Biallelic BRCA2 mutations are associated with multiple malignancies in childhood including familial Wilms tumour (original) (raw)

Biallelic BRCA2 mutations are associated with multiple malignancies in childhood including familial Wilms tumour

S Reid1,
A Renwick1,
S Seal1,
L Baskcomb1,
R Barfoot1,
H Jayatilake1,
The Breast Cancer Susceptibility Collaboration (UK),
K Pritchard-Jones2,
M R Stratton1,
A Ridolfi-Lüthy3,
N Rahman1,
for the Familial Wilms Tumour Collaboration
1Section of Cancer Genetics, Institute of Cancer Research, Sutton, Surrey, UK
2Section of Pediatrics, Institute of Cancer Research, Sutton, Surrey, UK
3Division of Pediatric Hematology and Oncology, University Children’s Hospital, Inselspital, CH-3010 Bern, Switzerland
Correspondence to: Dr Nazneen Rahman Section of Cancer Genetics, Brookes Lawley Building, Institute of Cancer Research, 15 Cotswold Road, Sutton, Surrey SM2 5NG, UK; nazneen.rahmanicr.ac.uk

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Wilms tumour (WT) is an embryonal tumour of the kidney that occurs in 1 in 10 000 children. Familial clusters are rare and account for only 1–3% of cases. Mutations in WT1 account for a minority of WT families and two autosomal dominant familial WT predisposition genes have been mapped to chromosomes 17q21 and 19q13.1–3 However, a considerable proportion of familial WT pedigrees are not attributable to any of these loci.4

Fanconi anaemia (FA, MIM 227650) is a rare autosomal recessive condition affecting ∼1 in 300 000 children. FA is 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 childhood.5 FA is heterogeneous and consists of at least 11 complementation groups, A, B, C, D1, D2, E, F, G, I, J, and L.6–8 Eight FA genes have been cloned and at least six FA proteins, FANCA, FANCC, FANCE, FANCF, FANCG, and FANCL, form a nuclear complex required for monoubiquitination of FANCD2. This modification promotes translocation of FANCD2 to DNA repair foci that also contain BRCA1, BRCA2, and RAD51.9

In 2002, Howlett and colleagues reported biallelic BRCA2 mutations in individuals with Fanconi anaemia D1 (FA-D1). Subsequently, additional FA-D1 and unclassified FA cases were examined and cases with BRCA2 mutations and WT and/or brain tumours were reported.10–13 These data prompted us to investigate BRCA2 in a familial WT pedigree, WILMS2, which includes siblings with both WT and brain tumours.4,14,15

METHODS

Family report

WILMS2 was ascertained as part of our research on susceptibility to WT, which is approved by the London Multicentre Research Ethics Committee. The family includes two affected brothers with WT. The elder child first came to attention when his cryptorchidism was corrected at …