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

TY - JOUR

T1 - Cancer spectrum and frequency among children with Noonan, Costello, and cardio-facio-cutaneous syndromes

AU - Kratz, C P

AU - Franke, L

AU - Peters, H

AU - Kohlschmidt, N

AU - Kazmierczak, B

AU - Finckh, U

AU - Bier, A

AU - Eichhorn, B

AU - Blank, C

AU - Kraus, C

AU - Kohlhase, J

AU - Pauli, S

AU - Wildhardt, G

AU - Kutsche, K

AU - Auber, B

AU - Christmann, A

AU - Bachmann, N

AU - Mitter, D

AU - Cremer, F W

AU - Mayer, K

AU - Daumer-Haas, C

AU - Nevinny-Stickel-Hinzpeter, C

AU - Oeffner, F

AU - Schlüter, G

AU - Gencik, M

AU - Überlacker, B

AU - Lissewski, C

AU - Schanze, I

AU - Greene, M H

AU - Spix, C

AU - Zenker, M

PY - 2015/4/14

Y1 - 2015/4/14

N2 - 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.

AB - 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.

U2 - 10.1038/bjc.2015.75

DO - 10.1038/bjc.2015.75

M3 - SCORING: Journal article

C2 - 25742478

VL - 112

SP - 1392

EP - 1397

JO - BRIT J CANCER

JF - BRIT J CANCER

SN - 0007-0920

IS - 8

ER -