Report 177
DICER1 Syndrome: A New Cancer Syndrome A Natural History Study
Das DICER1 Syndrom: Ein neues Krebssyndrom Notwendigkeit einer Beobachtungsstudie
Authors
R. E. Schultze-Florey1, N. Graf2, P. Vorwerk3, E. Koscielniak4, D. T. Schneider5, C. P. Kratz6
Affiliations
Affiliation addresses are listed at the end of the article
Key words ▶ DICER1 syndrome ● ▶ pleuropulmonary blastoma ● ▶ natural history study ● ▶ cancer syndrome ● ▶ altered miRNA biogenesis ● ▶ Dicer1 ●
Abstract
Zusammenfassung
Recently, germline mutations of DICER1 have been identified in patients with rare neoplasms suggesting the existence of a newly discovered cancer prone syndrome. Initially, DICER1 mutations were identified in patients with familial pleuropulmonary blastoma. Subsequently, additional manifestations of the syndrome have been identified including cystic nephroma, medulloepithelioma, Sertoli-Leydig cell tumor and others. The DICER1 gene encodes an enzyme that is involved in the biogenesis of microRNAs. The entire tumor spectrum and the respective tumor risks are unknown. We are in the process of launching a natural history study aimed at identifying more information on this new cancer syndrome.
Kürzlich wurden DICER1 Keimbahnmutationen bei Patienten mit seltenen Neoplasien entdeckt. Diese Beobachtung deutete auf die Existenz eines zuvor nicht bekannten Tumor-Prädispositionssyndroms hin. Zuerst wurden DICER1 Mutationen bei Patienten mit familiärem pleuropulmonalem Blastom entdeckt. Bis heute sind weitere Manifestationen des Syndroms beschrieben worden, einschließlich zystisches Nephrom, Medulloepitheliom, Sertoli-Leydig-Zell-Tumor und andere. Das DICER1 Gen kodiert für ein Enzym, welches an der Biogenese von MikroRNAs maßgeblich beteiligt ist. Das genaue Tumorspektrum sowie das Tumorrisiko sind nicht bekannt. Wir planen eine Registerstudie, um mehr Informationen über dieses neue Krebssyndrom zu erlangen.
Background
DICER1 germline mutations were identified in patients with additional rare tumors including ovarian Sertoli-Leydig cell tumor, uterine cervix embryonal rhabdomyosarcoma, pituitary blastoma, pineoblastoma, multinodular goiter, cystic nephroma and intraocular medulloepithelioma ▶ Fig. 1). [1, 3, 4, 6, 12] (●
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▼ Bibliography DOI http://dx.doi.org/ 10.1055/s-0033-1337976 Published online: April 26, 2013 Klin Padiatr 2013; 225: 177–178 © Georg Thieme Verlag KG Stuttgart · New York ISSN 0300-8630 Correspondence Dr. Rebecca Elisabeth Schultze-Florey Pediatric Hematology/ Oncology Hannover Medical School Carl-Neuberg-Straße 1 30625 Hannover Germany Tel.: + 49/511/532 6711 Fax: + 49/511/532 8207
[email protected]
Pleuropulmonary blastoma (PPB) is a rare tumor of the lungs occurring in early childhood. Many patients with PPB have a family history of either benign or malignant tumors suggesting that PPB may arise in the context of a hereditary tumor predisposition syndrome [10]. PPB is classified into 3 pathologic subtypes – type I: purely cystic stage; type II: cystic and solid stage; and, type III: purely solid stage. The prognosis of type I PPB is good with surgery and adjuvant chemotherapy [9]. Types II and III PPB confer a poor prognosis and require more intense therapy [9]. In 2009, Hill and colleagues identified heterozygous DICER1 germline mutations in familial PPB by genome-wide linkage analysis [8]. DICER1 is located on chromosome 14q32 and encodes a ribonuclease, participating in the generation of microRNAs (miRNA). These short, doublestranded, noncoding RNAs modulate mRNA levels by direct base-pairing interactions and play a key role in oncogenesis [11, 13]. Subsequently,
Open questions
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To date, the clinical course, the cancer epidemiology, and the molecular mechanisms of DICER1 syndrome are poorly understood. Several open questions remain: What is the risk of malignancies in carriers of a DICER1 mutation and what other types of neoplasms occur? What are the disease genes in DICER1 mutation negative patients? What are the genetic modifiers? What are the second hits? Do genotype-phenotypecorrelations exist? How does mutant DICER1 promote tumorigenesis? To answer these questions, natural history and biologic studies are needed.
Schultze-Florey RE et al. DICER1-syndrome: A New Cancer … Klin Padiatr 2013; 225: 177–178
Downloaded by: Dominik Schneider. Copyrighted material.
Schlüsselwörter ▶ DICER1 Syndrom ● ▶ pleuropulmonales Blastom ● ▶ Beobachtungsstudie ● ▶ Krebssyndrom ● ▶ veränderte miRNA ● Biogenese ▶ Dicer1 ●
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178 Report
Pineoblastoma Pituitary blastoma Ocular medulloepithelioma
Nodular hyperplasia & carcinoma of thyroid
Nasal chondromesenchymal hamartoma
Pleuropulmonary blastoma
Cystic nephroma Ovarian sex cord-stromal tumor Ovarian SertoliLeydig cell tumor
Cervical embryonal rhabdomyosarcoma
PPB). However, genetic testing is not mandatory and will follow current standards with regard to new gene diagnostic regulations. Gene testing is currently being established in one of the authors’ institutions. The study will also include bio-banking as other groups already established and secondary research on molecular mechanisms underlying the disease [5]. These studies will complement research activities launched by the partnering study in the US. A major aim of the study will be to develop evidence-based management guidelines for cancer prevention and risk-reduction.
Conclusion
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Conflict of interest: The authors have no conflict of interest to disclose. Affiliations Klinik für Pädiatrische Hämatologie und Onkologie, Medizinische Hochschule, Hannover, Germany 2 Klinik für Päd. Onkologie und Hämatologie, Universität des Saarlandes, Homburg, Germany 3 Pädiatrische Onkologie, Otto von Guericke Universität, Kinderhospital, Magdeburg, Germany 4 Klinik für Kinder- und Jugendmedizin – Pädiatrie 5, Klinikum Stuttgart – Olgahospital, Stuttgart, Germany 5 Klinik für Kinder- und Jugendmedizin, Klinikum Dortmund gGmbH, Dortmund, Germany 6 Klinik für Pädiatrische Hämatologie und Onkologie, Medizinische Hochschule, Hannover, Germany 1
Fig. 1 Tumor manifestations of DICER1-associated syndrome.
Methods and perspective
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In Germany, Switzerland, and Austria, most children with tumors of the DICER1 syndrome spectrum are enrolled in a variety of studies and registries of the German Society of Pediatric Oncology and Hematology (GPOH) (e. g. PPB: CWS-Study; cystic nephroma: Wilms tumor study; thyroid tumors: GPOH-MET; Sertoli-Leydig cell tumors: MAKEI, rare tumor registry; very rare tumors: EXPeRT) [2, 7]. We are planning a DICER1 syndrome natural history study. The proposed study will partner with a similar study that has been recently initiated in the U.S. by the National Cancer Institute and the International PPB Registry. This international collaboration is essential to increase our understanding on this rare syndrome. After IRB approval, index patients with PPB, ovarian Sertoli-Leydig cell tumor, uterine cervix embryonal rhabdomyosarcoma, pituitary blastoma, pineoblastoma, multinodular goiter, cystic nephroma, intraocular medulloepithelioma or other manifestations of the syndrome will be identified through existing GPOH studies and registries and the parents will be contacted. Index cases as well as other family members may participate. The families will be asked to complete health related questionnaires and will be examined by physicians to identify and clinically characterize additional affected family members. After informed consent, a detailed medical history will be obtained to identify additional manifestations of the syndrome in all family members. Original medical records will be collected and medical information between the participating registries will be exchanged to verify individual statements. Genetic testing/counseling will be offered and treatment recommendations will be provided. In the authors’ view genetic testing is clinically indicated because early detection of the syndrome may lead to better outcomes (e. g. in children with
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Schultze-Florey RE et al. DICER1-syndrome: A New Cancer … Klin Padiatr 2013; 225: 177–178
Downloaded by: Dominik Schneider. Copyrighted material.
The DICER1 syndrome is the first cancer predisposition syndrome caused by impaired miRNA biogenesis. A natural history study of the syndrome will improve the understanding of the disorder and improve the care of affected patients. All authors of this paper serve as contact persons for new or suspected cases.
