BRCA2 Haploinsufficiency in Telomere Maintenance.

Soffía R Gunnarsdottir,Jórunn E Eyfjörd,Hördur Bjarnason,Felice Paland,Margrét Steinarsdottir,Sigrídur K Bödvarsdottir,Birna Thorvaldsdottir

doi:10.3390/genes13010083

Soffía R Gunnarsdottir, Jórunn E Eyfjörd + Show 5 more

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https://doi.org/10.3390/genes13010083

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Journal: Genes	Publication Date: Dec 28, 2021
Citations: 1	License type: CC BY 4.0

Affiliation: University of Iceland, University of Tübingen

Abstract

Our previous studies showed an association between monoallelic BRCA2 germline mutations and dysfunctional telomeres in epithelial mammary cell lines and increased risk of breast cancer diagnosis for women with BRCA2 999del5 germline mutation and short telomeres in blood cells. In the current study, we analyzed telomere dysfunction in lymphoid cell lines from five BRCA2 999del5 mutation carriers and three Fanconi Anemia D1 patients by fluorescence in situ hybridization (FISH). Metaphase chromosomes were harvested from ten lymphoid cell lines of different BRCA2 genotype origin and analyzed for telomere loss (TL), multitelomeric signals (MTS), interstitial telomere signals (ITS) and extra chromosomal telomere signals (ECTS). TL, ITS and ECTS were separately found to be significantly increased gradually between the BRCA2+/+, BRCA2+/- and BRCA2-/- lymphoid cell lines. MTS were found to be significantly increased between the BRCA2+/+ and the BRCA2+/- heterozygous (p < 0.0001) and the BRCA2-/- lymphoid cell lines (p < 0.0001) but not between the BRCA2 mutated genotypes. Dysfunctional telomeres were found to be significantly increased in a stepwise manner between the BRCA2 genotypes indicating an effect of BRCA2 haploinsufficiency on telomere maintenance.

Highlights

The breast cancer susceptibility 2 (BRCA2) gene was identified in 1995 and has been shown to play an essential role in DNA double strand break (DSB) repair by homologous recombination (HR) and DNA crosslink repair by the Fanconi anemia (FA) pathway [1,2]
In the current study we found a significant stepwise increase in telomere loss (TL) between the BRCA2+/+, BRCA2+/- and BRCA2-/- genotypes with a high difference between the BRCA2+/+ and BRCA2+/- genotypes of the single telomere end (STE) subgroup and between the BRCA2+/- and BRCA2-/- genotypes of the telomere free ends (TFE) subgroup (Figure 1)
We found a significant increase of multitelomeric signals (MTS) between the BRCA2+/+ and the BRCA2+/- and BRCA2-/- lymphoid cell lines, respectively (Figure 2)

Summary

Introduction

The breast cancer susceptibility 2 (BRCA2) gene was identified in 1995 and has been shown to play an essential role in DNA double strand break (DSB) repair by homologous recombination (HR) and DNA crosslink repair by the Fanconi anemia (FA) pathway [1,2]. Germline mutations in the BRCA2 gene are known to be highly associated with the risk of diagnosis with breast, ovarian, prostate, and pancreatic cancer [3–6]. In Iceland, a BRCA2 999del truncation mutation in exon 9 was isolated in a family with several cases of male and female breast cancer [3]. This mutation has been shown to have a high frequency (0.7%) in the Icelandic population [5,7]. Cloning of the 999del mutant and expression studies showed that even though the short mutant RNA is produced there is no detectable corresponding protein, indicating BRCA2 heterozygosity [8]

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