All in our genes? From foetal nonsense to adult neoplasia
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1 All in our genes? From foetal nonsense to adult neoplasia Raoul CM Hennekam Department of Pediatrics, AMC, Amsterdam
2 Robert J Gorlin
3 minor anomaly > malformation
4 minor anomaly > malformation
5 minor anomaly > malformation
6 minor anomaly > malformation Major malformations in children with mild errors of morphogenesis or more Marden, 1964 Mehes, 1983 Merlob, 1985 Leppig, 1987
7 malformation > cancer Malformations and cancer Down syndrome
8 malformation > cancer Malformations and cancer Beckwith-Wiedemann syndrome
9 malformation < > cancer Principle Ponder, Nature 2001;411:336
10 malformation < > cancer Principle Villavicencio, Am J Hum Genet 2000;67:1047
11 malformation < > cancer Holoprosencephaly
12 malformation < > cancer Holoprosencephaly
13 malformation < > cancer Holoprosencephaly Amsterdam / Enschede study - all holoprosencephaly patients n = lobar, 15 alobar, 2 lobar, 2? - 15 isolated, 26 syndromic - 4 survivors (4y,14y, 26y, 30y) - no consanguinity - parental age: somewhat increased - recurrence: 1 family - family: 7 times NTD 4 times brain tumor Van Eeghen et al, unpublished
14 freq cancer in malformation Frequency Malformation: chance cancer? - depending entity - depending cause - depending knowledge
15 freq cancer in malformation Malformation syndrome and cancer Gorlin syndrome
16 freq cancer in malformation Malformation syndrome and cancer Gorlin syndrome
17 freq cancer in malformation Malformation syndrome and cancer Gorlin syndrome
18 freq cancer in malformation Malformation syndrome and cancer Gorlin syndrome
19 freq cancer in malformation Malformation syndrome and cancer Gorlin syndrome
20 freq cancer in malformation Malformation syndrome and cancer 20% develops cancer <40yr Rubinstein-Taybi syndrome
21 freq cancer in malformation Beckwith-Wiedemann s
22 freq cancer in malformation Beckwith-Wiedemann s (n=1,923) tumour/total tumour % Wilms Hepatoblastoma Other IC2 26/ % +/- +/- +/- IC1 41/ % UPD 59/ % CDKN1C 5/72 8.0% no defect 23/ % Total 155/ % Maas S, Am J Med Genet 2016 [Epub ahead of print]
23 freq cancer in malformation Beckwith-Wiedemann s Maas S, Am J Med Genet 2016 [Epub ahead of print]
24 freq cancer in malformation Malformation syndrome and cancer Cordeddu, Nat Genet 2014;46:815 one patient twice testis carcinoma 27y / 39y n = 8 Primrose syndrome
25 freq malformation in cancer Frequency Cancer: chance malformation? - 1,073 consecutive children with cancer all dysmorphisms - single investigator - 7% scored independently 2nd investigator - kappa analyses; syndromes? Merks J, Am J Med Genet 2005;134A:132
26 freq malformation in cancer Frequency Tumor Groups Neuroblastoma Rhabdomyosarcoma Germ cell tumors Nephroblastoma Osteosarcoma Ewing sarcoma Medulloblastoma Non-Hodgkin Lymphoma Hodgkin Disease ALL n
27 freq malformation in cancer Frequency Neuroblastoma (n=66) Acute Lymphoblastic Leukemia (n=190) Hodgkin's disease (n=87) Non-Hodgkin's Lymphoma (n=124) Nephroblastoma (n=122) Rhabdomyosarcoma (n=87) Osteosarcoma (n=52) FA HT DSE BP EF RMG SNN APC ALL MCAL specific combinations of minor anomalies per tumor type
28 freq malformation in cancer % 60 Frequency Controls (n=4,412) Merks (n=1,073) Number of minor anomalies per patient Merks J, Am J Med Genet 2005;134A:132
29 freq malformation in cancer Frequency - 44 known syndromes pm 24 newly diagnosed - 34 patients syndrome suspected 1:15 children with cancer has a syndrome Merks J, Am J Med Genet 2005;134A:132 Merks J, JAMA 2008;299:61
30 freq malformation in cancer Diagnoses Cleidocranial Dysostosis
31 freq malformation in cancer Diagnoses Cleidocranial Dysostosis
32 freq malformation in cancer Diagnoses BPES
33 freq malformation in cancer Diagnoses 1994 neuroblastoma stage IV
34 freq malformation in cancer Diagnoses 2003 LEOPARD SYNDROME
35 type malformation in cancer Definitions Malformation A non-progressive congenital morphologic anomaly of a single organ or body part due to an alteration of the primary developmental program Dysplasia A morphologic anomaly arising either prenatally or postnatally from dynamic or ongoing alteration of cellular constitution, tissue organization or function within specific organ or a specific tissue type Hennekam, Am J Med Genet 2013;161A:2726
36 type malformation in cancer Cellular Growth and Development Hennekam, Am J Med Genet A:2726
37 type malformation in cancer Definitions Marfan syndrome dysplasia? FBN1 through TGFBR2
38 type malformation in cancer Definitions EEC syndrome? TP63 Van Bokhoven, personal communication 2013
39 co-localisation Localisation Site tumours vs site malformation: co-localisation? Major malformations Minor characteristics Benign tumours Malign tumours Bleeker, Eur J Med Genet 2014;57:480
40 co-localisation Localisation 2 examples microtia syndromic in 20-60% hypospadias syndromic in 10-30% sources for syndromes with tumours Winter-Baraitser Dysmorphology Database (1987) Gorlin s Syndromes of the Head and Neck (2010) PubMed at least n=100 Bleeker, Eur J Med Genet 2014;57:480
41 co-localisation Localisation Bleeker, Eur J Med Genet 2014;57:480
42 co-localisation Localisation Co-localisation of tumours with major characteristics Ab; Abdomen, Ba; Back/spine, Bl; Blood vessels, Br; Brain, Ey; Eye, Ge; Genitalia, He; Hematology/immunology, Mu; Muscle, Nec; Neck. Or; Oral region, Ske; Skeletal, Ski; Skin, Te; Teeth, Th; Thorax, Ur; Urinary system.
43 co-localisation Localisation Co-localisation of tumours with major or minor characteristics Ab; Abdomen, Ba; Back/spine, Bl; Blood vessels, Br; Brain, Ey; Eye, Ge; Genitalia, He; Hematology/immunology, Mu; Muscle, Nec; Neck. Or; Oral region, Ske; Skeletal, Ski; Skin, Te; Teeth, Th; Thorax, Ur; Urinary system.
44 co-localisation Localisation - co-localisation tumours in 60% of malformations - no difference between benign malign tumours pm reporting bias pm cave sequences: hypospadias ~ cryptorchidism ~ testis tumours
45 cancer vs development Development vs Cancer Bellacosa, Am J Med Genet 2013;161A:2788
46 cancer vs development Development vs Cancer Bellacosa, Am J Med Genet 2013;161A:2788
47 cancer vs development Development vs Cancer Cornelia de Lange s. Noonan s. Bellacosa, Am J Med Genet 2013;161A:2788
48 cancer vs development Development vs Cancer Cornelia de Lange s. Noonan s. Bloom s. Proteus s. Bellacosa, Am J Med Genet 2013;161A:2788
49 cancer vs development Development vs Cancer Cornelia de Lange s. Gorlin s. Noonan s. Bloom s. Proteus s. Bellacosa, Am J Med Genet 2013;161A:2788
50 Conclusions - 3 or more minor anomalies: high chance malformation - strong correlation cancer / malformations by - functions gene prenatal postnatal - pathway disturbances - chance for cancer in malformation depending of - entity - cause pm knowledge - chance for malformation in cancer 1:15
51 Conclusions - chance for cancer depending on type of anomaly - co-localisation cancer / malformation in 60% - change clinical manifestations from developmental disturbances to cancer cancer can be seen as a developmental disturbance / derangement of differentiation pm therapeutic consequences?
52 Complexity of relationships
53
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