Germline <i>ERBB2</i>/<i>HER2</i> Coding Variants Are Associated with Increased Risk of Myeloproliferative Neoplasms
Familial cases of myeloproliferative neoplasms (MPN) are relatively common, yet few inherited risk factors have been identified. Exome sequencing of a kindred with a familial cancer syndrome characterized by both MPN and melanoma produced a germline variant in the <i>ERBB2/HER2</i> gene...
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MDPI AG
2021-06-01
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| Series: | Cancers |
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| Online Access: | https://www.mdpi.com/2072-6694/13/13/3246 |
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| author | Evan M. Braunstein Hang Chen Felicia Juarez Fanghan Yang Lindsay Tao Igor Makhlin Donna M. Williams Shruti Chaturvedi Aparna Pallavajjala Theodoros Karantanos Renan Martin Elizabeth Wohler Nara Sobreira Christopher D. Gocke Alison R. Moliterno |
| author_facet | Evan M. Braunstein Hang Chen Felicia Juarez Fanghan Yang Lindsay Tao Igor Makhlin Donna M. Williams Shruti Chaturvedi Aparna Pallavajjala Theodoros Karantanos Renan Martin Elizabeth Wohler Nara Sobreira Christopher D. Gocke Alison R. Moliterno |
| author_sort | Evan M. Braunstein |
| collection | DOAJ |
| description | Familial cases of myeloproliferative neoplasms (MPN) are relatively common, yet few inherited risk factors have been identified. Exome sequencing of a kindred with a familial cancer syndrome characterized by both MPN and melanoma produced a germline variant in the <i>ERBB2/HER2</i> gene that co-segregates with disease. To further investigate whether germline <i>ERBB2</i> variants contribute to MPN predisposition, the frequency of <i>ERBB2</i> variants was analyzed in 1604 cases that underwent evaluation for hematologic malignancy, including 236 cases of MPN. MPN cases had a higher frequency of rare germline <i>ERBB2</i> coding variants compared to non-MPN hematologic malignancies (8.9% vs. 4.1%, OR 2.4, 95% CI: 1.4 to 4.0, <i>p</i> = 0.0028) as well as cases without a blood cancer diagnosis that served as an internal control (8.9% vs. 2.7%, OR 3.5, 95% CI: 1.4 to 8.3, <i>p</i> = 0.0053). This finding was validated via comparison to an independent control cohort of 1587 cases without selection for hematologic malignancy (8.9% in MPN cases vs. 5.2% in controls, <i>p</i> = 0.040). The most frequent variant identified, <i>ERBB2</i> c.1960A > G; p.I654V, was present in MPN cases at more than twice its expected frequency. These data indicate that rare germline coding variants in <i>ERBB2</i> are associated with an increased risk for development of MPN. The <i>ERBB2</i> gene is a novel susceptibility locus which likely contributes to cancer risk in combination with additional risk alleles. |
| first_indexed | 2024-03-10T09:59:15Z |
| format | Article |
| id | doaj.art-fb81543ef5fb4ad5954bc95122c77d4c |
| institution | Directory Open Access Journal |
| issn | 2072-6694 |
| language | English |
| last_indexed | 2024-03-10T09:59:15Z |
| publishDate | 2021-06-01 |
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| record_format | Article |
| series | Cancers |
| spelling | doaj.art-fb81543ef5fb4ad5954bc95122c77d4c2023-11-22T02:08:51ZengMDPI AGCancers2072-66942021-06-011313324610.3390/cancers13133246Germline <i>ERBB2</i>/<i>HER2</i> Coding Variants Are Associated with Increased Risk of Myeloproliferative NeoplasmsEvan M. Braunstein0Hang Chen1Felicia Juarez2Fanghan Yang3Lindsay Tao4Igor Makhlin5Donna M. Williams6Shruti Chaturvedi7Aparna Pallavajjala8Theodoros Karantanos9Renan Martin10Elizabeth Wohler11Nara Sobreira12Christopher D. Gocke13Alison R. Moliterno14Department of Medicine, Division of Haematology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USADepartment of Medicine, Division of Haematology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USADepartment of Medicine, Division of Haematology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USADepartment of Medicine, Division of Haematology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USADepartment of Medicine, Division of Haematology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USADepartment of Medicine, Division of Hematology & Oncology, University of Pennsylvania, Philadelphia, PA 19104, USADepartment of Medicine, Division of Haematology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USADepartment of Medicine, Division of Haematology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USADepartment of Pathology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USADepartment of Medical Oncology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USAMcKusick-Nathans Department of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USAMcKusick-Nathans Department of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USAMcKusick-Nathans Department of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USADepartment of Pathology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USADepartment of Medicine, Division of Haematology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USAFamilial cases of myeloproliferative neoplasms (MPN) are relatively common, yet few inherited risk factors have been identified. Exome sequencing of a kindred with a familial cancer syndrome characterized by both MPN and melanoma produced a germline variant in the <i>ERBB2/HER2</i> gene that co-segregates with disease. To further investigate whether germline <i>ERBB2</i> variants contribute to MPN predisposition, the frequency of <i>ERBB2</i> variants was analyzed in 1604 cases that underwent evaluation for hematologic malignancy, including 236 cases of MPN. MPN cases had a higher frequency of rare germline <i>ERBB2</i> coding variants compared to non-MPN hematologic malignancies (8.9% vs. 4.1%, OR 2.4, 95% CI: 1.4 to 4.0, <i>p</i> = 0.0028) as well as cases without a blood cancer diagnosis that served as an internal control (8.9% vs. 2.7%, OR 3.5, 95% CI: 1.4 to 8.3, <i>p</i> = 0.0053). This finding was validated via comparison to an independent control cohort of 1587 cases without selection for hematologic malignancy (8.9% in MPN cases vs. 5.2% in controls, <i>p</i> = 0.040). The most frequent variant identified, <i>ERBB2</i> c.1960A > G; p.I654V, was present in MPN cases at more than twice its expected frequency. These data indicate that rare germline coding variants in <i>ERBB2</i> are associated with an increased risk for development of MPN. The <i>ERBB2</i> gene is a novel susceptibility locus which likely contributes to cancer risk in combination with additional risk alleles.https://www.mdpi.com/2072-6694/13/13/3246familial cancermyeloproliferative neoplasmsgermline predisposition |
| spellingShingle | Evan M. Braunstein Hang Chen Felicia Juarez Fanghan Yang Lindsay Tao Igor Makhlin Donna M. Williams Shruti Chaturvedi Aparna Pallavajjala Theodoros Karantanos Renan Martin Elizabeth Wohler Nara Sobreira Christopher D. Gocke Alison R. Moliterno Germline <i>ERBB2</i>/<i>HER2</i> Coding Variants Are Associated with Increased Risk of Myeloproliferative Neoplasms Cancers familial cancer myeloproliferative neoplasms germline predisposition |
| title | Germline <i>ERBB2</i>/<i>HER2</i> Coding Variants Are Associated with Increased Risk of Myeloproliferative Neoplasms |
| title_full | Germline <i>ERBB2</i>/<i>HER2</i> Coding Variants Are Associated with Increased Risk of Myeloproliferative Neoplasms |
| title_fullStr | Germline <i>ERBB2</i>/<i>HER2</i> Coding Variants Are Associated with Increased Risk of Myeloproliferative Neoplasms |
| title_full_unstemmed | Germline <i>ERBB2</i>/<i>HER2</i> Coding Variants Are Associated with Increased Risk of Myeloproliferative Neoplasms |
| title_short | Germline <i>ERBB2</i>/<i>HER2</i> Coding Variants Are Associated with Increased Risk of Myeloproliferative Neoplasms |
| title_sort | germline i erbb2 i i her2 i coding variants are associated with increased risk of myeloproliferative neoplasms |
| topic | familial cancer myeloproliferative neoplasms germline predisposition |
| url | https://www.mdpi.com/2072-6694/13/13/3246 |
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