The role of mutations in fanconi anaemia genes in the aetiology of acute myeloid leukaemia and solid tissue malignancies
Fanconi anaemia (FA) is an autosomal recessive disorder caused by mutations in eight different genes (FANC A, B, C, D2, E, F, G and BRCA2). FA patients have a high risk of developing acute myeloid leukaemia (AML) and solid tumours such as squamous cell carcinoma of the head and neck (SCCHN). Using a combination of molecular and epidemiological methods, the possibility that acquired FA gene mutations predispose to the sporadic development of such malignancies, or that heterozygous carriers of FA mutations have an increased cancer risk, was investigated. -- AML samples were screened for intragenic loss of heterozygosity (LOH) in the FA genes by quantitative gene dosage assays. In the FANCA dosage assay, 103 samples were successfully screened and four FANCA deletions were detected. Further analysis of these samples did not detect any point mutations in the other allele or inactivation by promoter methylation, although gene expression was reduced compared to AML samples with no FANCA deletion. Gene inactivation by deletion mutations or methylation was not detected in FANCC, FANCD2, FANCE, FANCF or FANCG. However, FANCF promoter methylation was observed in an AML cell line with absent FANCF protein. -- Analysis of microsatellite polymorphisms linked to known FA gene loci in matched tumour/normal tissue pairs from sporadic SCCHN cases detected LOH in 7% of tumours at FANCG and in 36% at FANCD2, while gene silencing by methylation was not apparent. -- Epidemiological studies using data collected on 575 individuals from FA families showed that overall cancer incidence in FA heterozygotes was not significantly elevated compared to expected population levels. -- These combined observations indicate a limited role for FA genes in the aetiology of sporadic AML and solid tumours
Thesis, Dissertation, English, 2003