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Br J Cancer. 2015 Apr 14;112(8):1392-7. doi: 10.1038/bjc.2015.75. Epub 2015 Mar 5.

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

Author information

1
Department of Pediatric Hematology and Oncology, Hannover Medical School, Hannover, Carl-Neuberg-Str. 1, Hannover 30625, Germany.
2
Institute of Human Genetics, University Hospital Magdeburg, Leipziger Str. 44, Magdeburg 39120, Germany.
3
Institute of Medical and Human Genetics, Charité, Campus Virchow Klinikum, Augustenburger Platz 1, Berlin 13353, Germany.
4
Institut für Klinische Genetik, Maximilianstr. 28D, Bonn 53111, Germany.
5
Praxis für Humangenetik, Schwachhauser Heerstr. 50 a-c, Bremen 28209, Germany.
6
220;BAG Medizinisches Versorgungszentrum Dr. Eberhard & Partner, Brauhausstraße 4 44137, Dortmund, Germany.
7
Gemeinschaftspraxis für Humangenetik, Gutenbergstraße 5, Dresden 01307, Germany.
8
Mitteldeutscher Praxisverbund Humangenetik, Friedrichstraße 34, Dresden 01067, Germany.
9
Praenatal-Medizin, Graf-Adolf-Str. 35-37, Düsseldorf 40210, Germany.
10
Institute of Human Genetics, University Hospital Erlangen, Friedrich-Alexander-Universität Erlangen-Nürnberg (FAU), Schwabachanlage 10, Erlangen 91054, Germany.
11
Center for Human Genetics Freiburg, Heinrich-von-Stephan-Str. 5, Freiburg 79100, Germany.
12
Institute of Human Genetics, University of Göttingen, Heinrich-Düker-Weg 12, Göttingen 37073, Germany.
13
bio.logis, Zentrum für Humangenetik, Altenhöferallee 3, Frankfurt 60438, Germany.
14
Institute of Human Genetics, University Medical Center Hamburg-Eppendorf, Martinistraße 52, Hamburg 20246, Germany.
15
MVZ genteQ, Falkenried 88, Hamburg D-20251, Germany.
16
Praxis für Humangenetik, Kardinal-Wendel-Str. 14, 66424 Homburg/Saar, Germany.
17
Zentrum für Humangenetik, Bioscientia Ingelheim, Konrad-Adenauer-Straße 17, Ingelheim 55218, Germany.
18
Institute of Human Genetics, University Hospital Leipzig, Philipp-Rosenthal-Str. 55, Leipzig 04103, Germany.
19
Zentrum für Humangenetik Mannheim, Harrlachweg 1, Mannheim 68163, Germany.
20
Zentrum für Humangenetik und Laboratoriumsdiagnostik (MVZ), Lochhamer Straße 29, Martinsried 82152, Germany.
21
Pränatal-Medizin München, Lachnerstraße 20, München 80639, Germany.
22
Praxis für Humangenetik München, Synlab Medizinisches Versorgungszentrum Humane Genetik, Lindwurmstraße 23, München 80337, Germany.
23
Genetikum Neu-Ulm, Wegenerstr. 15, Neu-Ulm 89231, Germany.
24
Pränatalmedizin und Genetik, MVZ, Bankgasse 3, Nürnberg 90402, Germany.
25
Diagenos, Caprivistr. 30, Osnabrück 49076, Germany.
26
Institut für Medizinische Genetik und Molekulare Medizin, Paul-Schallück-Str. 8, Köln 50939, Germany.
27
Clinical Genetics Branch, National Cancer Institute, NCI Shady Grove Room 6E456, Bethesda, MD 20850-9772, USA.
28
German Childhood Cancer Registry, Institute for Medical Biostatistics, Epidemiology and Informatics, University Medical Center Mainz, Obere Zahlbacher Straße 69, Mainz 55131, Germany.

Abstract

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.

PMID:
25742478
PMCID:
PMC4402457
DOI:
10.1038/bjc.2015.75
[Indexed for MEDLINE]
Free PMC Article

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