Identification of a Cancer-Predisposing Germline <i>POT1</i> p.Ile49Metfs*7 Variant by Targeted Sequencing of a Splenic Marginal Zone Lymphoma
Germline disruptive variants in <i>Protection of Telomeres 1</i> (<i>POT1</i>) predispose to a wide variety of cancers, including melanoma, chronic lymphocytic leukemia (CLL), Hodgkin lymphoma, myeloproliferative neoplasms, and glioma. We report the first case of splenic marg...
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MDPI AG
2022-03-01
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| Series: | Genes |
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| Online Access: | https://www.mdpi.com/2073-4425/13/4/591 |
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| author | Audrey N. Jajosky Anna L. Mitchell Mahmut Akgul Shashirekha Shetty Jennifer M. Yoest Stanton L. Gerson Navid Sadri Kwadwo A. Oduro |
| author_facet | Audrey N. Jajosky Anna L. Mitchell Mahmut Akgul Shashirekha Shetty Jennifer M. Yoest Stanton L. Gerson Navid Sadri Kwadwo A. Oduro |
| author_sort | Audrey N. Jajosky |
| collection | DOAJ |
| description | Germline disruptive variants in <i>Protection of Telomeres 1</i> (<i>POT1</i>) predispose to a wide variety of cancers, including melanoma, chronic lymphocytic leukemia (CLL), Hodgkin lymphoma, myeloproliferative neoplasms, and glioma. We report the first case of splenic marginal zone lymphoma (SMZL) arising in a patient with a germline <i>POT1</i> variant: a 65-year-old male with an extensive history of cancer, including melanoma and papillary thyroid carcinoma, who presented with circulating atypical lymphocytosis. Bone marrow biopsy revealed 20% involvement by a CD5<sup>−</sup>CD10<sup>−</sup> B-cell lymphoma that was difficult to classify. During the clinical workup of his low-grade lymphoma, targeted next-generation sequencing (NGS) identified <i>POT1</i> p.I49Mfs*7 (NM_015450:c. 147delT) at a variant allele frequency (VAF) of 51%. NGS of skin fibroblasts confirmed the <i>POT1</i> variant was germline. This likely pathogenic <i>POT1</i> loss-of-function variant has only been reported once before as a germline variant in a patient with glioma and likely represents one of the most deleterious germline <i>POT1</i> variants ever linked to familial cancer. The spectrum of cancers associated with germline pathogenic <i>POT1</i> variants (i.e., autosomal dominant <i>POT1</i> tumor predisposition syndrome) should potentially be expanded to include SMZL, a disease often associated with the loss of chromosome 7q: the location of the <i>POT1</i> genetic locus (7q31.33). |
| first_indexed | 2024-03-09T13:38:18Z |
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| institution | Directory Open Access Journal |
| issn | 2073-4425 |
| language | English |
| last_indexed | 2024-03-09T13:38:18Z |
| publishDate | 2022-03-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Genes |
| spelling | doaj.art-9dec03550765494599eb65a68ad494512023-11-30T21:09:39ZengMDPI AGGenes2073-44252022-03-0113459110.3390/genes13040591Identification of a Cancer-Predisposing Germline <i>POT1</i> p.Ile49Metfs*7 Variant by Targeted Sequencing of a Splenic Marginal Zone LymphomaAudrey N. Jajosky0Anna L. Mitchell1Mahmut Akgul2Shashirekha Shetty3Jennifer M. Yoest4Stanton L. Gerson5Navid Sadri6Kwadwo A. Oduro7Department of Pathology and Laboratory Medicine, University Hospitals Cleveland Medical Center, 11100 Euclid Avenue, Cleveland, OH 44106, USADepartment of Genetics and Genome Sciences, University Hospitals Cleveland Medical Center, 11100 Euclid Avenue, Cleveland, OH 44106, USADepartment of Pathology and Laboratory Medicine, University Hospitals Cleveland Medical Center, 11100 Euclid Avenue, Cleveland, OH 44106, USADepartment of Pathology and Laboratory Medicine, University Hospitals Cleveland Medical Center, 11100 Euclid Avenue, Cleveland, OH 44106, USADepartment of Pathology and Laboratory Medicine, University Hospitals Cleveland Medical Center, 11100 Euclid Avenue, Cleveland, OH 44106, USADepartment of Medicine, Hematology Oncology Division, University Hospitals Cleveland Medical Center, 11100 Euclid Avenue, Cleveland, OH 44106, USADepartment of Pathology and Laboratory Medicine, University Hospitals Cleveland Medical Center, 11100 Euclid Avenue, Cleveland, OH 44106, USADepartment of Pathology and Laboratory Medicine, University Hospitals Cleveland Medical Center, 11100 Euclid Avenue, Cleveland, OH 44106, USAGermline disruptive variants in <i>Protection of Telomeres 1</i> (<i>POT1</i>) predispose to a wide variety of cancers, including melanoma, chronic lymphocytic leukemia (CLL), Hodgkin lymphoma, myeloproliferative neoplasms, and glioma. We report the first case of splenic marginal zone lymphoma (SMZL) arising in a patient with a germline <i>POT1</i> variant: a 65-year-old male with an extensive history of cancer, including melanoma and papillary thyroid carcinoma, who presented with circulating atypical lymphocytosis. Bone marrow biopsy revealed 20% involvement by a CD5<sup>−</sup>CD10<sup>−</sup> B-cell lymphoma that was difficult to classify. During the clinical workup of his low-grade lymphoma, targeted next-generation sequencing (NGS) identified <i>POT1</i> p.I49Mfs*7 (NM_015450:c. 147delT) at a variant allele frequency (VAF) of 51%. NGS of skin fibroblasts confirmed the <i>POT1</i> variant was germline. This likely pathogenic <i>POT1</i> loss-of-function variant has only been reported once before as a germline variant in a patient with glioma and likely represents one of the most deleterious germline <i>POT1</i> variants ever linked to familial cancer. The spectrum of cancers associated with germline pathogenic <i>POT1</i> variants (i.e., autosomal dominant <i>POT1</i> tumor predisposition syndrome) should potentially be expanded to include SMZL, a disease often associated with the loss of chromosome 7q: the location of the <i>POT1</i> genetic locus (7q31.33).https://www.mdpi.com/2073-4425/13/4/591hereditary cancer predispositiongermline <i>POT1</i> alterationsplenic marginal zone lymphomacancer genetics |
| spellingShingle | Audrey N. Jajosky Anna L. Mitchell Mahmut Akgul Shashirekha Shetty Jennifer M. Yoest Stanton L. Gerson Navid Sadri Kwadwo A. Oduro Identification of a Cancer-Predisposing Germline <i>POT1</i> p.Ile49Metfs*7 Variant by Targeted Sequencing of a Splenic Marginal Zone Lymphoma Genes hereditary cancer predisposition germline <i>POT1</i> alteration splenic marginal zone lymphoma cancer genetics |
| title | Identification of a Cancer-Predisposing Germline <i>POT1</i> p.Ile49Metfs*7 Variant by Targeted Sequencing of a Splenic Marginal Zone Lymphoma |
| title_full | Identification of a Cancer-Predisposing Germline <i>POT1</i> p.Ile49Metfs*7 Variant by Targeted Sequencing of a Splenic Marginal Zone Lymphoma |
| title_fullStr | Identification of a Cancer-Predisposing Germline <i>POT1</i> p.Ile49Metfs*7 Variant by Targeted Sequencing of a Splenic Marginal Zone Lymphoma |
| title_full_unstemmed | Identification of a Cancer-Predisposing Germline <i>POT1</i> p.Ile49Metfs*7 Variant by Targeted Sequencing of a Splenic Marginal Zone Lymphoma |
| title_short | Identification of a Cancer-Predisposing Germline <i>POT1</i> p.Ile49Metfs*7 Variant by Targeted Sequencing of a Splenic Marginal Zone Lymphoma |
| title_sort | identification of a cancer predisposing germline i pot1 i p ile49metfs 7 variant by targeted sequencing of a splenic marginal zone lymphoma |
| topic | hereditary cancer predisposition germline <i>POT1</i> alteration splenic marginal zone lymphoma cancer genetics |
| url | https://www.mdpi.com/2073-4425/13/4/591 |
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