ALT mechanism, which is typical of malignant tumours [ 61 ]. Therefore, telomere shortening in UL cells is most likely a factor contributing to chromosomal aberrations.…”

Section: Discussionmentioning

confidence: 99%

Cytogenomic Profile of Uterine Leiomyoma: In Vivo vs. In Vitro Comparison

et al. 2021

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We performed a comparative cytogenomic analysis of cultured and uncultured uterine leiomyoma (UL) samples. The experimental approach included karyotyping, aCGH, verification of the detected chromosomal abnormalities by metaphase and interphase FISH, MED12 mutation analysis and telomere measurement by Q-FISH. An abnormal karyotype was detected in 12 out of 32 cultured UL samples. In five karyotypically abnormal ULs, MED12 mutations were found. The chromosomal abnormalities in ULs were present mostly by complex rearrangements, including chromothripsis. In both karyotypically normal and abnormal ULs, telomeres were ~40% shorter than in the corresponding myometrium, being possibly prerequisite to chromosomal rearrangements. The uncultured samples of six karyotypically abnormal ULs were checked for the detected chromosomal abnormalities through interphase FISH with individually designed DNA probe sets. All chromosomal abnormalities detected in cultured ULs were found in corresponding uncultured samples. In all tumors, clonal spectra were present by the karyotypically abnormal cell clone/clones which coexisted with karyotypically normal ones, suggesting that chromosomal abnormalities acted as drivers, rather than triggers, of the neoplastic process. In vitro propagation did not cause any changes in the spectrum of the cell clones, but altered their ratio compared to uncultured sample. The alterations were unique for every UL. Compared to its uncultured counterpart, the frequency of chromosomally abnormal cells in the cultured sample was higher in some ULs and lower in others. To summarize, ULs are characterized by both inter- and intratumor genetic heterogeneity. Regardless of its MED12 status, a tumor may be comprised of clones with and without chromosomal abnormalities. In contrast to the clonal spectrum, which is unique and constant for each UL, the clonal frequency demonstrates up or down shifts under in vitro conditions, most probably determined by the unequal ability of cells with different genetic aberrations to exist outside the body.

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“…These tumors are prevalently of mesenchymal origin. They are characterized by high genetic instability, and, in many histotypes, ALT positivity is associated with worse prognosis [ 90 ]. In this regard, TERRA G4 ligands could represent an effective pharmacological strategy to hit this class of tumors.…”

Section: Discussionmentioning

confidence: 99%

Targeting of Telomeric Repeat-Containing RNA G-Quadruplexes: From Screening to Biophysical and Biological Characterization of a New Hit Compound

Marzano

Pagano

Iaccarino

et al. 2021

IJMS

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DNA G-quadruplex (G4) structures, either within gene promoter sequences or at telomeres, have been extensively investigated as potential small-molecule therapeutic targets. However, although G4s forming at the telomeric DNA have been extensively investigated as anticancer targets, few studies focus on the telomeric repeat-containing RNA (TERRA), transcribed from telomeres, as potential pharmacological targets. Here, a virtual screening approach to identify a library of drug-like putative TERRA G4 binders, in tandem with circular dichroism melting assay to study their TERRA G4-stabilizing properties, led to the identification of a new hit compound. The affinity of this compound for TERRA RNA and some DNA G4s was analyzed through several biophysical techniques and its biological activity investigated in terms of antiproliferative effect, DNA damage response (DDR) activation, and TERRA RNA expression in high vs. low TERRA-expressing human cancer cells. The selected hit showed good affinity for TERRA G4 and no binding to double-stranded DNA. In addition, biological assays showed that this compound is endowed with a preferential cytotoxic effect on high TERRA-expressing cells, where it induces a DDR at telomeres, probably by displacing TERRA from telomeres. Our studies demonstrate that the identification of TERRA G4-targeting drugs with potential pharmacological effects is achievable, shedding light on new perspectives aimed at discovering new anticancer agents targeting these G4 structures.

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ALT Positivity in Human Cancers: Prevalence and Clinical Insights

Cited by 53 publications

References 213 publications

How Do Telomere Abnormalities Regulate the Biology of Neuroblastoma?

How Do Telomere Abnormalities Regulate the Biology of Neuroblastoma?

Cytogenomic Profile of Uterine Leiomyoma: In Vivo vs. In Vitro Comparison

Targeting of Telomeric Repeat-Containing RNA G-Quadruplexes: From Screening to Biophysical and Biological Characterization of a New Hit Compound

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