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Volume 15
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10.3390/genes15030355
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Article

A POT1 Founder Variant Associated with Early Onset Recurrent Melanoma and Various Solid Malignancies

by
Aasem Abu Shtaya
1,2,
Inbal Kedar
1,
Lily Bazak
1,
Lina Basel-Salmon
1,3,4,5,
Sarit Farage Barhom
1,
Michal Naftali
6,
Marina Eskin-Schwartz
7,8,
Ohad S. Birk
7,8,
Shirley Polager-Modan
9,
Nitzan Keidar
5,
Gili Reznick Levi
10,
Zohar Levi
3,11,
Tamar Yablonski-Peretz
12,13,
Ahmad Mahamid
14,
Ori Segol
2,
Reut Matar
1,
Yifat Bareli
1,
Noy Azoulay
1 and
Yael Goldberg
1,3,*
1
Recanati Genetics Institute, Rabin Medical Center—Beilinson Hospital, Petach Tikva 4941492, Israel
2
Unit of Gastroenterology, Lady Davis Carmel Medical Center, Haifa 3436212, Israel
3
Faculty of Medicine, Tel Aviv University, Tel Aviv 6997801, Israel
4
Felsenstein Medical Research Center, Petach Tikva 4920235, Israel
5
Pediatric Genetic Unit, Schneider Children’s Medical Center of Israel, Petch Tikva 4920235, Israel
6
Clalit Genomic Center, Petach Tikva 5252247, Israel
7
Genetics Institute, Soroka University Medical Center, Beer Sheva 8410101, Israel
8
Faculty of Health Sciences, Ben Gurion University of the Negev, Beer Sheva 8410101, Israel
9
Genetics Institute, Carmel Medical Center, Haifa 3436212, Israel
10
Genetics Institute, Rambam Health Care Campus, Haifa 3525408, Israel
11
Division of Gastroenterology, Rabin Medical Center—Beilinson Hospital, Petach Tikva 4941492, Israel
12
Oncology Institute, Hadassah Medical Center, Jerusalem 9112001, Israel
13
Faculty of Medicine, Hebrew University of Jerusalem, Jerusalem 9190500, Israel
14
Department of Surgery B, Carmel Medical Center, Haifa 3436212, Israel
 
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Author to whom correspondence should be addressed.
Genes 2024, 15(3), 355; https://doi.org/10.3390/genes15030355
Submission received: 14 February 2024 / Revised: 11 March 2024 / Accepted: 11 March 2024 / Published: 13 March 2024
(This article belongs to the Section Human Genomics and Genetic Diseases)
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Abstract

POT1 (Protection of Telomeres 1) is a key component of the six-membered shelterin complex that plays a critical role in telomere protection and length regulation. Germline variants in the POT1 gene have been implicated in predisposition to cancer, primarily to melanoma and chronic lymphocytic leukemia (CLL). We report the identification of POT1 p.(I78T), previously ranked with conflicting interpretations of pathogenicity, as a founder pathogenic variant among Ashkenazi Jews (AJs) and describe its unique clinical landscape. A directed database search was conducted for individuals referred for genetic counselling from 2018 to 2023. Demographic, clinical, genetic, and pathological data were collected and analyzed. Eleven carriers, 25 to 67 years old, from ten apparently unrelated families were identified. Carriers had a total of 30 primary malignancies (range 1–6); nine carriers (82%) had recurrent melanoma between the ages of 25 and 63 years, three carriers (27%) had desmoid tumors, three (27%) had papillary thyroid cancer (PTC), and five women (63% of female carriers) had breast cancer between the ages of 44 and 67 years. Additional tumors included CLL; sarcomas; endocrine tumors; prostate, urinary, and colorectal cancers; and colonic polyps. A review of a local exome database yielded an allelic frequency of the variant of 0.06% among all ethnicities and of 0.25% in AJs. A shared haplotype was found in all carriers tested. POT1 p.(I78T) is a founder disease-causing variant associated with early-onset melanoma and additional various solid malignancies with a high tumor burden. We advocate testing for this variant in high-risk patients of AJ descent. The inclusion of POT1 in germline panels for various types of cancer is warranted.
Keywords: POT1; cancer; melanoma; desmoid; breast cancer; Ashkenazi POT1; cancer; melanoma; desmoid; breast cancer; Ashkenazi

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MDPI and ACS Style

Abu Shtaya, A.; Kedar, I.; Bazak, L.; Basel-Salmon, L.; Barhom, S.F.; Naftali, M.; Eskin-Schwartz, M.; Birk, O.S.; Polager-Modan, S.; Keidar, N.; et al. A POT1 Founder Variant Associated with Early Onset Recurrent Melanoma and Various Solid Malignancies. Genes 2024, 15, 355. https://doi.org/10.3390/genes15030355

AMA Style

Abu Shtaya A, Kedar I, Bazak L, Basel-Salmon L, Barhom SF, Naftali M, Eskin-Schwartz M, Birk OS, Polager-Modan S, Keidar N, et al. A POT1 Founder Variant Associated with Early Onset Recurrent Melanoma and Various Solid Malignancies. Genes. 2024; 15(3):355. https://doi.org/10.3390/genes15030355

Chicago/Turabian Style

Abu Shtaya, Aasem, Inbal Kedar, Lily Bazak, Lina Basel-Salmon, Sarit Farage Barhom, Michal Naftali, Marina Eskin-Schwartz, Ohad S. Birk, Shirley Polager-Modan, Nitzan Keidar, and et al. 2024. "A POT1 Founder Variant Associated with Early Onset Recurrent Melanoma and Various Solid Malignancies" Genes 15, no. 3: 355. https://doi.org/10.3390/genes15030355

APA Style

Abu Shtaya, A., Kedar, I., Bazak, L., Basel-Salmon, L., Barhom, S. F., Naftali, M., Eskin-Schwartz, M., Birk, O. S., Polager-Modan, S., Keidar, N., Reznick Levi, G., Levi, Z., Yablonski-Peretz, T., Mahamid, A., Segol, O., Matar, R., Bareli, Y., Azoulay, N., & Goldberg, Y. (2024). A POT1 Founder Variant Associated with Early Onset Recurrent Melanoma and Various Solid Malignancies. Genes, 15(3), 355. https://doi.org/10.3390/genes15030355

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