Lymphocyte Telomere Length Is Long in BRCA1 and BRCA2 Mutation Carriers Regardless of Cancer-Affected Status

Karen A. Pooley, Lesley McGuffog, Daniel Barrowdale, Debra Frost, Steve D. Ellis, Elena Fineberg, Radka Platte, Louise Izatt, Julian Adlard, Julian Bardwell, Carole Brewer, Trevor Cole, Jackie Cook, Rosemarie Davidson, Alan Donaldson, Huw Dorkins, Fiona Douglas, Jacqueline Eason, Catherine Houghton, M. John KennedyEmma McCann, Zosia Miedzybrodzka, Alex Murray, Mary E. Porteous, Mark T. Rogers, Lucy E. Side, Marc Tischkowitz, Lisa Walker, Shirley Hodgson, Diana M. Eccles, Patrick J. Morrison, D. Gareth Evans, Rosalind A. Eeles, Antonis C. Antoniou, Douglas F. Easton, Alison M. Dunning*, EMBRACE

*Corresponding author for this work

Research output: Contribution to journalArticle

11 Citations (Scopus)

Abstract

Background: Telomere length has been linked to risk of common diseases, including cancer, and has previously been proposed as a biomarker for cancer risk. Germline BRCA1 and BRCA2 mutations predispose to breast, ovarian, and other cancer types.

Methods: We investigated telomere length in BRCA mutation carriers and their non-carrier relatives and further examined whether telomere length is a modifier of cancer risk in mutation carriers. We measured mean telomere length in DNA extracted from whole blood using high-throughput quantitative PCR. Participants were from the EMBRACE study in United Kingdom and Eire (n = 4,822) and comprised BRCA1 (n = 1,628) and BRCA2 (n = 1,506) mutation carriers and their non-carrier relatives (n = 1,688).

Results: We find no significant evidence that mean telomere length is associated with breast or ovarian cancer risk in BRCA mutation carriers. However, we find mutation carriers to have longer mean telomere length than their non-carrier relatives (all carriers vs. non-carriers, P-trend = 0.0018), particularly in families with BRCA2 mutations (BRCA2 mutation carriers vs. all non-carriers, Ptrend = 0.0016).

Conclusions: Our findings lend little support to the hypothesis that short mean telomere length predisposes to cancer. Conversely, our main and unexpected finding is that BRCA mutation carriers (regardless of cancer status) have longer telomeres than their non-mutation carrier, non-cancer-affected relatives. The longer telomere length in BRCA2 mutation carriers is consistent with its role in DNA damage response. Overall, it seems that increased telomere length may be a consequence of these mutations, but is not itself directly related to the increased cancer risk in carriers.

Impact: The finding that mutation carriers have longer mean telomere lengths than their non-carrier relatives is unexpected but biologically plausible and could open up new lines of research into the functions of the BRCA proteins. To our knowledge, this is the largest study of telomere length in BRCA mutation carriers and their relatives. The null cancer-risk association supports recent large prospective studies of breast and ovarian cancer and indicates that mean telomere length would not be a useful biomarker in these cancers. (C) 2014 AACR.

Original languageEnglish
Pages (from-to)1018-1024
Number of pages7
JournalCancer Epidemiology, Biomarkers and Prevention
Volume23
Issue number6
Early online date18 Mar 2014
DOIs
Publication statusPublished - Jun 2014

Keywords

  • INCIDENT COLORECTAL-CARCINOMA
  • OVARIAN-CANCER
  • CELL-LINES
  • DYSKERATOSIS-CONGENITA
  • MYOCARDIAL-INFARCTION
  • SUSCEPTIBILITY GENES
  • HUMAN FIBROBLASTS
  • RISK
  • BREAST
  • DISEASE

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    Pooley, K. A., McGuffog, L., Barrowdale, D., Frost, D., Ellis, S. D., Fineberg, E., Platte, R., Izatt, L., Adlard, J., Bardwell, J., Brewer, C., Cole, T., Cook, J., Davidson, R., Donaldson, A., Dorkins, H., Douglas, F., Eason, J., Houghton, C., ... EMBRACE (2014). Lymphocyte Telomere Length Is Long in BRCA1 and BRCA2 Mutation Carriers Regardless of Cancer-Affected Status. Cancer Epidemiology, Biomarkers and Prevention, 23(6), 1018-1024. https://doi.org/10.1158/1055-9965.EPI-13-0635-T