Cancer risk in patients with Noonan syndrome carrying a PTPN11 mutation

Marjolijn C.J. Jongmans (1) , Ineke van Der Burgt (1) , Peter M Hoogerbrugge (1) , Cees Noordam (1) , Helger Yntema (1) , Willy M Nillesen (1) , Rp Kuiper (1) , Marjolijn Ligtenberg (1) , Ad Geurts van Kessel (1) , Joannes van Krieken (1) , Lambertus Kiemeney (1) , Nicoline Hoogerbrugge (1)

1 Human Genetics

Noonan syndrome (NS) is characterized by short stature, facial dysmorphisms and congenital heart defects. PTPN11 mutations are the most common cause of NS. Patients with NS have a predisposition for leukemia and certain solid tumors. Data on the incidence of malignancies in NS are lacking. Our objective was to estimate the cancer risk and spectrum in patients with NS carrying a PTPN11 mutation. In addition, we have investigated whether specific PTPN11 mutations result in an increased malignancy risk. We have performed a cohort study among 297 Dutch NS patients with a PTPN11 mutation (mean age 18 years). The cancer histories were collected from the referral forms for DNA diagnostics, and by consulting the Dutch national registry of pathology and the Netherlands Cancer Registry. The reported frequencies of cancer among NS patients were compared with the expected frequencies using population-based incidence rates. Twelve patients with NS developed a malignancy, yielding a cumulative risk for developing cancer of 23% [95% CI, 8-38%] up to age 55 years, which represents a 3.5-fold [95% CI, 2.0-5.9] increased risk compared to that in the general population. Hematological malignancies occurred most frequently. Two malignancies, not previously observed in NS, were found: a malignant mastocytosis and malignant epithelioid angiosarcoma. No correlation was found between specific PTPN11 mutations and cancer occurrence. In conclusion, this study provides first evidence of an increased risk of cancer in patients with NS and a PTPN11 mutation, compared to that in the general population. Our data do not warrant specific cancer surveillance.

Mots clés: Noonan syndrome; PTPN11 gene; Cancer incidence

Marjolijn C.J. Jongmans, Ineke van Der Burgt, Peter M Hoogerbrugge, Cees Noordam, Helger Yntema, et al.. Cancer risk in patients with Noonan syndrome carrying a PTPN11 mutation. European Journal of Human Genetics, 2011, ⟨10.1038/ejhg.2011.37⟩. ⟨hal-00624164⟩