Register-based and genetic studies of Prader-Willi syndrome show a high frequency of gonadal tumors and a possible mechanism for tumorigenesis through imprinting relaxation
Prader-Willi syndrome (PWS) is a rare disease caused by a lack of expression of inherited imprinted genes in the paternally derived Prader-Willi critical region on chromosome 15q11.2-q13. It is characterized by poor feeding and hypotonia in infancy, intellectual disability, behavioral abnormalities,...
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| Language: | English |
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Frontiers Media S.A.
2023-07-01
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| Series: | Frontiers in Medicine |
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| Online Access: | https://www.frontiersin.org/articles/10.3389/fmed.2023.1172565/full |
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| author | Carolina Maya-González Sandra Wessman Sandra Wessman Kristina Lagerstedt-Robinson Kristina Lagerstedt-Robinson Fulya Taylan Fulya Taylan Bianca Tesi Bianca Tesi Bianca Tesi Ekaterina Kuchinskaya Ekaterina Kuchinskaya W. Glenn McCluggage Anna Poluha Anna Poluha Stefan Holm Ricard Nergårdh Teresita Díaz De Ståhl Teresita Díaz De Ståhl Charlotte Höybye Charlotte Höybye Giorgio Tettamanti Giorgio Tettamanti Angelica Maria Delgado-Vega Angelica Maria Delgado-Vega Anna Skarin Nordenvall Anna Skarin Nordenvall Ann Nordgren Ann Nordgren Ann Nordgren Ann Nordgren |
| author_facet | Carolina Maya-González Sandra Wessman Sandra Wessman Kristina Lagerstedt-Robinson Kristina Lagerstedt-Robinson Fulya Taylan Fulya Taylan Bianca Tesi Bianca Tesi Bianca Tesi Ekaterina Kuchinskaya Ekaterina Kuchinskaya W. Glenn McCluggage Anna Poluha Anna Poluha Stefan Holm Ricard Nergårdh Teresita Díaz De Ståhl Teresita Díaz De Ståhl Charlotte Höybye Charlotte Höybye Giorgio Tettamanti Giorgio Tettamanti Angelica Maria Delgado-Vega Angelica Maria Delgado-Vega Anna Skarin Nordenvall Anna Skarin Nordenvall Ann Nordgren Ann Nordgren Ann Nordgren Ann Nordgren |
| author_sort | Carolina Maya-González |
| collection | DOAJ |
| description | Prader-Willi syndrome (PWS) is a rare disease caused by a lack of expression of inherited imprinted genes in the paternally derived Prader-Willi critical region on chromosome 15q11.2-q13. It is characterized by poor feeding and hypotonia in infancy, intellectual disability, behavioral abnormalities, dysmorphic features, short stature, obesity, and hypogonadism. PWS is not a known cancer predisposition syndrome, but previous investigations regarding the prevalence of cancer in these patients suggest an increased risk of developing specific cancer types such as myeloid leukemia and testicular cancer. We present the results from a Swedish national population-based cohort study of 360 individuals with PWS and 18,000 matched comparisons. The overall frequency of cancer was not increased in our PWS cohort, but we found a high frequency of pediatric cancers. We also performed whole-genome sequencing of blood- and tumor-derived DNAs from a unilateral dysgerminoma in a 13-year-old girl with PWS who also developed bilateral ovarian sex cord tumors with annular tubules. In germline analysis, there were no additional findings apart from the 15q11.2-q13 deletion of the paternal allele, while a pathogenic activating KIT mutation was identified in the tumor. Additionally, methylation-specific multiplex ligation-dependent probe amplification revealed reduced methylation at the PWS locus in the dysgerminoma but not in the blood. In conclusion, our register-based study suggests an increased risk of cancer at a young age, especially testicular and ovarian tumors. We found no evidence of a general increase in cancer risk in patients with PWS. However, given our limited observational time, further studies with longer follow-up times are needed to clarify the lifetime cancer risk in PWS. We have also described the second case of locus-specific loss-of-imprinting in a germ cell tumor in PWS, suggesting a possible mechanism of carcinogenesis. |
| first_indexed | 2024-03-12T21:21:38Z |
| format | Article |
| id | doaj.art-4621862bc38343c7ac090d169ff55210 |
| institution | Directory Open Access Journal |
| issn | 2296-858X |
| language | English |
| last_indexed | 2024-03-12T21:21:38Z |
| publishDate | 2023-07-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Medicine |
| spelling | doaj.art-4621862bc38343c7ac090d169ff552102023-07-28T17:58:52ZengFrontiers Media S.A.Frontiers in Medicine2296-858X2023-07-011010.3389/fmed.2023.11725651172565Register-based and genetic studies of Prader-Willi syndrome show a high frequency of gonadal tumors and a possible mechanism for tumorigenesis through imprinting relaxationCarolina Maya-González0Sandra Wessman1Sandra Wessman2Kristina Lagerstedt-Robinson3Kristina Lagerstedt-Robinson4Fulya Taylan5Fulya Taylan6Bianca Tesi7Bianca Tesi8Bianca Tesi9Ekaterina Kuchinskaya10Ekaterina Kuchinskaya11W. Glenn McCluggage12Anna Poluha13Anna Poluha14Stefan Holm15Ricard Nergårdh16Teresita Díaz De Ståhl17Teresita Díaz De Ståhl18Charlotte Höybye19Charlotte Höybye20Giorgio Tettamanti21Giorgio Tettamanti22Angelica Maria Delgado-Vega23Angelica Maria Delgado-Vega24Anna Skarin Nordenvall25Anna Skarin Nordenvall26Ann Nordgren27Ann Nordgren28Ann Nordgren29Ann Nordgren30Department of Molecular Medicine and Surgery, Center for Molecular Medicine, Karolinska Institutet, Stockholm, SwedenDepartment of Oncology-Pathology, Karolinska Institutet, Stockholm, SwedenDepartment of Pathology and Cancer Diagnostics, Karolinska University Hospital, Stockholm, SwedenDepartment of Molecular Medicine and Surgery, Center for Molecular Medicine, Karolinska Institutet, Stockholm, SwedenDepartment of Clinical Genetics, Karolinska University Hospital, Stockholm, SwedenDepartment of Molecular Medicine and Surgery, Center for Molecular Medicine, Karolinska Institutet, Stockholm, SwedenDepartment of Clinical Genetics, Karolinska University Hospital, Stockholm, SwedenDepartment of Molecular Medicine and Surgery, Center for Molecular Medicine, Karolinska Institutet, Stockholm, SwedenDepartment of Clinical Genetics, Karolinska University Hospital, Stockholm, SwedenDepartment of Medicine Huddinge, Karolinska Institutet, Stockholm, SwedenDepartment of Clinical Genetics, Karolinska University Hospital, Stockholm, SwedenDepartment of Clinical Experimental Medicine, Linköping University, Linköping, SwedenDepartment of Pathology, Belfast Health and Social Care Trust, Belfast, United KingdomClinical Genetics, Uppsala University Hospital, Uppsala, SwedenDepartment of Immunology, Genetics and Pathology, Faculty of Medicine, Uppsala University, Uppsala, Sweden0Department of Women's and Children's Health, Karolinska Institutet, Stockholm, Sweden0Department of Women's and Children's Health, Karolinska Institutet, Stockholm, SwedenDepartment of Oncology-Pathology, Karolinska Institutet, Stockholm, SwedenDepartment of Pathology and Cancer Diagnostics, Karolinska University Hospital, Stockholm, SwedenDepartment of Molecular Medicine and Surgery, Center for Molecular Medicine, Karolinska Institutet, Stockholm, Sweden1Department of Endocrinology, Karolinska University Hospital, Stockholm, SwedenDepartment of Molecular Medicine and Surgery, Center for Molecular Medicine, Karolinska Institutet, Stockholm, Sweden2Unit of Epidemiology, Institute of Environmental Medicine, Karolinska Institutet, Stockholm, SwedenDepartment of Molecular Medicine and Surgery, Center for Molecular Medicine, Karolinska Institutet, Stockholm, SwedenDepartment of Clinical Genetics, Karolinska University Hospital, Stockholm, SwedenDepartment of Molecular Medicine and Surgery, Center for Molecular Medicine, Karolinska Institutet, Stockholm, Sweden3Department of Radiology, Karolinska University Hospital, Stockholm, SwedenDepartment of Molecular Medicine and Surgery, Center for Molecular Medicine, Karolinska Institutet, Stockholm, SwedenDepartment of Clinical Genetics, Karolinska University Hospital, Stockholm, Sweden4Department of Laboratory Medicine, Institute of Biomedicine, University of Gothenburg, Gothenburg, Sweden5Department of Clinical Genetics and Genomics, Sahlgrenska University Hospital, Gothenburg, SwedenPrader-Willi syndrome (PWS) is a rare disease caused by a lack of expression of inherited imprinted genes in the paternally derived Prader-Willi critical region on chromosome 15q11.2-q13. It is characterized by poor feeding and hypotonia in infancy, intellectual disability, behavioral abnormalities, dysmorphic features, short stature, obesity, and hypogonadism. PWS is not a known cancer predisposition syndrome, but previous investigations regarding the prevalence of cancer in these patients suggest an increased risk of developing specific cancer types such as myeloid leukemia and testicular cancer. We present the results from a Swedish national population-based cohort study of 360 individuals with PWS and 18,000 matched comparisons. The overall frequency of cancer was not increased in our PWS cohort, but we found a high frequency of pediatric cancers. We also performed whole-genome sequencing of blood- and tumor-derived DNAs from a unilateral dysgerminoma in a 13-year-old girl with PWS who also developed bilateral ovarian sex cord tumors with annular tubules. In germline analysis, there were no additional findings apart from the 15q11.2-q13 deletion of the paternal allele, while a pathogenic activating KIT mutation was identified in the tumor. Additionally, methylation-specific multiplex ligation-dependent probe amplification revealed reduced methylation at the PWS locus in the dysgerminoma but not in the blood. In conclusion, our register-based study suggests an increased risk of cancer at a young age, especially testicular and ovarian tumors. We found no evidence of a general increase in cancer risk in patients with PWS. However, given our limited observational time, further studies with longer follow-up times are needed to clarify the lifetime cancer risk in PWS. We have also described the second case of locus-specific loss-of-imprinting in a germ cell tumor in PWS, suggesting a possible mechanism of carcinogenesis.https://www.frontiersin.org/articles/10.3389/fmed.2023.1172565/fullPrader-Willi syndromeovarian tumorgerm-cell tumorcancer predispositionloss-of-imprintingimprinting relaxation |
| spellingShingle | Carolina Maya-González Sandra Wessman Sandra Wessman Kristina Lagerstedt-Robinson Kristina Lagerstedt-Robinson Fulya Taylan Fulya Taylan Bianca Tesi Bianca Tesi Bianca Tesi Ekaterina Kuchinskaya Ekaterina Kuchinskaya W. Glenn McCluggage Anna Poluha Anna Poluha Stefan Holm Ricard Nergårdh Teresita Díaz De Ståhl Teresita Díaz De Ståhl Charlotte Höybye Charlotte Höybye Giorgio Tettamanti Giorgio Tettamanti Angelica Maria Delgado-Vega Angelica Maria Delgado-Vega Anna Skarin Nordenvall Anna Skarin Nordenvall Ann Nordgren Ann Nordgren Ann Nordgren Ann Nordgren Register-based and genetic studies of Prader-Willi syndrome show a high frequency of gonadal tumors and a possible mechanism for tumorigenesis through imprinting relaxation Frontiers in Medicine Prader-Willi syndrome ovarian tumor germ-cell tumor cancer predisposition loss-of-imprinting imprinting relaxation |
| title | Register-based and genetic studies of Prader-Willi syndrome show a high frequency of gonadal tumors and a possible mechanism for tumorigenesis through imprinting relaxation |
| title_full | Register-based and genetic studies of Prader-Willi syndrome show a high frequency of gonadal tumors and a possible mechanism for tumorigenesis through imprinting relaxation |
| title_fullStr | Register-based and genetic studies of Prader-Willi syndrome show a high frequency of gonadal tumors and a possible mechanism for tumorigenesis through imprinting relaxation |
| title_full_unstemmed | Register-based and genetic studies of Prader-Willi syndrome show a high frequency of gonadal tumors and a possible mechanism for tumorigenesis through imprinting relaxation |
| title_short | Register-based and genetic studies of Prader-Willi syndrome show a high frequency of gonadal tumors and a possible mechanism for tumorigenesis through imprinting relaxation |
| title_sort | register based and genetic studies of prader willi syndrome show a high frequency of gonadal tumors and a possible mechanism for tumorigenesis through imprinting relaxation |
| topic | Prader-Willi syndrome ovarian tumor germ-cell tumor cancer predisposition loss-of-imprinting imprinting relaxation |
| url | https://www.frontiersin.org/articles/10.3389/fmed.2023.1172565/full |
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