Genetic Epidemiology, Psychiatric Genetics, Asthma Genetics and Statistical Genetics Laboratories investigate the pattern of disease in families, particularly identical and non-identical twins, to assess the relative importance of genes and environment in a variety of important health problems.
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PMID
18957670
TITLE
Skewed X chromosome inactivation and breast and ovarian cancer status: evidence for X-linked modifiers of BRCA1.
ABSTRACT
BACKGROUND NlmCategory: BACKGROUND
X chromosome inactivation, which silences gene expression from one of the two X chromosomes in females, is usually random. Skewed X inactivation has been implicated in both the expression and the suppression of X-linked disease phenotypes and has been reported to occur more frequently in breast and ovarian cancer patients, including BRCA1 or BRCA2 mutation carriers, than in control subjects.
METHODS NlmCategory: METHODS
We assessed the pattern of X chromosome inactivation using methylation-specific polymerase chain reaction amplification of the exon 1 microsatellite region of the X-linked androgen receptor (AR) gene in DNA from blood samples obtained from control subjects without a personal history of breast or ovarian cancer (n = 735), ovarian cancer patients (n = 313), familial breast cancer patients who did not carry mutations in BRCA1 or BRCA2 (n = 235), and affected and unaffected carriers of mutations in BRCA1 (n = 260) or BRCA2 (n = 63). We defined the pattern of X chromosome inactivation as skewed when the same X chromosome was active in at least 90% of cells. The association between skewed X inactivation and disease and/or BRCA mutation status was assessed by logistic regression analysis. The association between skewed X inactivation and age at cancer diagnosis was assessed by Cox proportional hazards regression analysis. All statistical tests were two-sided.
RESULTS NlmCategory: RESULTS
The age-adjusted frequency of skewed X inactivation was not statistically significantly higher in ovarian cancer or familial breast cancer case subjects compared with control subjects. Skewed X inactivation was higher in BRCA1 mutation carriers than in control subjects (odds ratio [OR] = 2.7, 95% confidence interval [CI] = 1.1 to 6.2; P = .02), particularly among unaffected women (OR = 6.1, 95% CI = 1.5 to 31.8; P = .005). Among BRCA1 mutation carriers, those with skewed X inactivation were older at diagnosis of breast or ovarian cancer than those without skewed X inactivation (hazard ratio [HR] of breast or ovarian cancer = 0.37, 95% CI = 0.14 to 0.95; P = .04). Among BRCA2 mutation carriers, skewed X inactivation also occurred more frequently in unaffected carriers than in those diagnosed with breast or ovarian cancer (OR = 5.2, 95% CI = 0.5 to 28.9; P = .08) and was associated with delayed age at onset (HR = 0.59, 95% CI = 0.37 to 0.94; P = .03).
CONCLUSIONS NlmCategory: CONCLUSIONS
Skewed X inactivation occurs at an increased frequency in BRCA1 (and possibly BRCA2) mutation carriers compared with control subjects and is associated with a statistically significant increase in age at diagnosis of breast and ovarian cancer.
DATE PUBLISHED
2008 Nov 5
HISTORY
PUBSTATUS PUBSTATUSDATE
aheadofprint 2008/10/28
pubmed 2008/10/30 09:00
medline 2008/11/15 09:00
entrez 2008/10/30 09:00
AUTHORS
NAME COLLECTIVENAME LASTNAME FORENAME INITIALS AFFILIATION AFFILIATIONINFO
Lose F Lose Felicity F Cancer and Cell Biology Division, Queensland Institute of Medical Research, Herston, Brisbane, Queensland, Australia.
Duffy DL Duffy David L DL
Kay GF Kay Graham F GF
Kedda MA Kedda Mary A MA
Spurdle AB Spurdle Amanda B AB
Kathleen Cuningham Foundation Consortium for Research into Familial Breast Cancer
Australian Ovarian Cancer Study Management Group
INVESTIGATORS
LASTNAME FORENAME INITIALS AFFILIATION
Bowtell D D
Chenevix-Trench G G
Green A A
Webb P P
deFazio A A
Gertig D D
Traficante N N
Moore S S
Hung J J
Fereday S S
Harrap K K
Sadkowsky T T
Mellon A A
Robertson R R
Vanden Bergh T T
Jones Megan M
Maidens J J
Nattress K K
Chiew Y E YE
Stenlake A A
Sullivan H H
Alexander B B
Ashover P P
Brown S S
Corrish T T
Green L L
Jackman L L
Martin K K
Ranieri B B
White J J
Jayde V V
Bowes L L
Mamers P P
Schmidt T T
Shirley H H
Viduka S S
Tran Hoa H
Bilic Sanela S
Glavinas Lydia L
Stuart-Harris R R
Kirsten F F
Rutovitz J J
Clingan P P
Glasgow A A
Proietto A A
Braye S S
Otton G G
Shannon J J
Bonaventura T T
Stewart J J
Begbie S S
Friedlander M M
Bell D D
Baron-Hay S S
Ferrier A A
Gard G G
Nevell D D
Pavlakis N N
Young B B
Camaris C C
Crouch R R
Edwards L L
Hacker N N
Marsden D D
Robertson G G
Beale P P
Beith J J
Carter J J
Dalrymple C C
Hamilton A A
Houghton R R
Russell P P
Links M M
Grygiel J J
Hill J J
Brand A A
Byth K K
Jaworski R R
Harnett P P
Sharma R R
Wain G G
Purdie D D
Whiteman D D
Ward B B
Papadimos D D
Crandon A A
Cummings M M
Horwood K K
Obermair A A
Perrin L L
Wyld D D
Nicklin J J
Davy M M
Oehler M M
Hall C C
Dodd T T
Healy T T
Pittman K K
Henderson D D
Hyde S S
Miller J J
Pierdes J J
Blomfield P P
Challis D D
McIntosh R R
Parker A A
Brown B B
Rome R R
Allen D D
Grant P P
Hyde S S
Laurie R R
Robbie M M
Healy D D
Jobling T T
Manolitsas T T
McNealage J J
Rogers P P
Susil B B
Sumithran E E
Simpson I I
Haviv I I
Phillips K K
Rischin D D
Fox S S
Johnson D D
Waring P P
Loughrey M M
O'Callaghan N N
Murray Bill B
Billson V V
Pyman J J
Neesham D D
Quinn M M
Underhill C C
Bell R R
Ng L F LF
Blum R R
Ganju V V
Hammond I I
McCartney A A
Leung Y Y
Buck M M
Zeps N N
JOURNAL
VOLUME: 100
ISSUE: 21
TITLE: Journal of the National Cancer Institute
ISOABBREVIATION: J. Natl. Cancer Inst.
YEAR: 2008
MONTH: Nov
DAY: 5
MEDLINEDATE:
SEASON:
CITEDMEDIUM: Internet
ISSN: 1460-2105
ISSNTYPE: Electronic
MEDLINE JOURNAL
MEDLINETA: J Natl Cancer Inst
COUNTRY: United States
ISSNLINKING: 0027-8874
NLMUNIQUEID: 7503089
PUBLICATION TYPE
PUBLICATIONTYPE TEXT
Comparative Study
Journal Article
Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, Non-P.H.S.
COMMENTS AND CORRECTIONS
GRANTS
GENERAL NOTE
KEYWORDS
MESH HEADINGS
DESCRIPTORNAME QUALIFIERNAME
Adolescent
Adult
Age Factors
Aged
Aged, 80 and over
Base Sequence
Breast Neoplasms genetics
Case-Control Studies genetics
Chromosomes, Human, X genetics
DNA Methylation genetics
DNA Primers genetics
DNA, Neoplasm genetics
Female genetics
Genes, BRCA1 genetics
Genes, BRCA2 genetics
Genes, X-Linked genetics
Genetic Predisposition to Disease genetics
Genotype genetics
Heterozygote genetics
Humans genetics
Kaplan-Meier Estimate genetics
Logistic Models genetics
Middle Aged genetics
Molecular Sequence Data genetics
Mutation genetics
Odds Ratio genetics
Ovarian Neoplasms genetics
Polymerase Chain Reaction methods
Proportional Hazards Models methods
Receptors, Androgen genetics
Up-Regulation genetics
X Chromosome Inactivation genetics
SUPPLEMENTARY MESH
GENE SYMBOLS
CHEMICALS
REGISTRYNUMBER NAMEOFSUBSTANCE
0 DNA Primers
0 DNA, Neoplasm
0 Receptors, Androgen
OTHER ID's