Medizinische Universität Graz Austria/Österreich - Forschungsportal - Medical University of Graz
Gewählte Publikation:
SHR Neuro Krebs Kardio Lipid Stoffw Microb
Schulz, E; Valentin, A; Ulz, P; Beham-Schmid, C; Lind, K; Rupp, V; Lackner, H; Wölfler, A; Zebisch, A; Olipitz, W; Geigl, J; Berghold, A; Speicher, MR; Sill, H.
Germline mutations in the DNA damage response genes BRCA1, BRCA2, BARD1 and TP53 in patients with therapy related myeloid neoplasms.
J Med Genet. 2012; 49(7):422-428
Doi: 10.1136/jmedgenet-2011-100674
Web of Science
PubMed
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- Führende Autor*innen der Med Uni Graz
- Schulz Eduard
- Sill Heinz
- Co-Autor*innen der Med Uni Graz
- Beham-Schmid Christine
- Berghold Andrea
- Geigl Jochen Bernd
- Lackner Herwig
- Lind Karin
- Rupp Verena
- Speicher Michael
- Ulz Peter
- Wölfler Albert
- Zebisch Armin
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- Abstract:
- Therapy related myeloid neoplasms (t-MNs) are complex diseases originating from an interplay between exogenous toxicities and a susceptible organism. It has been hypothesised that in a subset of cases t-MNs develop in the context of hereditary cancer predisposition syndromes. The study systematically evaluated pedigrees of patients with t-MNs for cancer incidences and the possibility of a hereditary cancer predisposition syndrome. In addition, mutational analyses were performed using constitutional DNA from index patients, and deleterious heterozygous germline mutations were assessed for loss of heterozygosity in sorted leukaemic cells by single nucleotide polymorphism array. A nuclear pedigree was obtained in 51/53 patients with t-MNs resulting in a total of 828 individuals analysed. With a standardised incidence ratio of 1.03 (95% CI 0.74 to 1.39), the tumour incidence of first- degree relatives was not increased. However, six pedigrees were suggestive for a hereditary breast and ovarian cancer syndrome, three of a Li-Fraumeni like syndrome, and three index patients showed multiple primary neoplasms. Mutational analysis revealed two BRCA1 (c.3112G→T, c.5251C→T), one BRCA2 (c.4027A→G), two BARD1 (C557S) and four TP53 germline mutations (g.18508_18761delinsGCC, c.847C→T, c.845_848dupGGCG, c.1146delA) in nine of 53 (17%) index patients with t-MNs. Loss of heterozygosity in leukaemic cells was demonstrated for the BRCA1c.3112G→T and TP53c.845_848dupGGCG mutations, respectively. It is concluded that a proportion of patients with t-MNs carry cancer susceptibility mutations which are likely to contribute to therapy related leukaemogenesis.
- Find related publications in this database (using NLM MeSH Indexing)
- Adolescent -
- Adult -
- Aged -
- Aged, 80 and over -
- BRCA1 Protein - genetics BRCA1 Protein - metabolism
- BRCA2 Protein - genetics BRCA2 Protein - metabolism
- Child -
- Child, Preschool -
- DNA Damage -
- DNA Mutational Analysis -
- Female -
- Genetic Predisposition to Disease -
- Germ-Line Mutation -
- Hereditary Breast and Ovarian Cancer Syndrome - genetics Hereditary Breast and Ovarian Cancer Syndrome - pathology Hereditary Breast and Ovarian Cancer Syndrome - therapy
- Heterozygote -
- Humans -
- Immunohistochemistry -
- Incidence -
- Male -
- Middle Aged -
- Neoplasms, Second Primary - genetics Neoplasms, Second Primary - pathology Neoplasms, Second Primary - therapy
- Pedigree -
- Tumor Suppressor Protein p53 - genetics Tumor Suppressor Protein p53 - metabolism
- Tumor Suppressor Proteins - genetics Tumor Suppressor Proteins - metabolism
- Ubiquitin-Protein Ligases - genetics Ubiquitin-Protein Ligases - metabolism
- Young Adult -