Temporal order of RNase IIIb and loss-of-function mutations during development determines phenotype in pleuropulmonary blastoma / DICER1 syndrome: a unique variant of the two-hit tumor suppression model [version 2; referees: 2 approved]
Pleuropulmonary blastoma (PPB) is the most frequent pediatric lung tumor and often the first indication of a pleiotropic cancer predisposition, DICER1 syndrome, comprising a range of other individually rare, benign and malignant tumors of childhood and early adulthood. The genetics of DICER1-associa...
| Main Authors: | , , , , , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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F1000 Research Ltd
2018-01-01
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| Online Access: | https://f1000research.com/articles/4-214/v2 |
| _version_ | 1811331376763371520 |
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| author | Mark Brenneman Amanda Field Jiandong Yang Gretchen Williams Leslie Doros Christopher Rossi Kris Ann Schultz Avi Rosenberg Jennifer Ivanovich Joyce Turner Heather Gordish-Dressman Douglas Stewart Weiying Yu Anne Harris Peter Schoettler Paul Goodfellow Louis Dehner Yoav Messinger D. Ashley Hill |
| author_facet | Mark Brenneman Amanda Field Jiandong Yang Gretchen Williams Leslie Doros Christopher Rossi Kris Ann Schultz Avi Rosenberg Jennifer Ivanovich Joyce Turner Heather Gordish-Dressman Douglas Stewart Weiying Yu Anne Harris Peter Schoettler Paul Goodfellow Louis Dehner Yoav Messinger D. Ashley Hill |
| author_sort | Mark Brenneman |
| collection | DOAJ |
| description | Pleuropulmonary blastoma (PPB) is the most frequent pediatric lung tumor and often the first indication of a pleiotropic cancer predisposition, DICER1 syndrome, comprising a range of other individually rare, benign and malignant tumors of childhood and early adulthood. The genetics of DICER1-associated tumorigenesis are unusual in that tumors typically bear neomorphic missense mutations at one of five specific “hotspot” codons within the RNase IIIb domain of DICER 1, combined with complete loss of function (LOF) in the other allele. We analyzed a cohort of 124 PPB children for predisposing DICER1 mutations and sought correlations with clinical phenotypes. Over 70% have inherited or de novo germline LOF mutations, most of which truncate the DICER1 open reading frame. We identified a minority of patients who have no germline mutation, but are instead mosaic for predisposing DICER1 mutations. Mosaicism for RNase IIIb domain hotspot mutations defines a special category of DICER1 syndrome patients, clinically distinguished from those with germline or mosaic LOF mutations by earlier onsets and numerous discrete foci of neoplastic disease involving multiple syndromic organ sites. A final category of PBB patients lack predisposing germline or mosaic mutations and have sporadic (rather than syndromic) disease limited to a single PPB tumor bearing tumor-specific RNase IIIb and LOF mutations. We propose that acquisition of a neomorphic RNase IIIb domain mutation is the rate limiting event in DICER1-associated tumorigenesis, and that distinct clinical phenotypes associated with mutational categories reflect the temporal order in which LOF and RNase IIIb domain mutations are acquired during development. |
| first_indexed | 2024-04-13T16:19:38Z |
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| institution | Directory Open Access Journal |
| issn | 2046-1402 |
| language | English |
| last_indexed | 2024-04-13T16:19:38Z |
| publishDate | 2018-01-01 |
| publisher | F1000 Research Ltd |
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| spelling | doaj.art-04154497f25e48c9a54b0a211da3903d2022-12-22T02:39:58ZengF1000 Research LtdF1000Research2046-14022018-01-01410.12688/f1000research.6746.214447Temporal order of RNase IIIb and loss-of-function mutations during development determines phenotype in pleuropulmonary blastoma / DICER1 syndrome: a unique variant of the two-hit tumor suppression model [version 2; referees: 2 approved]Mark Brenneman0Amanda Field1Jiandong Yang2Gretchen Williams3Leslie Doros4Christopher Rossi5Kris Ann Schultz6Avi Rosenberg7Jennifer Ivanovich8Joyce Turner9Heather Gordish-Dressman10Douglas Stewart11Weiying Yu12Anne Harris13Peter Schoettler14Paul Goodfellow15Louis Dehner16Yoav Messinger17D. Ashley Hill18Division of Pathology, Children’s Research Institute, Children's National Medical Center and the George Washington University School of Medicine & Health Sciences, Washington, DC, 20010, USADivision of Pathology, Children’s Research Institute, Children's National Medical Center and the George Washington University School of Medicine & Health Sciences, Washington, DC, 20010, USADivision of Pathology, Children’s Research Institute, Children's National Medical Center and the George Washington University School of Medicine & Health Sciences, Washington, DC, 20010, USAInternational Pleuropulmonary Blastoma Registry, Children’s Hospitals and Clinics of Minnesota, Minneapolis, MN, 55404, USADivision of Oncology, Children’s Research Institute, Children's National Medical Center and the George Washington University School of Medicine & Health Sciences, Washington, DC, 20010, USADivision of Pathology, Children’s Research Institute, Children's National Medical Center and the George Washington University School of Medicine & Health Sciences, Washington, DC, 20010, USAInternational Pleuropulmonary Blastoma Registry, Children’s Hospitals and Clinics of Minnesota, Minneapolis, MN, 55404, USADepartment of Pathology, Johns Hopkins School of Medicine, Baltimore, MD, 21205, USADepartment of Surgery, Washington University Medical Center, St. Louis, MO, 63110, USADivision of Pathology, Children’s Research Institute, Children's National Medical Center and the George Washington University School of Medicine & Health Sciences, Washington, DC, 20010, USACenter for Genetic Medicine Research, Children’s Research Institute, Children's National Medical Center and the George Washington University School of Medicine & Health Sciences, Washington, DC, 20010, USAClinical Genetics Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, NIH, Rockville, MD, 20892, USACenter for Genetic Medicine Research, Children’s Research Institute, Children's National Medical Center and the George Washington University School of Medicine & Health Sciences, Washington, DC, 20010, USAInternational Pleuropulmonary Blastoma Registry, Children’s Hospitals and Clinics of Minnesota, Minneapolis, MN, 55404, USACenter for Genetic Medicine Research, Children’s Research Institute, Children's National Medical Center and the George Washington University School of Medicine & Health Sciences, Washington, DC, 20010, USACollege of Medicine, The Ohio State University, Columbus, OH, 43210, USADepartment of Oncology, Children’s Hospitals and Clinics of Minnesota, Minneapolis, MN, 55404, USAInternational Pleuropulmonary Blastoma Registry, Children’s Hospitals and Clinics of Minnesota, Minneapolis, MN, 55404, USADivision of Pathology, Children’s Research Institute, Children's National Medical Center and the George Washington University School of Medicine & Health Sciences, Washington, DC, 20010, USAPleuropulmonary blastoma (PPB) is the most frequent pediatric lung tumor and often the first indication of a pleiotropic cancer predisposition, DICER1 syndrome, comprising a range of other individually rare, benign and malignant tumors of childhood and early adulthood. The genetics of DICER1-associated tumorigenesis are unusual in that tumors typically bear neomorphic missense mutations at one of five specific “hotspot” codons within the RNase IIIb domain of DICER 1, combined with complete loss of function (LOF) in the other allele. We analyzed a cohort of 124 PPB children for predisposing DICER1 mutations and sought correlations with clinical phenotypes. Over 70% have inherited or de novo germline LOF mutations, most of which truncate the DICER1 open reading frame. We identified a minority of patients who have no germline mutation, but are instead mosaic for predisposing DICER1 mutations. Mosaicism for RNase IIIb domain hotspot mutations defines a special category of DICER1 syndrome patients, clinically distinguished from those with germline or mosaic LOF mutations by earlier onsets and numerous discrete foci of neoplastic disease involving multiple syndromic organ sites. A final category of PBB patients lack predisposing germline or mosaic mutations and have sporadic (rather than syndromic) disease limited to a single PPB tumor bearing tumor-specific RNase IIIb and LOF mutations. We propose that acquisition of a neomorphic RNase IIIb domain mutation is the rate limiting event in DICER1-associated tumorigenesis, and that distinct clinical phenotypes associated with mutational categories reflect the temporal order in which LOF and RNase IIIb domain mutations are acquired during development.https://f1000research.com/articles/4-214/v2Lung CancerPediatric Oncology |
| spellingShingle | Mark Brenneman Amanda Field Jiandong Yang Gretchen Williams Leslie Doros Christopher Rossi Kris Ann Schultz Avi Rosenberg Jennifer Ivanovich Joyce Turner Heather Gordish-Dressman Douglas Stewart Weiying Yu Anne Harris Peter Schoettler Paul Goodfellow Louis Dehner Yoav Messinger D. Ashley Hill Temporal order of RNase IIIb and loss-of-function mutations during development determines phenotype in pleuropulmonary blastoma / DICER1 syndrome: a unique variant of the two-hit tumor suppression model [version 2; referees: 2 approved] F1000Research Lung Cancer Pediatric Oncology |
| title | Temporal order of RNase IIIb and loss-of-function mutations during development determines phenotype in pleuropulmonary blastoma / DICER1 syndrome: a unique variant of the two-hit tumor suppression model [version 2; referees: 2 approved] |
| title_full | Temporal order of RNase IIIb and loss-of-function mutations during development determines phenotype in pleuropulmonary blastoma / DICER1 syndrome: a unique variant of the two-hit tumor suppression model [version 2; referees: 2 approved] |
| title_fullStr | Temporal order of RNase IIIb and loss-of-function mutations during development determines phenotype in pleuropulmonary blastoma / DICER1 syndrome: a unique variant of the two-hit tumor suppression model [version 2; referees: 2 approved] |
| title_full_unstemmed | Temporal order of RNase IIIb and loss-of-function mutations during development determines phenotype in pleuropulmonary blastoma / DICER1 syndrome: a unique variant of the two-hit tumor suppression model [version 2; referees: 2 approved] |
| title_short | Temporal order of RNase IIIb and loss-of-function mutations during development determines phenotype in pleuropulmonary blastoma / DICER1 syndrome: a unique variant of the two-hit tumor suppression model [version 2; referees: 2 approved] |
| title_sort | temporal order of rnase iiib and loss of function mutations during development determines phenotype in pleuropulmonary blastoma dicer1 syndrome a unique variant of the two hit tumor suppression model version 2 referees 2 approved |
| topic | Lung Cancer Pediatric Oncology |
| url | https://f1000research.com/articles/4-214/v2 |
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