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Acta Neuropathologica

, Volume 128, Issue 1, pp 111–122 | Cite as

Pituitary blastoma: a pathognomonic feature of germ-line DICER1 mutations

  • Leanne de Kock
  • Nelly Sabbaghian
  • François Plourde
  • Archana Srivastava
  • Evan Weber
  • Dorothée Bouron-Dal Soglio
  • Nancy Hamel
  • Joon Hyuk Choi
  • Sung-Hye Park
  • Cheri L. Deal
  • Megan M. Kelsey
  • Megan K. Dishop
  • Adam Esbenshade
  • John F. Kuttesch
  • Thomas S. Jacques
  • Arie Perry
  • Heinz Leichter
  • Philippe Maeder
  • Marie-Anne Brundler
  • Justin Warner
  • James Neal
  • Margaret Zacharin
  • Márta Korbonits
  • Trevor Cole
  • Heidi Traunecker
  • Thomas W. McLean
  • Fabio Rotondo
  • Pierre Lepage
  • Steffen Albrecht
  • Eva Horvath
  • Kalman Kovacs
  • John R. Priest
  • William D. FoulkesEmail author
Original Paper

Abstract

Individuals harboring germ-line DICER1 mutations are predisposed to a rare cancer syndrome, the DICER1 Syndrome or pleuropulmonary blastoma-familial tumor and dysplasia syndrome [online Mendelian inheritance in man (OMIM) #601200]. In addition, specific somatic mutations in the DICER1 RNase III catalytic domain have been identified in several DICER1-associated tumor types. Pituitary blastoma (PitB) was identified as a distinct entity in 2008, and is a very rare, potentially lethal early childhood tumor of the pituitary gland. Since the discovery by our team of an inherited mutation in DICER1 in a child with PitB in 2011, we have identified 12 additional PitB cases. We aimed to determine the contribution of germ-line and somatic DICER1 mutations to PitB. We hypothesized that PitB is a pathognomonic feature of a germ-line DICER1 mutation and that each PitB will harbor a second somatic mutation in DICER1. Lymphocyte or saliva DNA samples ascertained from ten infants with PitB were screened and nine were found to harbor a heterozygous germ-line DICER1 mutation. We identified additional DICER1 mutations in nine of ten tested PitB tumor samples, eight of which were confirmed to be somatic in origin. Seven of these mutations occurred within the RNase IIIb catalytic domain, a domain essential to the generation of 5p miRNAs from the 5′ arm of miRNA-precursors. Germ-line DICER1 mutations are a major contributor to PitB. Second somatic DICER1 “hits” occurring within the RNase IIIb domain also appear to be critical in PitB pathogenesis.

Keywords

DICER1 Pituitary blastoma miRNA Pediatric tumors 

Notes

Acknowledgements

We thank the families involved in this research for their consent to participation and all the clinicians for referring cases and providing samples. We thank Dr. Benoît Lhermitte, Dr. Alistair Lammie, Dr. Cynthia Andoniadou, Dr. Helen Spoudeas, Dr. Oh-Lyong Kim, Dr. Andrew Peet, Dr. Angela Hübner, Dr. Walter Miller, Claudia Retamal-Muñoz, Dr. Bénédict Rilliet, Dr. Ty W. Abel and Dr. Duncan MacGregor for their assistance with ascertainment and analysis of their respective cases. We thank the MUGQIC staff for assisting Pierre Lepage with the Fluidigm Access Array and next-generation sequencing. This research was made possible thanks to the support of the Lady Davis Institute/TD Bank Studentship Award, CCSRI Innovative grant to Dr. William D. Foulkes and K12 CA 090625 to Dr. Adam Esbenshade.

Conflict of interest

The authors have no conflicts of interest to disclose.

Supplementary material

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Supplementary material 1 (DOCX 1068 kb)
401_2014_1285_MOESM2_ESM.pdf (16 kb)
Supplementary material 2 (PDF 15 kb)
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Supplementary material 3 (PDF 27 kb)
401_2014_1285_MOESM4_ESM.pdf (9 kb)
Supplementary material 4 (PDF 9 kb)
401_2014_1285_MOESM5_ESM.pdf (332 kb)
Supplementary material 5 (PDF 331 kb)

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Copyright information

© Springer-Verlag Berlin Heidelberg 2014

Authors and Affiliations

  • Leanne de Kock
    • 1
    • 2
  • Nelly Sabbaghian
    • 2
  • François Plourde
    • 2
  • Archana Srivastava
    • 2
  • Evan Weber
    • 3
  • Dorothée Bouron-Dal Soglio
    • 4
  • Nancy Hamel
    • 3
    • 5
  • Joon Hyuk Choi
    • 6
  • Sung-Hye Park
    • 7
  • Cheri L. Deal
    • 8
  • Megan M. Kelsey
    • 9
    • 10
  • Megan K. Dishop
    • 11
  • Adam Esbenshade
    • 12
  • John F. Kuttesch
    • 13
    • 30
  • Thomas S. Jacques
    • 14
  • Arie Perry
    • 15
  • Heinz Leichter
    • 16
  • Philippe Maeder
    • 17
  • Marie-Anne Brundler
    • 18
    • 31
  • Justin Warner
    • 19
  • James Neal
    • 20
  • Margaret Zacharin
    • 21
  • Márta Korbonits
    • 22
  • Trevor Cole
    • 23
  • Heidi Traunecker
    • 24
  • Thomas W. McLean
    • 25
  • Fabio Rotondo
    • 26
  • Pierre Lepage
    • 27
  • Steffen Albrecht
    • 28
  • Eva Horvath
    • 26
  • Kalman Kovacs
    • 26
  • John R. Priest
    • 29
  • William D. Foulkes
    • 1
    • 2
    • 3
    • 5
    Email author
  1. 1.Department of Human GeneticsMcGill UniversityMontrealCanada
  2. 2.Department of Medical Genetics, The Lady Davis Institute, Segal Cancer CentreJewish General HospitalMontrealCanada
  3. 3.The Research Institute of the McGill University Health CentreMontrealCanada
  4. 4.Department of PathologyCHU-Sainte Justine and University of MontrealMontrealCanada
  5. 5.Program in Cancer Genetics, Department of Oncology and Human GeneticsMcGill UniversityMontrealCanada
  6. 6.Department of PathologyYeungnam University College of MedicineTaegu CitySouth Korea
  7. 7.Department of PathologySeoul National University, College of MedicineSeoulRepublic of Korea
  8. 8.Department of EndocrinologyCHU-Sainte Justine and University of MontrealMontrealCanada
  9. 9.Department of PediatricsUniversity of Colorado School of MedicineAuroraUSA
  10. 10.Children’s Hospital ColoradoAuroraUSA
  11. 11.Department of Pathology and Laboratory MedicineChildren’s Hospital ColoradoAuroraUSA
  12. 12.Department of PediatricsMonroe Carell Jr. Children’s HospitalNashvilleUSA
  13. 13.Department of PediatricsVanderbilt School of Medicine and Vanderbilt Ingram Cancer CenterNashvilleUSA
  14. 14.Neural Development Unit, UCL Institute of Child Health and Department of HistopathologyGreat Ormond Street Hospital for Children NHS Foundation TrustLondonUK
  15. 15.Departments of Pathology and Neurological SurgeryUCSF Medical CentreSan FranciscoUSA
  16. 16.Department of Pediatrics 2OlgahospitalStuttgartGermany
  17. 17.Department of RadiologyCentre Hospitalier Universitaire VaudoisLausanneSwitzerland
  18. 18.Birmingham Children’s Hospital NHS Foundation TrustBirminghamUK
  19. 19.Department of Child HealthUniversity Hospital of WalesCardiffUK
  20. 20.Department of HistopathologyUniversity Hospital of WalesCardiffUK
  21. 21.Department of Endocrinology and DiabetesRoyal Children’s HospitalMelbourneAustralia
  22. 22.Department of Endocrinology, Barts and the London School of MedicineQueen Mary University of LondonLondonUK
  23. 23.West Midlands Regional Genetics ServiceBirmingham Women’s NHS Foundation TrustBirminghamUK
  24. 24.Department of PediatricsThe Children’s Hospital for Wales, Cardiff and Vale University Health BoardCardiffUK
  25. 25.Department of PediatricsWake Forest University School of Medicine, Medical Center BoulevardWinston-SalemUSA
  26. 26.Division of Pathology, Department of Laboratory Medicine, St. Michael’s HospitalUniversity of TorontoTorontoCanada
  27. 27.McGill University and Génome Québec Innovation CentreMontrealCanada
  28. 28.Department of PathologyMontreal Children’s Hospital, McGill University Health CentreMontrealCanada
  29. 29.MinneapolisUSA
  30. 30.Division of Pediatric Hematology/Oncology, Department of PediatricsUniversity of New Mexico School of Medicine and the University of New Mexico Cancer CenterAlbuquerqueUSA
  31. 31.Department of Pathology and Laboratory MedicineUniversity of CalgaryCalgaryCanada

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