A heterozygous frameshift mutation in the Fanconi Anemia C gene in familiary T-ALL and secondary malignancy

Background: Patients with Fanconi Anemia (FANC) have a well documented incr eased 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 hetero zygous individuals to develop malignancies was increased, they should be fo und in groups of patients with AML or MDS at higher proportion than in the normal population. We are currently screening a pediatric population with h ematologic malignancies for mutations in the FANCA, FANCC and FANCC gene, a nd report here on siblings carrying a heterozygous frameshift mutation in t he FANCC Gene. Patients and Methods: Using PCR based single strand conforma tional analysis we screened the DNA from pediatric patients suffering from 1 degrees 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 patie nt with refractory I-ALL, being the brother of a patient with I-ALL and MDS transforming into AML. Aberrant PCR products were directly sequenced. Flow cytometric measurement of mitogen- sensitivity and G2-phase arrest is used to evaluate cultured stimulated lymphocytes from individuals carrying FANC- mutations. Results: A novel heterozygous frameshift mutation, 377-378delGA in the FANCC gene was found in 2 siblings, both suffering from I-ALL with subsequent MDS transforming to AML in one of them. No other mutation was fo und by direct sequencing of the complete FANCC gene. Both patients died und er therapy. The parents (first degree cousins) and one healthy brother are also carriers. Their lymphocytes show a higher mutagen sensitivity than nor mal, 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 fi ndings within this family support the hypothesis of an increased risk to de velop malignancies in heterozygous carriers of FANC- mutations. A systemati c 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.