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Cancer spectrum and frequency among children with Noonan, Costello, and cardio-facio-cutaneous syndromes.

AbstractBACKGROUND:
Somatic mutations affecting components of the Ras-MAPK pathway are a common feature of cancer, whereas germline Ras pathway mutations cause developmental disorders including Noonan, Costello, and cardio-facio-cutaneous syndromes. These 'RASopathies' also represent cancer-prone syndromes, but the quantitative cancer risks remain unknown.
METHODS:
We investigated the occurrence of childhood cancer including benign and malignant tumours of the central nervous system in a group of 735 individuals with germline mutations in Ras signalling pathway genes by matching their information with the German Childhood Cancer Registry.
RESULTS:
We observed 12 cases of cancer in the entire RASopathy cohort vs 1.12 expected (based on German population-based incidence rates). This corresponds to a 10.5-fold increased risk of all childhood cancers combined (standardised incidence ratio (SIR)=10.5, 95% confidence interval=5.4-18.3). The specific cancers included juvenile myelomonocytic leukaemia=4; brain tumour=3; acute lymphoblastic leukaemia=2; rhabdomyosarcoma=2; and neuroblastoma=1. The childhood cancer SIR in Noonan syndrome patients was 8.1, whereas that for Costello syndrome patients was 42.4.
CONCLUSIONS:
These data comprise the first quantitative evidence documenting that the germline mutations in Ras signalling pathway genes are associated with increased risks of both childhood leukaemia and solid tumours.
AuthorsC P Kratz, L Franke, H Peters, N Kohlschmidt, B Kazmierczak, U Finckh, A Bier, B Eichhorn, C Blank, C Kraus, J Kohlhase, S Pauli, G Wildhardt, K Kutsche, B Auber, A Christmann, N Bachmann, D Mitter, F W Cremer, K Mayer, C Daumer-Haas, C Nevinny-Stickel-Hinzpeter, F Oeffner, G Schlüter, M Gencik, B Überlacker, C Lissewski, I Schanze, M H Greene, C Spix, M Zenker
JournalBritish journal of cancer (Br J Cancer) Vol. 112 Issue 8 Pg. 1392-7 (Apr 14 2015) ISSN: 1532-1827 [Electronic] England
PMID25742478 (Publication Type: Journal Article, Research Support, N.I.H., Intramural, Research Support, Non-U.S. Gov't)
Chemical References
  • ras Proteins
Topics
  • Adolescent
  • Child
  • Child, Preschool
  • Costello Syndrome (genetics, pathology)
  • Ectodermal Dysplasia (genetics, pathology)
  • Facies
  • Failure to Thrive (genetics, pathology)
  • Female
  • Germ-Line Mutation
  • Germany (epidemiology)
  • Heart Defects, Congenital (genetics, pathology)
  • Humans
  • Infant
  • Male
  • Neoplasms (epidemiology, etiology, pathology)
  • Noonan Syndrome (genetics, pathology)
  • Registries
  • Risk Factors
  • Signal Transduction
  • ras Proteins (genetics)

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