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

Lookup NU author(s): Dr Fiona Douglas

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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.


Publication metadata

Author(s): Pooley KA, McGuffog L, Barrowdale D, Frost D, Ellis SD, 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, Kennedy MJ, McCann E, Miedzybrodzka Z, Murray A, Porteous ME, Rogers MT, Side LE, Tischkowitz M, Walker L, Hodgson S, Eccles DM, Morrison PJ, Evans DG, Eeles RA, Antoniou AC, Easton DF, Dunning AM, EMBRACE

Publication type: Article

Publication status: Published

Journal: Cancer Epidemiology, Biomarkers & Prevention

Year: 2014

Volume: 23

Issue: 6

Pages: 1018-1024

Print publication date: 01/06/2014

Online publication date: 18/03/2014

Acceptance date: 28/02/2014

ISSN (print): 1055-9965

ISSN (electronic): 1538-7755

Publisher: American Association for Cancer Research

URL: http://dx.doi.org/10.1158/1055-9965.EPI-13-0635-T

DOI: 10.1158/1055-9965.EPI-13-0635-T

PubMed id: 24642354


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Funding

Funder referenceFunder name
IsaacNewton Trust
1U19CA148965-01NIH
1U19CA148537-01NIH
c12292/A11174Cancer Research UK
C1287/ A9540Cancer Research UK
C1287/A10118Cancer Research UK
C1287/A11990Cancer Research UK
c1287/A12014Cancer Research UK
C8197/A10123Cancer Research UK
C8197/A10865Cancer Research UK
C1287/A9540Cancer Research UK

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