Medizinische Universität Graz Austria/Österreich - Forschungsportal - Medical University of Graz
Gewählte Publikation:
Schulz, E.
PEDIGREE ANALYSIS OF PATIENTS WITH THERAPY-RELATED MYELOID NEOPLASMS REVEALS GERM-LINE MUTATIONS IN THE DNA DAMAGE RESPONSE GENES BRCA1, BARD1 AND TP53
[ Diplomarbeit ] Medical University of Graz, 2011. pp. 99
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- Autor*innen der Med Uni Graz:
- Schulz Eduard
- Betreuer*innen:
- Sill Heinz
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- Abstract:
- Background: Therapy-related myeloid neoplasms (t-MNs) are severe long-term sequelae of cytotoxic treatments for a primary, often malignant disorder accounting for 10% of all MDS/AML cases. Aims: We hypothesized that cancer predisposition syndromes are prevalent in this cohort of patients and germ-line mutations in respective genes contribute to leukemogenesis. Methods: A ¿nuclear pedigree¿ consisting of all first- and second degree relatives was obtained from 51 adult and pediatric index patients with t-MNs and evaluated for cancer predisposition syndromes according to established criteria. In conspicuous cases, genomic DNA from cultured skin fibroblasts of t-MN patients was analyzed for deleterious germ-line mutations by PCR, direct sequencing and MLPA, respectively. Deleterious heterozygous germ-line mutations were further assessed for loss of the wild-type allele in CD34+ sorted leukemic cells by PCR, direct sequencing and SNP array, respectively. Results: Twenty-five of 51 (49%) patients with t-MNs had a hematological malignancy and 26 (51%) a solid tumor as primary disease. Non-Hodgkin´s lymphoma (29%) and breast cancer (25%) were the most frequent primary neoplasms found in more than 50% of all patients. Twelve index patients indicated a hereditary cancer syndrome initiating a search for BRCA1, BRCA2, BARD1, TP53 and PTEN germ-line mutations, respectively. Deleterious, heterozygous germ-line mutations were found in 5/51 (9.8%) individuals: Two in BRCA1 (c.5251C>T; c.3112G>T), one in BARD1 (c.1670G>C) and two in TP53 (c.1146delA; c.849-852insGGCG). The TP53 germ-line mutations have not been previously described and developed most likely de novo. SNP array revealed loss of heterozygosity (LOH) for BRCA1 c.3112G>T and TP53 c.849-852insGGCG germ-line mutations in sorted CD34+ leukemic cells. Conclusion: The prevalence of deleterious germ-line mutations seems to be increased in this cohort of t-MN patients. Preliminary data indicate that these mutations contribute to therapy-related leukemogenesis. Furthermore, results may have clinical implications with respect to genetic counseling of these patients and their relatives.