Genetic variation in POT1 and risk of thyroid subsequent malignant neoplasm: A report from the Childhood Cancer Survivor Study

Richard, Melissa A.; Lupo, Philip J.; Morton, Lindsay M.; Yasui, Yutaka; Sapkota, Yadav; Arnold, Michael A.; Aubert, Geraldine; Neglia, Joseph P.; Turcotte, Lucie M.; Leisenring, Wendy M.; Sampson, Joshua N.; Chanock, Stephen J.; Hudson, Melissa M.; Armstrong, Gregory T.; Robison, Leslie L.; Bhatia, Smita; Gramatges, Maria Monica

doi:10.1371/journal.pone.0228887

Cited by 20 publications

(17 citation statements)

References 49 publications

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“…Although a number of studies show telomere shortening to be associated with cancers of the thyroid [6,23,24], mutations in POT1 are predicted to cause telomere lengthening and increase susceptibility to various cancers [25]. A study on participants of the Childhood Cancer Survivor Study identified an association between a low-frequency intronic regulatory variant in POT1 and the risk for thyroid subsequent malignant neoplasm in the survivors and provided evidence that the variant may be related to longer TL [26]. Thus, the cancer-telomere length paradox is a known phenomenon and requires further research before a consensus can be reached.…”

Section: Discussionmentioning

confidence: 99%

A Germline Mutation in the POT1 Gene Is a Candidate for Familial Non-Medullary Thyroid Cancer

Srivastava

Miao

Skopelitou

et al. 2020

Cancers

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Non-medullary thyroid cancer (NMTC) is a common endocrine malignancy with a genetic basis that has yet to be unequivocally established. In a recent whole-genome sequencing study of five families with occurrence of NMTCs, we shortlisted promising variants with the help of bioinformatics tools. Here, we report in silico analyses and in vitro experiments on a novel germline variant (p.V29L) in the highly conserved oligonucleotide/oligosaccharide binding domain of the Protection of Telomeres 1 (POT1) gene in one of the families. The results showed a reduction in telomere-bound POT1 levels in the mutant protein as compared to its wild-type counterpart. HEK293T cells carrying POT1 p.V29L showed increased telomere length in comparison to wild-type cells, suggesting that the mutation causes telomere dysfunction and may play a role in predisposition to NMTC in this family. While one germline mutation in POT1 has already been reported in a melanoma-prone family with prevalence of thyroid cancers, we report the first of such mutations in a family affected solely by NMTCs, thus expanding current knowledge on shelterin complex-associated cancers.

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Section: Discussionmentioning

confidence: 99%

A Germline Mutation in the POT1 Gene Is a Candidate for Familial Non-Medullary Thyroid Cancer

Srivastava

Miao

Skopelitou

et al. 2020

Cancers

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“…Germline POT1 mutations have been initially described as increasing the risk of melanoma, but later studies indicate a broader cancer spectrum associated with these mutations. Notably, POT1 mutations have recently been associated with familial non-medullary thyroid cancer [ 40 , 41 , 42 ]. A duplicity of thyroid cancer with melanoma has been identified in a patient with a newly characterized splicing POT1 mutation (thyroid cancer was present in the patient’s untested mother’s mother).…”

Section: Discussionmentioning

confidence: 99%

Identification of Germline Mutations in Melanoma Patients with Early Onset, Double Primary Tumors, or Family Cancer History by NGS Analysis of 217 Genes

et al. 2020

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Cutaneous melanoma is the deadliest skin malignity with a rising prevalence worldwide. Patients carrying germline mutations in melanoma-susceptibility genes face an increased risk of melanoma and other cancers. To assess the spectrum of germline variants, we analyzed 264 Czech melanoma patients indicated for testing due to early melanoma (at <25 years) or the presence of multiple primary melanoma/melanoma and other cancer in their personal and/or family history. All patients were analyzed by panel next-generation sequencing targeting 217 genes in four groups: high-to-moderate melanoma risk genes, low melanoma risk genes, cancer syndrome genes, and other genes with an uncertain melanoma risk. Population frequencies were assessed in 1479 population-matched controls. Selected POT1 and CHEK2 variants were characterized by functional assays. Mutations in clinically relevant genes were significantly more frequent in melanoma patients than in controls (31/264; 11.7% vs. 58/1479; 3.9%; p = 2.0 × 10−6). A total of 9 patients (3.4%) carried mutations in high-to-moderate melanoma risk genes (CDKN2A, POT1, ACD) and 22 (8.3%) patients in other cancer syndrome genes (NBN, BRCA1/2, CHEK2, ATM, WRN, RB1). Mutations in high-to-moderate melanoma risk genes (OR = 52.2; 95%CI 6.6–413.1; p = 3.2 × 10−7) and in other cancer syndrome genes (OR = 2.3; 95%CI 1.4–3.8; p = 0.003) were significantly associated with melanoma risk. We found an increased potential to carry these mutations (OR = 2.9; 95%CI 1.2–6.8) in patients with double primary melanoma, melanoma and other primary cancer, but not in patients with early age at onset. The analysis revealed affected genes in Czech melanoma patients and identified individuals who may benefit from genetic testing and future surveillance management of mutation carriers.

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“…For example, the POT1 variant rs35439397 has been associated with poor survival in breast cancer [ 131 ]. In survivors of childhood cancer, the presence of the POT1 rs58722976 variant has been linked with an increased risk of developing a subsequent thyroid cancer [ 132 ]. In CLL, a four-gene panel that includes POT1 , XPO1 , MYC88 and BIRC3 can predict reduced survival in CLL and monoclonal B-cell lymphocytosis [ 83 ].…”

Section: Clinical Implications Of Pot1 Alterations In Cancermentioning

confidence: 99%

Role of POT1 in Human Cancer

Poulos

Reddel

2020

Cancers

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Telomere abnormalities facilitate cancer development by contributing to genomic instability and cellular immortalization. The Protection of Telomeres 1 (POT1) protein is an essential subunit of the shelterin telomere binding complex. It directly binds to single-stranded telomeric DNA, protecting chromosomal ends from an inappropriate DNA damage response, and plays a role in telomere length regulation. Alterations of POT1 have been detected in a range of cancers. Here, we review the biological functions of POT1, the prevalence of POT1 germline and somatic mutations across cancer predisposition syndromes and tumor types, and the dysregulation of POT1 expression in cancers. We propose a framework for understanding how POT1 abnormalities may contribute to oncogenesis in different cell types. Finally, we summarize the clinical implications of POT1 alterations in the germline and in cancer, and possible approaches for the development of targeted cancer therapies.

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Genetic variation in POT1 and risk of thyroid subsequent malignant neoplasm: A report from the Childhood Cancer Survivor Study

Cited by 20 publications

References 49 publications

A Germline Mutation in the POT1 Gene Is a Candidate for Familial Non-Medullary Thyroid Cancer

A Germline Mutation in the POT1 Gene Is a Candidate for Familial Non-Medullary Thyroid Cancer

Identification of Germline Mutations in Melanoma Patients with Early Onset, Double Primary Tumors, or Family Cancer History by NGS Analysis of 217 Genes

Role of POT1 in Human Cancer

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