Líf - og heilbrigðisvísindaráðstefna Háskóla Íslands 2021

BRCA2 haploinsufficiency in telomere maintenance

Main author: Sigríður Klara Böðvarsdóttir
Institution or Company: University of Iceland

Co-Authors, Institution or Company:
Birna Þorvaldsdóttir, University of Iceland. Hörður Bjarnason,University of Iceland. Jórunn Erla Eyfjörð, University of Iceland. Margrét Steinarsdóttir, Landspítali. Soffía Rún Gunnarsdóttir, University of Iceland.

Introduction: In our previous studies we found association between the BRCA2 999del5 germline mutation and dysfunctional telomeres in breast cell lines and that BRCA2 999del5 mutation carriers with short telomere length in blood cells had higher risk of being diagnosed with breast cancer 1,2. In the current study we analysed dysfunctional telomeres in lymphocyte cell lines from heterozygous BRCA2 999del5 mutation carriers as well as Fanconi Anemia D1 patients with homozygous BRCA2 mutations and compared those to a BRCA2 wild type cell line. The aim was to find out if telomere maintenance was affected by a single BRCA2 mutation.

Methods: Metaphase chromosomes were harvested from nine lymphocyte cell lines that were wild type, heterozygous or homozygous for BRCA2 mutations and analysed by telomere and centromere fluorescence in situ hybridization. Approximately 60 metaphases from each cell line were analysed for telomere free ends (TFE), multiple telomere signals (MTS), interstitial telomere signals (ITS) and extra chromosomal telomere signals (ECTS). Differences between the three BRCA2 genotypes were analysed by the Student´s t-test.

Results: TFE, ITS and ECTS were separately found to be significantly increased stepwise between the wild type, BRCA2 heterozygous and BRCA2 homozygous lymphocytes (p < 0.0001, between each genotype). MTS were found to be significantly increased between the BRCA2 wild type and BRCA2 heterozygous lymphocytes (p < 0.0001) and the BRCA2 homozygous mutated lymphocytes (p < 0.05) but not between the two BRCA2 mutated genotypes.

Conclusions: Dysfunctional telomeres were found to be significantly increased in a stepwise manner between the three BRCA2 genotypes indicating BRCA2 haploinsufficiency in telomere maintenance.


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