Background: Patients with Fanconi Anemia (FANC) have a well documented increased risk to develop malignancies, especially Acute Myeloid Leukemia (AML) and Myelodysplastic Syndrome (MDS). The risk for heterozygous individuals is not clear, epidemiological data are inconsistent. If the risk for heterozygous individuals to develop malignancies was increased, they should be found in groups of patients with AML or MDS at higher proportion than in the normal population. We are currently screening a pediatric population with hematologic malignancies for mutations in the FANCA, FANCC and FANCG gene, and report here on siblings carrying a heterozygous frameshift mutation in the FANCC Gene.
Patients and methods: Using PCR based single strand conformational analysis we screened the DNA from pediatric patients suffering from 1 degree or 2 degrees MDS, CMML/JMML or AML for mutations in the FANCA (43 exons), FANCC (14 exons) and FANCG (14 exons) gene, and included one patient with refractory T-ALL, being the brother of a patient with T-ALL and MDS transforming into AML. Aberrant PCR products were directly sequenced. Flowcytometric measurement of mitogen-sensitivity and G2-phase arrest is used to evaluate cultured stimulated lymphocytes from individuals carrying FANC-mutations.
Results: A novel heterozygous frame-shift mutation, 377-378delGA in the FANCC gene was found in 2 siblings, both suffering from T-ALL with subsequent MDS transforming to AML in one of them. No other mutation was found by direct sequencing of the complete FANCC gene. Both patients died under therapy. The parents (first degree cousins) and one healthy brother are also carriers. Their lymphocytes show a higher mutagen sensitivity than normal, but do not get blocked in G2 phase as being typical for Fanconi Anemia.
Conclusion: As the mutation causes a premature Stopcodon within exon 4 of the FANCC gene it has to be regarded as a causal FANCC gene defect. The findings within this family support the hypothesis of an increased risk to develop malignancies in heterozygous carriers of FANC-mutations. A systematic screening of further patients is needed, and we are currently examining a larger cohort to get a better estimate of the true risk of heterozygosity.