Developmental disease or cancer: the crucial role of timing and type of new mutations
In this project we hypothesize that mainly two factors influence the seemingly dual role of developmental disease genes: first, the timing of the mutational process determines whether mutations cause a developmental disorder (if mutated constitutionally) or cancer (if mutated somatically); second, the mutation type influences the outcome as different genetic alterations may, for example, result in a gain or loss of function, which impacts on the molecular and clinical phenotype.
- Gain fundamental insight into the biological pathways underlying normal development in humans by identifying disruptive de novo germline mutations in patients with severe developmental disorders and prenatal lethality.
- identify novel conditions due to aneuploidy
- Gain fundamental insight into the association between human development and cancer development through bioinformatics and functional studies.
Embryonic development is a process of cell proliferation, differentiation, migration and apoptosis. Abnormal development is the result of a disruption of one or several of these processes. This disruption can lead to different phenotypes involving congenital malformations and/or intellectual disability, which are categorized altogether as developmental disorders. Developmental disorders are clinically diverse, comprising both common and rare phenotypes with a wide spectrum of severity covering mild phenotypes with no morbidity (for instance, cleft uvula), clinically significant abnormalities (like cleft lip and/or palate) and severe malformations (for example, holoprosencephaly). The most severe extreme of the disease spectrum involves malformations and disorders leading to prenatal or early postnatal death.
The recent introduction of "next-generation" sequencing technologies, including exome sequencing, has revolutionized the field of gene discovery for developmental disorders1-3. This approach has been particularly successful in solving sporadic disorders in which healthy parents conceive a child with a condition so severe that it prevents the child from reproducing. Sporadic disorders typically affect single cases within a family, making them virtually impossible to solve using traditional strategies like gene mapping or Sanger sequencing. However, in-depth comparison of the exomes of patients and their healthy parents has pinpointed de novo germline mutations as the main cause of these sporadic disorders. Such mutations have been found to cause both common and rare developmental disorders characterized by congenital malformations and/or intellectual disability, autism or schizophrenia 4-8.
Strikingly, a growing number of genes in which germline mutations cause developmental disorders, like NRAS, KRAS, KIT and NOCHT2, are also known as cancer genes9-18. This is not entirely unexpected since aberrant cell proliferation, differentiation, migration and apoptosis are both characteristics of cancer and abnormal embryonic development19. Additionally, clinical studies have shown that individuals with different forms of childhood cancer have a higher prevalence of congenital malformations20-23, while other publications report a higher incidence of tumorigenesis in overgrowth syndromes" 24, 25.
In contrast to previous work, this study will focus on developmental disorders for which no cancer predisposition is known or is impossible to observe in cases involving prenatal death. We will explore whether the genes underlying these disorders are enriched for cancer driver mutations. We will follow up several developmental disorders, such as Bohring-Opitz syndrome and Schinzel-Giedeon syndrome, which were recently solved by exome-sequencing in Nijmegen7,8. While de novo germline mutations in ASXL1 and SETBP1 cause Bohring-Opitz syndrome and Schinzel-Giedeon syndrome respectively, de novo somatic mutations in the same genes can drive myeloproliferative disorders like leukemia26-30. Both syndromes are severe human developmental disorders caused by mutations in genes related to leukemia, clearly hinting at associations between the molecular mechanism underlying these diseases and cancer. Interestingly, both syndromes have a very specific mutational profile; we only observe de novo nonsense mutations in ASXL1 in patients with Bohring-Opitz syndrome whereas all mutations causing Schizel-Giedeon syndrome are de novo missense mutations within a 12 nucleotide stretch in SETBP1.
We hypothesize that mainly two factors influence the seemingly dual role of developmental disease genes: first, the timing of the mutational process determines whether mutations cause a developmental disorder (if mutated constitutionally) or cancer (if mutated somatically); second, the mutation type influences the outcome as different genetic alterations may, for example, result in a gain or loss of function, which impacts on the molecular and clinical phenotype.