Genetic anticipation is associated with telomere shortening in hereditary breast cancer.
Beatriz Martinez-Delgado,Kira Yanowsky,Lucía Inglada-Pérez,Samuel Domingo,Miguel Urioste,Ana Osorio,Javier Benitez +6 more
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TLDR
Evidence is provided that telomere shortening is associated with earlier age of cancer onset in successive generations of affected families, suggesting that it might be a mechanism of genetic anticipation in hereditary breast cancer.Abstract:
There is increasing evidence suggesting that short telomeres and subsequent genomic instability contribute to malignant transformation. Telomere shortening has been described as a mechanism to explain genetic anticipation in dyskeratosis congenita and Li-Fraumeni syndrome. Since genetic anticipation has been observed in familial breast cancer, we aimed to study telomere length in familial breast cancer patients and hypothesized that genetic defects causing this disease would affect telomere maintenance resulting in shortened telomeres. Here, we first investigated age anticipation in mother-daughter pairs with breast cancer in 623 breast cancer families, classified as BRCA1, BRCA2, and BRCAX. Moreover, we analyzed telomere length in DNA from peripheral blood leukocytes by quantitative PCR in a set of 198 hereditary breast cancer patients, and compared them with 267 control samples and 71 sporadic breast cancer patients. Changes in telomere length in mother-daughter pairs from breast cancer families and controls were also evaluated to address differences through generations. We demonstrated that short telomeres characterize hereditary but not sporadic breast cancer. We have defined a group of BRCAX families with short telomeres, suggesting that telomere maintenance genes might be susceptibility genes for breast cancer. Significantly, we described that progressive telomere shortening is associated with earlier onset of breast cancer in successive generations of affected families. Our results provide evidence that telomere shortening is associated with earlier age of cancer onset in successive generations, suggesting that it might be a mechanism of genetic anticipation in hereditary breast cancer.read more
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References
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Journal ArticleDOI
Telomere measurement by quantitative PCR
TL;DR: A primer pair is presented that eliminates the problem of presumed impossible to measure telomeres in vertebrate DNA by PCR amplification with oligonucleotide primers designed to hybridize to the TTAGGG and CCCTAA repeats, allowing simple and rapid measurement of telomere length in a closed tube, fluorescence-based assay.
Journal ArticleDOI
Accelerated telomere shortening in response to life stress
Elissa S. Epel,Elizabeth H. Blackburn,Jue Lin,Firdaus S. Dhabhar,Nancy E. Adler,Jason D. Morrow,Richard M. Cawthon +6 more
TL;DR: Evidence is provided that psychological stress--both perceived stress and chronicity of stress--is significantly associated with higher oxidative stress, lower telomerase activity, and shorter telomere length, in peripheral blood mononuclear cells from healthy premenopausal women.
Journal ArticleDOI
Molecular basis of myotonic dystrophy: Expansion of a trinucleotide (CTG) repeat at the 3′ end of a transcript encoding a protein kinase family member
J. David Brook,Mila E. McCurrach,H G Harley,Alan Buckler,Deanna M. Church,Hiroyuki Aburatani,Kent W. Hunter,Vincent P. Stanton,Jean Paul Thirion,Thomas J. Hudson,Robert L. Sohn,Boris V. Zemelman,Russell G. Snell,S A Rundle,Steve Crow,June Davies,Peggy Shelbourne,Jessica L. Buxton,Clare Jones,Vesa Juvonen,Keith J. Johnson,Peter S. Harper,D.J. Shaw,David E. Housman +23 more
TL;DR: Using positional cloning strategies, this work has identified a CTG triplet repeat that undergoes expansion in myotonic dystrophy patients and PCR analysis of the interval containing this repeat indicates that unaffected individuals have been 5 and 27 copies.
Journal ArticleDOI
Genome-wide association study identifies novel breast cancer susceptibility loci
Douglas F. Easton,Karen A. Pooley,Alison M. Dunning,Paul D.P. Pharoah,Deborah J. Thompson,Dennis G. Ballinger,Jeffery P. Struewing,Jonathan J. Morrison,Helen I. Field,Robert Luben,Nicholas J. Wareham,Shahana Ahmed,Catherine S. Healey,Richard Bowman,Kerstin B. Meyer,Christopher A. Haiman,Laurence K. Kolonel,Brian E. Henderson,Loic Le Marchand,Paul Brennan,Suleeporn Sangrajrang,Valerie Gaborieau,Fabrice Odefrey,Chen-Yang Shen,Pei-Ei Wu,Hui-Chun Wang,Diana Eccles,D. Gareth Evans,Julian Peto,Olivia Fletcher,Nichola Johnson,Sheila Seal,Michael R. Stratton,Nazneen Rahman,Georgia Chenevix-Trench,Georgia Chenevix-Trench,Stig E. Bojesen,Børge G. Nordestgaard,C K Axelsson,Montserrat Garcia-Closas,Louise A. Brinton,Stephen J. Chanock,Jolanta Lissowska,Beata Peplonska,Heli Nevanlinna,Rainer Fagerholm,H Eerola,Daehee Kang,Keun-Young Yoo,Dong-Young Noh,Sei Hyun Ahn,David J. Hunter,Susan E. Hankinson,David G. Cox,Per Hall,Sara Wedrén,Jianjun Liu,Yen-Ling Low,Natalia Bogdanova,Peter Schu¨rmann,Do¨rk Do¨rk,Rob A. E. M. Tollenaar,Catharina E. Jacobi,Peter Devilee,Jan G. M. Klijn,Alice J. Sigurdson,Michele M. Doody,Bruce H. Alexander,Jinghui Zhang,Angela Cox,Ian W. Brock,Gordon MacPherson,Malcolm W.R. Reed,Fergus J. Couch,Ellen L. Goode,Janet E. Olson,Hanne Meijers-Heijboer,Hanne Meijers-Heijboer,Ans M.W. van den Ouweland,André G. Uitterlinden,Fernando Rivadeneira,Roger L. Milne,Gloria Ribas,Anna González-Neira,Javier Benitez,John L. Hopper,Margaret R. E. McCredie,Margaret R. E. McCredie,Margaret R. E. McCredie,Melissa C. Southey,Melissa C. Southey,Graham G. Giles,Chris Schroen,Christina Justenhoven,Christina Justenhoven,Hiltrud Brauch,Hiltrud Brauch,Ute Hamann,Yon-Dschun Ko,Amanda B. Spurdle,Jonathan Beesley,Xiaoqing Chen,_ kConFab,Arto Mannermaa,Veli-Matti Kosma,Vesa Kataja,Jaana M. Hartikainen,Nicholas E. Day,David Cox,Bruce A.J. Ponder +109 more
TL;DR: To identify further susceptibility alleles, a two-stage genome-wide association study in 4,398 breast cancer cases and 4,316 controls was conducted, followed by a third stage in which 30 single nucleotide polymorphisms were tested for confirmation.
Journal ArticleDOI
Oxidative stress shortens telomeres
TL;DR: It is suggested here that oxidative stress is an important modulator of telomeres loss and that telomere-driven replicative senescence is primarily a stress response.