RT Journal Article
SR Electronic
T1 Germline mutations in the DNA damage response genes <em>BRCA1</em>, <em>BRCA2</em>, <em>BARD1</em> and <em>TP53</em> in patients with therapy related myeloid neoplasms
JF Journal of Medical Genetics
JO J Med Genet
FD BMJ Publishing Group Ltd
SP 422
OP 428
DO 10.1136/jmedgenet-2011-100674
VO 49
IS 7
A1 Eduard Schulz
A1 Angelika Valentin
A1 Peter Ulz
A1 Christine Beham-Schmid
A1 Karin Lind
A1 Verena Rupp
A1 Herwig Lackner
A1 Albert Wölfler
A1 Armin Zebisch
A1 Werner Olipitz
A1 Jochen Geigl
A1 Andrea Berghold
A1 Michael R Speicher
A1 Heinz Sill
YR 2012
UL http://jmg.bmj.com/content/49/7/422.abstract
AB Background 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.Methods 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.Results 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.Conclusion It is concluded that a proportion of patients with t-MNs carry cancer susceptibility mutations which are likely to contribute to therapy related leukaemogenesis.