Childhood Cancer Syndromes
Section:
Section of Cancer Genetics
Investigation of childhood cancer syndromes has led to the identification and/or characterisation of several important cancer genes, including RB1, WT1 and TP53. However, there still remain syndromes in which the causative genes are unknown or in which the clinical spectrum and management on children with the syndromes is unclear. We will investigate any childhood cancer syndrome with unknown cause to try to identify the underlying mechanism and currently particularly focus on the following syndromes.
Aneuploidy-Cancer syndromes
Gains and losses of chromosomes (aneuploidy) frequently occur in cancer, but the mechanisms leading to aneuploidy are largely unknown. Aneuploidy-cancer syndromes are rare genetic conditions characterised by variable gains and losses of chromosomes affecting a proportion cells. Affected children have a variety of medical problems and a high risk of cancer in childhood. In 2004 we demonstrated that biallelic BUB1B mutations are one cause of aneuploidy-cancer predisposition. These data were the first to relate defects in the mitotic spindle checkpoint with a human disorder and provided the most direct evidence to date that aneuploidy is causally related in cancer development.
We have several cases that are not due to BUB1B and are conducting genetic mapping studies and candidate gene screening to identify the underlying genes. We are also undertaking functional studies to evaluate whether re-introduction of BUBR1 (the protein encoded by BUB1B) can complement the defect in BUB1B related and non-BUB1B related cases. We evaluate the role of genes we identify as somatic targets in cancer and investigate whether monoallelic mutation carriers are at increased risk of cancer.
Biallelic Mismatch Repair syndromes
Monoallelic mutations in mismatch repair genes such as MLH1, MSH2 and MSH6 cause hereditary non-polyposis colorectal cancer (HNPCC) syndrome and are associated with increased risks of colorectal and endometrial cancer in adults. In recent years it has become apparent that carriers of biallelic mutations in these genes are at high risk of a variety of childhood cancers including brain tumours, lymphomas and gastrointestinal cancers. We are investigating the phenotypic spectrum of these conditions with a view to producing diagnostic and management criteria.
Fanconi Anemia syndrome
Fanconi anemia is a rare autosomal recessive condition characterised by variable congenital abnormalities, short stature, bone marrow failure, hypersensitivity to DNA crosslinking agents and a predisposition to haematological malignancies such as acute myeloid leukaemia in children. FA is heterogeneous and is caused by several different genes. Some of these genes form a nuclear complex required for monoubiquitination and translocation of FANCD2 to DNA repair foci that also contain BRCA1, BRCA2 and RAD51. In collaboration with Christopher Mathew and Arleen Auerbach we are collecting Fanconi anemia cases that are not due to known genes, with the aim of undertaking linkage and candidate gene analyses to identify novel Fanconi anemia genes. We have a particular focus on biallelic BRCA2 mutations, which cause Fanconi anemia subtype D1 and are associated with high risks of childhood solid tumours, particularly Wilms tumour and brain tumours and are a rare cause of familial Wilms tumour.
In the Section of Cancer Genetics
