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 Kennedy; Emma 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

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

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 journal › Article › peer-review

12 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 language	English
Pages (from-to)	1018-1024
Number of pages	7
Journal	Cancer Epidemiology, Biomarkers and Prevention
Volume	23
Issue number	6
Early online date	18 Mar 2014
DOIs	https://doi.org/10.1158/1055-9965.EPI-13-0635-T
Publication status	Published - Jun 2014

Bibliographical note

Grant Support

The following authors have received grant funding relevant to this publication: EMBRACE authors received funding from Cancer Research UK (Grant Number c1287/A12014); A.C. Antoniou received funding from Cancer Research UK (Grant Number c12292/A11174); D.F. Easton received funding from Cancer Research UK (Grant Numbers C1287/A9540, C1287/A11990, and C1287/A10118) and NIH (Grant Numbers 1U19CA148965-01 and 1U19CA148537-01); and A.M. Dunning and K.A. Pooley received funding from Cancer Research UK (Grant Numbers C1287/A9540, C8197/A10123, and C8197/A10865) and The Isaac Newton Trust.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

Keywords

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

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1158/1055-9965.EPI-13-0635-TLicence: Unspecified

Cite this

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

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 2014, 'Lymphocyte Telomere Length Is Long in BRCA1 and BRCA2 Mutation Carriers Regardless of Cancer-Affected Status', Cancer Epidemiology, Biomarkers and Prevention, vol. 23, no. 6, pp. 1018-1024. https://doi.org/10.1158/1055-9965.EPI-13-0635-T

@article{b60baf3d44894ea8a1d78455139f4e79,

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

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.",

keywords = "INCIDENT COLORECTAL-CARCINOMA, OVARIAN-CANCER, CELL-LINES, DYSKERATOSIS-CONGENITA, MYOCARDIAL-INFARCTION, SUSCEPTIBILITY GENES, HUMAN FIBROBLASTS, RISK, BREAST, DISEASE",

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

note = "Grant Support The following authors have received grant funding relevant to this publication: EMBRACE authors received funding from Cancer Research UK (Grant Number c1287/A12014); A.C. Antoniou received funding from Cancer Research UK (Grant Number c12292/A11174); D.F. Easton received funding from Cancer Research UK (Grant Numbers C1287/A9540, C1287/A11990, and C1287/A10118) and NIH (Grant Numbers 1U19CA148965-01 and 1U19CA148537-01); and A.M. Dunning and K.A. Pooley received funding from Cancer Research UK (Grant Numbers C1287/A9540, C8197/A10123, and C8197/A10865) and The Isaac Newton Trust. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.",

year = "2014",

month = jun,

doi = "10.1158/1055-9965.EPI-13-0635-T",

language = "English",

volume = "23",

pages = "1018--1024",

journal = "Cancer Epidemiology, Biomarkers and Prevention",

issn = "1055-9965",

publisher = "AMER ASSOC CANCER RESEARCH",

number = "6",

}

TY - JOUR

T1 - Lymphocyte Telomere Length Is Long in BRCA1 and BRCA2 Mutation Carriers Regardless of Cancer-Affected Status

AU - Pooley, Karen A.

AU - McGuffog, Lesley

AU - Barrowdale, Daniel

AU - Frost, Debra

AU - Ellis, Steve D.

AU - Fineberg, Elena

AU - Platte, Radka

AU - Izatt, Louise

AU - Adlard, Julian

AU - Bardwell, Julian

AU - Brewer, Carole

AU - Cole, Trevor

AU - Cook, Jackie

AU - Davidson, Rosemarie

AU - Donaldson, Alan

AU - Dorkins, Huw

AU - Douglas, Fiona

AU - Eason, Jacqueline

AU - Houghton, Catherine

AU - Kennedy, M. John

AU - McCann, Emma

AU - Miedzybrodzka, Zosia

AU - Murray, Alex

AU - Porteous, Mary E.

AU - Rogers, Mark T.

AU - Side, Lucy E.

AU - Tischkowitz, Marc

AU - Walker, Lisa

AU - Hodgson, Shirley

AU - Eccles, Diana M.

AU - Morrison, Patrick J.

AU - Evans, D. Gareth

AU - Eeles, Rosalind A.

AU - Antoniou, Antonis C.

AU - Easton, Douglas F.

AU - Dunning, Alison M.

AU - EMBRACE

N1 - Grant Support The following authors have received grant funding relevant to this publication: EMBRACE authors received funding from Cancer Research UK (Grant Number c1287/A12014); A.C. Antoniou received funding from Cancer Research UK (Grant Number c12292/A11174); D.F. Easton received funding from Cancer Research UK (Grant Numbers C1287/A9540, C1287/A11990, and C1287/A10118) and NIH (Grant Numbers 1U19CA148965-01 and 1U19CA148537-01); and A.M. Dunning and K.A. Pooley received funding from Cancer Research UK (Grant Numbers C1287/A9540, C8197/A10123, and C8197/A10865) and The Isaac Newton Trust. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

PY - 2014/6

Y1 - 2014/6

N2 - 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.

AB - 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.

KW - INCIDENT COLORECTAL-CARCINOMA

KW - OVARIAN-CANCER

KW - CELL-LINES

KW - DYSKERATOSIS-CONGENITA

KW - MYOCARDIAL-INFARCTION

KW - SUSCEPTIBILITY GENES

KW - HUMAN FIBROBLASTS

KW - RISK

KW - BREAST

KW - DISEASE

U2 - 10.1158/1055-9965.EPI-13-0635-T

DO - 10.1158/1055-9965.EPI-13-0635-T

M3 - Article

C2 - 24642354

SN - 1055-9965

VL - 23

SP - 1018

EP - 1024

JO - Cancer Epidemiology, Biomarkers and Prevention

JF - Cancer Epidemiology, Biomarkers and Prevention

IS - 6

ER -

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

Abstract

Bibliographical note

Keywords

UN SDGs

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