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

Srivastava, Aayushi; Miao, Benchun; Skopelitou, Diamanto; Kumar, Vaijayanti A.; Kumar, Abhishek; Paramasivam, Nagarajan; Bonora, Elena; Hemminki, Kari; Försti, Asta; Bandapalli, Obul Reddy

doi:10.3390/cancers12061441

Cited by 33 publications

(31 citation statements)

References 53 publications

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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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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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“…Germline mutation in POT1 has been reported in a melanoma-prone family with thyroid cancer and MNG [ 65 , 66 ], as well as in a family affected solely by NSFNMTC [ 68 ]. Thyroid lesions included PTC, benign and malignant Hürthle cell neoplasms and MNG [ 65 , 66 , 68 ]. Loss-of-function or reduced activity of POT1 seems to play a pathogenetic role via dysregulation of telomere protection [ 68 ].…”

Section: Non-syndromic Familial Non-medullary Thyroid Carcinoma (Nsfnmentioning

confidence: 99%

“…Thyroid lesions included PTC, benign and malignant Hürthle cell neoplasms and MNG [ 65 , 66 , 68 ]. Loss-of-function or reduced activity of POT1 seems to play a pathogenetic role via dysregulation of telomere protection [ 68 ]. However, a lack of mutations in the POT1 gene in selected families with NSFNMTC, with at least three affected members, has been reported in another recent study [ 102 ].…”

Section: Non-syndromic Familial Non-medullary Thyroid Carcinoma (Nsfnmentioning

confidence: 99%

Inherited Follicular Epithelial-Derived Thyroid Carcinomas: From Molecular Biology to Histological Correlates

et al. 2021

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Cancer derived from thyroid follicular epithelial cells is common; it represents the most common endocrine malignancy. The molecular features of sporadic tumors have been clarified in the past decade. However the incidence of familial disease has not been emphasized and is often overlooked in routine practice. A careful clinical documentation of family history or familial syndromes that can be associated with thyroid disease can help identify germline susceptibility-driven thyroid neoplasia. In this review, we summarize a large body of information about both syndromic and non-syndromic familial thyroid carcinomas. A significant number of patients with inherited non-medullary thyroid carcinomas manifest disease that appears to be sporadic disease even in some syndromic cases. The cytomorphology of the tumor(s), molecular immunohistochemistry, the findings in the non-tumorous thyroid parenchyma and other associated lesions may provide insight into the underlying syndromic disorder. However, the increasing evidence of familial predisposition to non-syndromic thyroid cancers is raising questions about the importance of genetics and epigenetics. What appears to be “sporadic” is becoming less often truly so and more often an opportunity to identify and understand novel genetic variants that underlie tumorigenesis. Pathologists must be aware of the unusual morphologic features that should prompt germline screening. Therefore, recognition of harbingers of specific germline susceptibility syndromes can assist in providing information to facilitate early detection to prevent aggressive disease.

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“…Another group reported a new mutation in POT1 (c.85G>T; p.V29L) [ 122 ] in an Italian FNMTC. POT1 disruptions can interfere with the interaction of the POT1-ACD complex.…”

Section: Non-syndromic Fnmtcmentioning

confidence: 99%

Genetic Mutations and Variants in the Susceptibility of Familial Non-Medullary Thyroid Cancer

Miasaki

Fuziwara

Carvalho

et al. 2020

Genes

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Thyroid cancer is the most frequent endocrine malignancy with the majority of cases derived from thyroid follicular cells and caused by sporadic mutations. However, when at least two or more first degree relatives present thyroid cancer, it is classified as familial non-medullary thyroid cancer (FNMTC) that may comprise 3–9% of all thyroid cancer. In this context, 5% of FNMTC are related to hereditary syndromes such as Cowden and Werner Syndromes, displaying specific genetic predisposition factors. On the other hand, the other 95% of cases are classified as non-syndromic FNMTC. Over the last 20 years, several candidate genes emerged in different studies of families worldwide. Nevertheless, the identification of a prevalent polymorphism or germinative mutation has not progressed in FNMTC. In this work, an overview of genetic alteration related to syndromic and non-syndromic FNMTC is presented.

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

Cited by 33 publications

References 53 publications

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

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

Inherited Follicular Epithelial-Derived Thyroid Carcinomas: From Molecular Biology to Histological Correlates

Genetic Mutations and Variants in the Susceptibility of Familial Non-Medullary Thyroid Cancer

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