Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
. 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

C P Kratz  1 , L Franke  2 , H Peters  3 , N Kohlschmidt  4 , B Kazmierczak  5 , U Finckh  6 , A Bier  7 , B Eichhorn  8 , C Blank  9 , C Kraus  10 , J Kohlhase  11 , S Pauli  12 , G Wildhardt  13 , K Kutsche  14 , B Auber  15 , A Christmann  16 , N Bachmann  17 , D Mitter  18 , F W Cremer  19 , K Mayer  20 , C Daumer-Haas  21 , C Nevinny-Stickel-Hinzpeter  22 , F Oeffner  23 , G Schlüter  24 , M Gencik  25 , B Überlacker  26 , C Lissewski  2 , I Schanze  2 , M H Greene  27 , C Spix  28 , M Zenker  2
Affiliations

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

C P Kratz et al. Br J Cancer. .

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.

PubMed Disclaimer

References

    1. Aoki Y, Niihori T, Banjo T, Okamoto N, Mizuno S, Kurosawa K, Ogata T, Takada F, Yano M, Ando T, Hoshika T, Barnett C, Ohashi H, Kawame H, Hasegawa T, Okutani T, Nagashima T, Hasegawa S, Funayama R, Nagashima T, Nakayama K, Inoue S, Watanabe Y, Ogura T, Matsubara Y. Gain-of-function mutations in RIT1 cause Noonan syndrome, a RAS/MAPK pathway syndrome. Am J Hum Genet. 2013;93 (1:173–180. - PMC - PubMed
    1. Flex E, Jaiswal M, Pantaleoni F, Martinelli S, Strullu M, Fansa EK, Caye A, De Luca A, Lepri F, Dvorsky R, Pannone L, Paolacci S, Zhang SC, Fodale V, Bocchinfuso G, Rossi C, Burkitt-Wright EM, Farrotti A, Stellacci E, Cecchetti S, Ferese R, Bottero L, Castro S, Fenneteau O, Brethon B, Sanchez M, Roberts AE, Yntema HG, Van Der Burgt I, Cianci P, Bondeson ML, Cristina Digilio M, Zampino G, Kerr B, Aoki Y, Loh ML, Palleschi A, Di Schiavi E, Care A, Selicorni A, Dallapiccola B, Cirstea IC, Stella L, Zenker M, Gelb BD, Cave H, Ahmadian MR, Tartaglia M. Activating mutations in RRAS underlie a phenotype within the RASopathy spectrum and contribute to leukaemogenesis. Hum Mol Genet. 2014;23 (16:4315–4327. - PMC - PubMed
    1. Gripp KW. Tumor predisposition in Costello syndrome. Am J Med Genet C Semin Med Genet. 2005;137C (1:72–77. - PubMed
    1. Hammer GP, Seidenbusch MC, Schneider K, Regulla DF, Zeeb H, Spix C, Blettner M. A cohort study of childhood cancer incidence after postnatal diagnostic X-ray exposure. Radiat Res. 2009;171 (4:504–512. - PubMed
    1. Jongmans MC, van der Burgt I, Hoogerbrugge PM, Noordam K, Yntema HG, Nillesen WM, Kuiper RP, Ligtenberg MJ, van Kessel AG, van Krieken JH, Kiemeney LA, Hoogerbrugge N. Cancer risk in patients with Noonan syndrome carrying a PTPN11 mutation. Eur J Hum Genet. 2011;19 (8:870–874. - PMC - PubMed

Publication types

MeSH terms

Supplementary concepts