Abstract 3371: Analysis of telomere length and dysfunction in normal breast tissue from BRCA2 mutation carriers
Authors: Thorvaldsdottir Birna , Cimini Beth A. , Diolaiti Morgan E. , Olafsdottir Katrin , Jonasson Jon G. , Eyfjörd Jorunn E. 
Published: August 2018

Abstract
The tumor suppressor protein BRCA2 is important for maintaining genomic stability. BRCA2 is essential for homologous recombination repair of DNA double strand breaks and also has a role in protection of stalled replication forks as well as in telomere protection and maintenance. Disruptions in telomere homeostasis can result in excessive telomere shortening and drive chromosome instability, a hallmark of BRCA2-related cancers. Germline mutations in the BRCA2 gene are associated with highly increased risk of breast cancer. A single deleterious founder mutation, BRCA2999del5, has been detected in the gene in the Icelandic population, making it feasible to study the influence of a single mutation at a population level. The BRCA2999del5 mutation is found in 6-7% of female breast cancer patients in Iceland and is associated with complex chromosomal changes in tumor tissue. Furthermore, the BRCA2999del5 mutation is associated with poor prognosis, although mutation carriers seem to differ with respect to age of onset and severity of disease. It is therefore of great interest to identify factors that influence breast cancer risk within the mutation carrier group. The aim of the study was to measure telomere length (TL) and levels of telomere dysfunction in tumor-adjacent normal breast tissue from BRCA2 mutation carriers and non-carriers and investigate their potential relationship with breast cancer risk. The study group consisted of 186 Icelandic breast cancer patients; BRCA2999del5 mutation carriers and sporadic cases, matched with respect to age and year of diagnosis. For TL measurements, paraffin embedded normal breast tissue samples were analyzed by Quantitative Fluorescence in Situ Hybridization. Telomere dysfunction induced foci (TIFs) can be detected where co-localization of telomere and DNA-damage signals occur. For this purpose, the samples were also immunofluorocently stained for the DNA damage repair protein 53BP1. In concordance with previously reported data in the literature, luminal epithelial cells showed the shortest TL and highest number TIFs of the cell types in normal breast tissue. This observation is highly relevant as these are the cells from which most breast cancers originate. No difference was detected in age-adjusted TL between BRCA2 mutation carriers and non-carriers. However, consistent with our recently published data from TL measurements in blood from the same study group, shorter TL is correlated with younger age at breast cancer diagnosis in BRCA2 mutation carriers but not in non-carriers. In conclusion, these results indicate that in BRCA2 mutation carriers, shorter TL in normal breast tissue is associated with earlier breast cancer occurrence.
Citation Format: Birna Thorvaldsdottir, Beth A. Cimini, Morgan E. Diolaiti, Katrin Olafsdottir, Jon G. Jonasson, Jorunn E. Eyfjörd. Analysis of telomere length and dysfunction in normal breast tissue from BRCA2 mutation carriers [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 3371.