Whole exome sequencing identified a novel POT1 variant as a candidate pathogenic allele underlying a Li–Fraumeni-like family

Li, Yuping; Xie, Yupeng; Wang, Di; Xu, Hong; Ye, Junru; Yin, Jiani C.; Chen, Junjie; Yan, Junrong; Ye, Bin; Chen, Chengshui

doi:10.3389/fonc.2022.963364

Cited by 4 publications

(1 citation statement)

References 49 publications

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“…On a side note, a WES study identified the p.P35L variant in one out of 13 probands of LFL families. The variant is not reported in any database, and its pathogenicity is predicted by in silico structural analysis [20].…”

Section: Sarcomamentioning

confidence: 99%

Germline POT1 Variants: A Critical Perspective on POT1 Tumor Predisposition Syndrome

Andreotti,

Vanni,

Pastorino

et al. 2024

Genes

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The Protection of Telomere 1 (POT1) gene was identified as a melanoma predisposition candidate nearly 10 years ago. Thereafter, various cancers have been proposed as associated with germline POT1 variants in the context of the so-called POT1 Predisposition Tumor Syndrome (POT1–TPD). While the key role, and related risks, of the alterations in POT1 in melanoma are established, the correlation between germline POT1 variants and the susceptibility to other cancers partially lacks evidence, due also to the rarity of POT1–TPD. Issues range from the absence of functional or segregation studies to biased datasets or the need for a revised classification of variants. Furthermore, a proposal of a surveillance protocol related to the cancers associated with POT1 pathogenic variants requires reliable data to avoid an excessive, possibly unjustified, burden for POT1 variant carriers. We propose a critical perspective regarding data published over the last 10 years that correlate POT1 variants to various types of cancer, other than cutaneous melanoma, to offer food for thought for the specialists who manage cancer predisposition syndromes and to stimulate a debate on the grey areas that have been exposed.

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Section: Sarcomamentioning

confidence: 99%

Germline POT1 Variants: A Critical Perspective on POT1 Tumor Predisposition Syndrome

Andreotti,

Vanni,

Pastorino

et al. 2024

Genes

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Dissecting the oncogenic mechanisms of POT1 cancer mutations through deep scanning mutagenesis

Martin,

Schabort,

Bartke-Croughan

et al. 2024

Preprint

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Mutations in the shelterin protein POT1 are associated with diverse cancers, but their role in cancer progression remains unclear. To resolve this, we performed deep scanning mutagenesis in POT1 locally haploid human stem cells to assess the impact of POT1 variants on cellular viability and cancer-associated telomeric phenotypes. Though POT1 is essential, frame-shift mutants are rescued by chemical ATR inhibition, indicating that POT1 is not required for telomere replication or lagging strand synthesis. In contrast, a substantial fraction of clinically-validated pathogenic mutations support normal cellular proliferation, but still drive ATR-dependent telomeric DNA damage signaling and ATR-independent telomere elongation. Moreover, this class of cancer-associated POT1 variants elongates telomeres more rapidly than POT1 frame-shifts, indicating they actively drive oncogenesis and are not simple loss-of-function mutations.

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Germline mutations predisposing to melanoma and associated malignancies and syndromes: a narrative review

López Riquelme,

Martínez García,

Serrano Ordónez

et al. 2024

Int J Dermatology

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The pathogenesis of melanoma is influenced by a complex combination of environmental factors and individual genetic susceptibility. Familial melanoma refers to cases where there are two first‐degree relatives with a melanoma diagnosis. Less strict definitions include second‐degree relatives or even three or more of any degree from the same family, although this is not clearly defined in the literature. The term hereditary melanoma is reserved for sporadic or familial melanomas linked to high‐risk genes with high penetrance. The first genes related to melanoma were CDKN2A and CDK4, but recently, other genes, mostly tumor suppressor genes, have been described. Internal malignancies, particularly pancreatic cancer, have also been associated with melanoma. Recent studies suggest that there could be a link between melanoma and other neoplasms and tumor predisposition syndromes. This review presents an updated overview of familial melanoma criteria and genes involved in melanoma pathogenesis, emphasizing their clinicopathological aspects and other associated malignancies.

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Whole exome sequencing identified a novel POT1 variant as a candidate pathogenic allele underlying a Li–Fraumeni-like family

Cited by 4 publications

References 49 publications

Germline POT1 Variants: A Critical Perspective on POT1 Tumor Predisposition Syndrome

Germline POT1 Variants: A Critical Perspective on POT1 Tumor Predisposition Syndrome

Dissecting the oncogenic mechanisms of POT1 cancer mutations through deep scanning mutagenesis

Germline mutations predisposing to melanoma and associated malignancies and syndromes: a narrative review

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