Cancer spectrum and frequency among children with Noonan, Costello, and cardio-facio-cutaneous syndromes.
BACKGROUND
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.
Department of Pediatric Hematology and Oncology, Hannover Medical School, Hannover, Carl-Neuberg-Str. 1, Hannover 30625, Germany.
C P
CP
Kratz
Institute of Human Genetics, University Hospital Magdeburg, Leipziger Str. 44, Magdeburg 39120, Germany.
L
L
Franke
Institute of Medical and Human Genetics, Charité, Campus Virchow Klinikum, Augustenburger Platz 1, Berlin 13353, Germany.
H
H
Peters
Institut für Klinische Genetik, Maximilianstr. 28D, Bonn 53111, Germany.
N
N
Kohlschmidt
Praxis für Humangenetik, Schwachhauser Heerstr. 50 a-c, Bremen 28209, Germany.
B
B
Kazmierczak
220;BAG Medizinisches Versorgungszentrum Dr. Eberhard & Partner, Brauhausstraße 4 44137, Dortmund, Germany.
U
U
Finckh
Gemeinschaftspraxis für Humangenetik, Gutenbergstraße 5, Dresden 01307, Germany.
A
A
Bier
Mitteldeutscher Praxisverbund Humangenetik, Friedrichstraße 34, Dresden 01067, Germany.
B
B
Eichhorn
Praenatal-Medizin, Graf-Adolf-Str. 35-37, Düsseldorf 40210, Germany.
C
C
Blank
Institute of Human Genetics, University Hospital Erlangen, Friedrich-Alexander-Universität Erlangen-Nürnberg (FAU), Schwabachanlage 10, Erlangen 91054, Germany.
C
C
Kraus
Center for Human Genetics Freiburg, Heinrich-von-Stephan-Str. 5, Freiburg 79100, Germany.
J
J
Kohlhase
Institute of Human Genetics, University of Göttingen, Heinrich-Düker-Weg 12, Göttingen 37073, Germany.
S
S
Pauli
bio.logis, Zentrum für Humangenetik, Altenhöferallee 3, Frankfurt 60438, Germany.
G
G
Wildhardt
Institute of Human Genetics, University Medical Center Hamburg-Eppendorf, Martinistraße 52, Hamburg 20246, Germany.
K
K
Kutsche
MVZ genteQ, Falkenried 88, Hamburg D-20251, Germany.
B
B
Auber
Praxis für Humangenetik, Kardinal-Wendel-Str. 14, 66424 Homburg/Saar, Germany.
A
A
Christmann
Zentrum für Humangenetik, Bioscientia Ingelheim, Konrad-Adenauer-Straße 17, Ingelheim 55218, Germany.
N
N
Bachmann
Institute of Human Genetics, University Hospital Leipzig, Philipp-Rosenthal-Str. 55, Leipzig 04103, Germany.
D
D
Mitter
Zentrum für Humangenetik Mannheim, Harrlachweg 1, Mannheim 68163, Germany.
F W
FW
Cremer
Zentrum für Humangenetik und Laboratoriumsdiagnostik (MVZ), Lochhamer Straße 29, Martinsried 82152, Germany.
K
K
Mayer
Pränatal-Medizin München, Lachnerstraße 20, München 80639, Germany.
C
C
Daumer-Haas
Praxis für Humangenetik München, Synlab Medizinisches Versorgungszentrum Humane Genetik, Lindwurmstraße 23, München 80337, Germany.
C
C
Nevinny-Stickel-Hinzpeter
Genetikum Neu-Ulm, Wegenerstr. 15, Neu-Ulm 89231, Germany.
F
F
Oeffner
Pränatalmedizin und Genetik, MVZ, Bankgasse 3, Nürnberg 90402, Germany.
G
G
Schlüter
Diagenos, Caprivistr. 30, Osnabrück 49076, Germany.
M
M
Gencik
Institut für Medizinische Genetik und Molekulare Medizin, Paul-Schallück-Str. 8, Köln 50939, Germany.
B
B
Überlacker
Institute of Human Genetics, University Hospital Magdeburg, Leipziger Str. 44, Magdeburg 39120, Germany.
C
C
Lissewski
Institute of Human Genetics, University Hospital Magdeburg, Leipziger Str. 44, Magdeburg 39120, Germany.
I
I
Schanze
Clinical Genetics Branch, National Cancer Institute, NCI Shady Grove Room 6E456, Bethesda, MD 20850-9772, USA.
M H
MH
Greene
German Childhood Cancer Registry, Institute for Medical Biostatistics, Epidemiology and Informatics, University Medical Center Mainz, Obere Zahlbacher Straße 69, Mainz 55131, Germany.
C
C
Spix
Institute of Human Genetics, University Hospital Magdeburg, Leipziger Str. 44, Magdeburg 39120, Germany.
M
M
Zenker
D000293:Adolescent; D002648:Child; D002675:Child, Preschool; D056685:Costello Syndrome / Q000235:genetics* / Q000473:pathology; D004476:Ectodermal Dysplasia / Q000235:genetics* / Q000473:pathology; D019066:Facies; D005183:Failure to Thrive / Q000235:genetics* / Q000473:pathology; D005260:Female; D018095:Germ-Line Mutation; D005858:Germany / Q000453:epidemiology; D006330:Heart Defects, Congenital / Q000235:genetics* / Q000473:pathology; D006801:Humans; D007223:Infant; D008297:Male; D009369:Neoplasms / Q000453:epidemiology* / Q000209:etiology / Q000473:pathology; D009634:Noonan Syndrome / Q000235:genetics* / Q000473:pathology; D012042:Registries; D012307:Risk Factors; D015398:Signal Transduction; D018631:ras Proteins / Q000235:genetics*
D018631:ras Proteins