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

C 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, C 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

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.

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.
    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.
    1. Gripp KW. Tumor predisposition in Costello syndrome. Am J Med Genet C Semin Med Genet. 2005;137C (1:72–77.
    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.
    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.
    1. Kaatsch P. [German Childhood Cancer Registry and its favorable setting] Bundesgesundheitsblatt Gesundheitsforschung Gesundheitsschutz. 2004;47 (5:437–443.
    1. Karow A, Steinemann D, Gohring G, Hasle H, Greiner J, Harila-Saari A, Flotho C, Zenker M, Schlegelberger B, Niemeyer CM, Kratz CP. Clonal duplication of a germline PTPN11 mutation due to acquired uniparental disomy in acute lymphoblastic leukemia blasts from a patient with Noonan syndrome. Leukemia. 2007;21 (6:1303–1305.
    1. Kerr B, Delrue MA, Sigaudy S, Perveen R, Marche M, Burgelin I, Stef M, Tang B, Eden OB, O'Sullivan J, De Sandre-Giovannoli A, Reardon W, Brewer C, Bennett C, Quarell O, M'Cann E, Donnai D, Stewart F, Hennekam R, Cave H, Verloes A, Philip N, Lacombe D, Levy N, Arveiler B, Black G. Genotype-phenotype correlation in Costello syndrome: HRAS mutation analysis in 43 cases. J Med Genet. 2006;43 (5:401–405.
    1. Kratz CP, Niemeyer CM, Castleberry RP, Cetin M, Bergstrasser E, Emanuel PD, Hasle H, Kardos G, Klein C, Kojima S, Stary J, Trebo M, Zecca M, Gelb BD, Tartaglia M, Loh ML. The mutational spectrum of PTPN11 in juvenile myelomonocytic leukemia and Noonan syndrome/myeloproliferative disease. Blood. 2005;106 (6:2183–2185.
    1. Kratz CP, Rapisuwon S, Reed H, Hasle H, Rosenberg PS. Cancer in Noonan, Costello, cardiofaciocutaneous and LEOPARD syndromes. Am J Med Genet C Semin Med Genet. 2011;157C (2:83–89.
    1. Laux D, Kratz C, Sauerbrey A. Common acute lymphoblastic leukemia in a girl with genetically confirmed LEOPARD syndrome. J Pediatr Hematol Oncol. 2008;30 (8:602–604.
    1. Martinelli S, De Luca A, Stellacci E, Rossi C, Checquolo S, Lepri F, Caputo V, Silvano M, Buscherini F, Consoli F, Ferrara G, Digilio MC, Cavaliere ML, van Hagen JM, Zampino G, van der Burgt I, Ferrero GB, Mazzanti L, Screpanti I, Yntema HG, Nillesen WM, Savarirayan R, Zenker M, Dallapiccola B, Gelb BD, Tartaglia M. Heterozygous germline mutations in the CBL tumor-suppressor gene cause a Noonan syndrome-like phenotype. Am J Hum Genet. 2010;87 (2:250–257.
    1. Niemeyer CM, Kang MW, Shin DH, Furlan I, Erlacher M, Bunin NJ, Bunda S, Finklestein JZ, Sakamoto KM, Gorr TA, Mehta P, Schmid I, Kropshofer G, Corbacioglu S, Lang PJ, Klein C, Schlegel PG, Heinzmann A, Schneider M, Stary J, van den Heuvel-Eibrink MM, Hasle H, Locatelli F, Sakai D, Archambeault S, Chen L, Russell RC, Sybingco SS, Ohh M, Braun BS, Flotho C, Loh ML. Germline CBL mutations cause developmental abnormalities and predispose to juvenile myelomonocytic leukemia. Nat Genet. 2010;42 (9:794–800.
    1. Roberts AE, Allanson JE, Tartaglia M, Gelb BD. Noonan syndrome. Lancet. 2013;381 (9863:333–342.
    1. Saint Pierre A, Genin E. How important are rare variants in common disease. Brief Funct Genomics. 2014;13 (5:353–361.
    1. Schubbert S, Shannon K, Bollag G. Hyperactive Ras in developmental disorders and cancer. Nat Rev Cancer. 2007;7 (4:295–308.
    1. Schubbert S, Zenker M, Rowe SL, Boll S, Klein C, Bollag G, van der Burgt I, Musante L, Kalscheuer V, Wehner LE, Nguyen H, West B, Zhang KY, Sistermans E, Rauch A, Niemeyer CM, Shannon K, Kratz CP. Germline KRAS mutations cause Noonan syndrome. Nat Genet. 2006;38 (3:331–336.
    1. Selter M, Dresel R, Althaus J, Baz Bartels M, Dittrich S, Geb S, Hoche F, Qirshi M, Vlaho S, Zielen S, Kieslich M. Dysembryoplastic neuroepithelial tumor (DNET) in a patient with Noonan syndrome. Neuropediatrics. 2010;41:P1356.
    1. Steliarova-Foucher E, Stiller C, Lacour B, Kaatsch P. International Classification of Childhood Cancer, third edition. Cancer. 2005;103 (7:1457–1467.
    1. Strullu M, Caye A, Lachenaud J, Cassinat B, Gazal S, Fenneteau O, Pouvreau N, Pereira S, Baumann C, Contet A, Sirvent N, Mechinaud F, Guellec I, Adjaoud D, Paillard C, Alberti C, Zenker M, Chomienne C, Bertrand Y, Baruchel A, Verloes A, Cave H. Juvenile myelomonocytic leukaemia and Noonan syndrome. J Med Genet. 2014;51 (10:689–697.
    1. Tartaglia M, Niemeyer CM, Fragale A, Song X, Buechner J, Jung A, Hahlen K, Hasle H, Licht JD, Gelb BD. Somatic mutations in PTPN11 in juvenile myelomonocytic leukemia, myelodysplastic syndromes and acute myeloid leukemia. Nat Genet. 2003;34 (2:148–150.
    1. Ucar C, Calyskan U, Martini S, Heinritz W. Acute myelomonocytic leukemia in a boy with LEOPARD syndrome (PTPN11 gene mutation positive) J Pediatr Hematol Oncol. 2006;28 (3:123–125.
    1. Yokoyama S, Woods SL, Boyle GM, Aoude LG, MacGregor S, Zismann V, Gartside M, Cust AE, Haq R, Harland M, Taylor JC, Duffy DL, Holohan K, Dutton-Regester K, Palmer JM, Bonazzi V, Stark MS, Symmons J, Law MH, Schmidt C, Lanagan C, O'Connor L, Holland EA, Schmid H, Maskiell JA, Jetann J, Ferguson M, Jenkins MA, Kefford RF, Giles GG, Armstrong BK, Aitken JF, Hopper JL, Whiteman DC, Pharoah PD, Easton DF, Dunning AM, Newton-Bishop JA, Montgomery GW, Martin NG, Mann GJ, Bishop DT, Tsao H, Trent JM, Fisher DE, Hayward NK, Brown KM. A novel recurrent mutation in MITF predisposes to familial and sporadic melanoma. Nature. 2011;480 (7375:99–103.
    1. Zenker M, Lehmann K, Schulz AL, Barth H, Hansmann D, Koenig R, Korinthenberg R, Kreiss-Nachtsheim M, Meinecke P, Morlot S, Mundlos S, Quante AS, Raskin S, Schnabel D, Wehner LE, Kratz CP, Horn D, Kutsche K. Expansion of the genotypic and phenotypic spectrum in patients with KRAS germline mutations. J Med Genet. 2007;44 (2:131–135.

Source: PubMed

赞助者和合作者

医疗条件

药物干预

3
订阅