Skewed X chromosome inactivation and breast and ovarian cancer status: Evidence for X-linked modifiers of BRCA1

Felicity Lose; David L. Duffy; Graham F. Kay; Mary A. Kedda; Amanda B. Spurdle; D. Bowtell; G. Chenevix-Trench; A. Green; P. Webb; A. DeFazio; D. Gertig; N. Traficante; S. Moore; J. Hung; S. Fereday; K. Harrap; T. Sadkowsky; A. Mellon; R. Robertson; T. Vanden Bergh; Megan Jones; J. Maidens; K. Nattress; Y. E. Chiew; A. Stenlake; H. Sullivan; B. Alexander; P. Ashover; S. Brown; T. Corrish; L. Green; L. Jackman; K. Martin; B. Ranieri; J. White; V. Jayde; L. Bowes; P. Mamers; T. Schmidt; H. Shirley; S. Viduka; Hoa Tran; Sanela Bilic; Lydia Glavinas; R. Stuart-Harris; F. Kirsten; J. Rutovitz; P. Clingan; A. Glasgow; A. Proietto; S. Braye; G. Otton; J. Shannon; T. Bonaventura; J. Stewart; S. Begbie; M. Friedlander; D. Bell; S. Baron-Hay; A. Ferrier; G. Gard; D. Nevell; N. Pavlakis; B. Young; C. Camaris; R. Crouch; L. Edwards; N. Hacker; D. Marsden; G. Robertson; P. Beale; J. Beith; J. Carter; C. Dalrymple; A. Hamilton; R. Houghton; P. Russell; M. Links; J. Grygiel; J. Hill; A. Brand; K. Byth; R. Jaworski; P. Harnett; R. Sharma; G. Wain; D. Purdie; D. Whiteman; B. Ward; D. Papadimos; A. Crandon; M. Cummings; K. Horwood; A. Obermair; L. Perrin; D. Wyld; J. Nicklin; M. Davy; M. Oehler; C. Hall; T. Dodd; T. Healy; K. Pittman; D. Henderson; S. Hyde; J. Miller; J. Pierdes; P. Blomfield; D. Challis; R. McIntosh; A. Parker; B. Brown; R. Rome; D. Allen; P. Grant; S. Hyde; R. Laurie; M. Robbie; D. Healy; T. Jobling; T. Manolitsas; J. McNealage; P. Rogers; B. Susil; E. Sumithran; I. Simpson; I. Haviv; K. Phillips; D. Rischin; S. Fox; D. Johnson; P. Waring; M. Loughrey; N. O'Callaghan; Bill Murray; V. Billson; J. Pyman; D. Neesham; M. Quinn; C. Underhill; R. Bell; L. F. Ng; R. Blum; V. Ganju; I. Hammond; A. McCartney; Y. Leung; M. Buck; N. Zeps

doi:10.1093/jnci/djn345

Skewed X chromosome inactivation and breast and ovarian cancer status: Evidence for X-linked modifiers of BRCA1

Felicity Lose, David L. Duffy, Graham F. Kay, Mary A. Kedda, Amanda B. Spurdle, D. Bowtell, G. Chenevix-Trench, A. Green, P. Webb, A. DeFazio, D. Gertig, N. Traficante, S. Moore, J. Hung, S. Fereday, K. Harrap, T. Sadkowsky, A. Mellon, R. Robertson, T. Vanden BerghMegan Jones, J. Maidens, K. Nattress, Y. E. Chiew, A. Stenlake, H. Sullivan, B. Alexander, P. Ashover, S. Brown, T. Corrish, L. Green, L. Jackman, K. Martin, B. Ranieri, J. White, V. Jayde, L. Bowes, P. Mamers, T. Schmidt, H. Shirley, S. Viduka, Hoa Tran, Sanela Bilic, Lydia Glavinas, R. Stuart-Harris, F. Kirsten, J. Rutovitz, P. Clingan, A. Glasgow, A. Proietto, S. Braye, G. Otton, J. Shannon, T. Bonaventura, J. Stewart, S. Begbie, M. Friedlander, D. Bell, S. Baron-Hay, A. Ferrier, G. Gard, D. Nevell, N. Pavlakis, B. Young, C. Camaris, R. Crouch, L. Edwards, N. Hacker, D. Marsden, G. Robertson, P. Beale, J. Beith, J. Carter, C. Dalrymple, A. Hamilton, R. Houghton, P. Russell, M. Links, J. Grygiel, J. Hill, A. Brand, K. Byth, R. Jaworski, P. Harnett, R. Sharma, G. Wain, D. Purdie, D. Whiteman, B. Ward, D. Papadimos, A. Crandon, M. Cummings, K. Horwood, A. Obermair, L. Perrin, D. Wyld, J. Nicklin, M. Davy, M. Oehler, C. Hall, T. Dodd, T. Healy, K. Pittman, D. Henderson, S. Hyde, J. Miller, J. Pierdes, P. Blomfield, D. Challis, R. McIntosh, A. Parker, B. Brown, R. Rome, D. Allen, P. Grant, S. Hyde, R. Laurie, M. Robbie, D. Healy, T. Jobling, T. Manolitsas, J. McNealage, P. Rogers, B. Susil, E. Sumithran, I. Simpson, I. Haviv, K. Phillips, D. Rischin, S. Fox, D. Johnson, P. Waring, M. Loughrey, N. O'Callaghan, Bill Murray, V. Billson, J. Pyman, D. Neesham, M. Quinn, C. Underhill, R. Bell, L. F. Ng, R. Blum, V. Ganju, I. Hammond, A. McCartney, Y. Leung, M. Buck, N. Zeps

Research output: Contribution to journal › Article › peer-review

33 Scopus citations

Abstract

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: 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: 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: 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.

Original language	English
Pages (from-to)	1519-1529
Number of pages	11
Journal	Journal of the National Cancer Institute
Volume	100
Issue number	21
DOIs	https://doi.org/10.1093/jnci/djn345
State	Published - 5 Nov 2008
Externally published	Yes

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10.1093/jnci/djn345

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Lose, F., Duffy, D. L., Kay, G. F., Kedda, M. A., Spurdle, A. B., Bowtell, D., Chenevix-Trench, G., Green, A., Webb, P., DeFazio, A., Gertig, D., Traficante, N., Moore, S., Hung, J., Fereday, S., Harrap, K., Sadkowsky, T., Mellon, A., Robertson, R., ... Zeps, N. (2008). Skewed X chromosome inactivation and breast and ovarian cancer status: Evidence for X-linked modifiers of BRCA1. Journal of the National Cancer Institute, 100(21), 1519-1529. https://doi.org/10.1093/jnci/djn345

@article{88464ce3484e47cb8e0d1ffb1ef2d574,

title = "Skewed X chromosome inactivation and breast and ovarian cancer status: Evidence for X-linked modifiers of BRCA1",

abstract = "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: 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: 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: 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.",

author = "Felicity Lose and Duffy, {David L.} and Kay, {Graham F.} and Kedda, {Mary A.} and Spurdle, {Amanda B.} and D. Bowtell and G. Chenevix-Trench and A. Green and P. Webb and A. DeFazio and D. Gertig and N. Traficante and S. Moore and J. Hung and S. Fereday and K. Harrap and T. Sadkowsky and A. Mellon and R. Robertson and {Vanden Bergh}, T. and Megan Jones and J. Maidens and K. Nattress and Chiew, {Y. E.} and A. Stenlake and H. Sullivan and B. Alexander and P. Ashover and S. Brown and T. Corrish and L. Green and L. Jackman and K. Martin and B. Ranieri and J. White and V. Jayde and L. Bowes and P. Mamers and T. Schmidt and H. Shirley and S. Viduka and Hoa Tran and Sanela Bilic and Lydia Glavinas and R. Stuart-Harris and F. Kirsten and J. Rutovitz and P. Clingan and A. Glasgow and A. Proietto and S. Braye and G. Otton and J. Shannon and T. Bonaventura and J. Stewart and S. Begbie and M. Friedlander and D. Bell and S. Baron-Hay and A. Ferrier and G. Gard and D. Nevell and N. Pavlakis and B. Young and C. Camaris and R. Crouch and L. Edwards and N. Hacker and D. Marsden and G. Robertson and P. Beale and J. Beith and J. Carter and C. Dalrymple and A. Hamilton and R. Houghton and P. Russell and M. Links and J. Grygiel and J. Hill and A. Brand and K. Byth and R. Jaworski and P. Harnett and R. Sharma and G. Wain and D. Purdie and D. Whiteman and B. Ward and D. Papadimos and A. Crandon and M. Cummings and K. Horwood and A. Obermair and L. Perrin and D. Wyld and J. Nicklin and M. Davy and M. Oehler and C. Hall and T. Dodd and T. Healy and K. Pittman and D. Henderson and S. Hyde and J. Miller and J. Pierdes and P. Blomfield and D. Challis and R. McIntosh and A. Parker and B. Brown and R. Rome and D. Allen and P. Grant and S. Hyde and R. Laurie and M. Robbie and D. Healy and T. Jobling and T. Manolitsas and J. McNealage and P. Rogers and B. Susil and E. Sumithran and I. Simpson and I. Haviv and K. Phillips and D. Rischin and S. Fox and D. Johnson and P. Waring and M. Loughrey and N. O'Callaghan and Bill Murray and V. Billson and J. Pyman and D. Neesham and M. Quinn and C. Underhill and R. Bell and Ng, {L. F.} and R. Blum and V. Ganju and I. Hammond and A. McCartney and Y. Leung and M. Buck and N. Zeps",

year = "2008",

month = nov,

day = "5",

doi = "10.1093/jnci/djn345",

language = "אנגלית",

volume = "100",

pages = "1519--1529",

journal = "Journal of the National Cancer Institute",

issn = "0027-8874",

publisher = "Oxford University Press",

number = "21",

}

Lose, F, Duffy, DL, Kay, GF, Kedda, MA, Spurdle, AB, Bowtell, D, Chenevix-Trench, G, Green, A, Webb, P, DeFazio, A, Gertig, D, Traficante, N, Moore, S, Hung, J, Fereday, S, Harrap, K, Sadkowsky, T, Mellon, A, Robertson, R, Vanden Bergh, T, Jones, M, Maidens, J, Nattress, K, Chiew, YE, Stenlake, A, Sullivan, H, Alexander, B, Ashover, P, Brown, S, Corrish, T, Green, L, Jackman, L, Martin, K, Ranieri, B, White, J, Jayde, V, Bowes, L, Mamers, P, Schmidt, T, Shirley, H, Viduka, S, Tran, H, Bilic, S, Glavinas, L, Stuart-Harris, R, Kirsten, F, Rutovitz, J, Clingan, P, Glasgow, A, Proietto, A, Braye, S, Otton, G, Shannon, J, Bonaventura, T, Stewart, J, Begbie, S, Friedlander, M, Bell, D, Baron-Hay, S, Ferrier, A, Gard, G, Nevell, D, Pavlakis, N, Young, B, Camaris, C, Crouch, R, Edwards, L, Hacker, N, Marsden, D, Robertson, G, Beale, P, Beith, J, Carter, J, Dalrymple, C, Hamilton, A, Houghton, R, Russell, P, Links, M, Grygiel, J, Hill, J, Brand, A, Byth, K, Jaworski, R, Harnett, P, Sharma, R, Wain, G, Purdie, D, Whiteman, D, Ward, B, Papadimos, D, Crandon, A, Cummings, M, Horwood, K, Obermair, A, Perrin, L, Wyld, D, Nicklin, J, Davy, M, Oehler, M, Hall, C, Dodd, T, Healy, T, Pittman, K, Henderson, D, Hyde, S, Miller, J, Pierdes, J, Blomfield, P, Challis, D, McIntosh, R, Parker, A, Brown, B, Rome, R, Allen, D, Grant, P, Hyde, S, Laurie, R, Robbie, M, Healy, D, Jobling, T, Manolitsas, T, McNealage, J, Rogers, P, Susil, B, Sumithran, E, Simpson, I, Haviv, I, Phillips, K, Rischin, D, Fox, S, Johnson, D, Waring, P, Loughrey, M, O'Callaghan, N, Murray, B, Billson, V, Pyman, J, Neesham, D, Quinn, M, Underhill, C, Bell, R, Ng, LF, Blum, R, Ganju, V, Hammond, I, McCartney, A, Leung, Y, Buck, M & Zeps, N 2008, 'Skewed X chromosome inactivation and breast and ovarian cancer status: Evidence for X-linked modifiers of BRCA1', Journal of the National Cancer Institute, vol. 100, no. 21, pp. 1519-1529. https://doi.org/10.1093/jnci/djn345

TY - JOUR

T1 - Skewed X chromosome inactivation and breast and ovarian cancer status

T2 - Evidence for X-linked modifiers of BRCA1

AU - Lose, Felicity

AU - Duffy, David L.

AU - Kay, Graham F.

AU - Kedda, Mary A.

AU - Spurdle, Amanda B.

AU - Bowtell, D.

AU - Chenevix-Trench, G.

AU - Green, A.

AU - Webb, P.

AU - DeFazio, A.

AU - Gertig, D.

AU - Traficante, N.

AU - Moore, S.

AU - Hung, J.

AU - Fereday, S.

AU - Harrap, K.

AU - Sadkowsky, T.

AU - Mellon, A.

AU - Robertson, R.

AU - Vanden Bergh, T.

AU - Jones, Megan

AU - Maidens, J.

AU - Nattress, K.

AU - Chiew, Y. E.

AU - Stenlake, A.

AU - Sullivan, H.

AU - Alexander, B.

AU - Ashover, P.

AU - Brown, S.

AU - Corrish, T.

AU - Green, L.

AU - Jackman, L.

AU - Martin, K.

AU - Ranieri, B.

AU - White, J.

AU - Jayde, V.

AU - Bowes, L.

AU - Mamers, P.

AU - Schmidt, T.

AU - Shirley, H.

AU - Viduka, S.

AU - Tran, Hoa

AU - Bilic, Sanela

AU - Glavinas, Lydia

AU - Stuart-Harris, R.

AU - Kirsten, F.

AU - Rutovitz, J.

AU - Clingan, P.

AU - Glasgow, A.

AU - Proietto, A.

AU - Braye, S.

AU - Otton, G.

AU - Shannon, J.

AU - Bonaventura, T.

AU - Stewart, J.

AU - Begbie, S.

AU - Friedlander, M.

AU - Bell, D.

AU - Baron-Hay, S.

AU - Ferrier, A.

AU - Gard, G.

AU - Nevell, D.

AU - Pavlakis, N.

AU - Young, B.

AU - Camaris, C.

AU - Crouch, R.

AU - Edwards, L.

AU - Hacker, N.

AU - Marsden, D.

AU - Robertson, G.

AU - Beale, P.

AU - Beith, J.

AU - Carter, J.

AU - Dalrymple, C.

AU - Hamilton, A.

AU - Houghton, R.

AU - Russell, P.

AU - Links, M.

AU - Grygiel, J.

AU - Hill, J.

AU - Brand, A.

AU - Byth, K.

AU - Jaworski, R.

AU - Harnett, P.

AU - Sharma, R.

AU - Wain, G.

AU - Purdie, D.

AU - Whiteman, D.

AU - Ward, B.

AU - Papadimos, D.

AU - Crandon, A.

AU - Cummings, M.

AU - Horwood, K.

AU - Obermair, A.

AU - Perrin, L.

AU - Wyld, D.

AU - Nicklin, J.

AU - Davy, M.

AU - Oehler, M.

AU - Hall, C.

AU - Dodd, T.

AU - Healy, T.

AU - Pittman, K.

AU - Henderson, D.

AU - Hyde, S.

AU - Miller, J.

AU - Pierdes, J.

AU - Blomfield, P.

AU - Challis, D.

AU - McIntosh, R.

AU - Parker, A.

AU - Brown, B.

AU - Rome, R.

AU - Allen, D.

AU - Grant, P.

AU - Hyde, S.

AU - Laurie, R.

AU - Robbie, M.

AU - Healy, D.

AU - Jobling, T.

AU - Manolitsas, T.

AU - McNealage, J.

AU - Rogers, P.

AU - Susil, B.

AU - Sumithran, E.

AU - Simpson, I.

AU - Haviv, I.

AU - Phillips, K.

AU - Rischin, D.

AU - Fox, S.

AU - Johnson, D.

AU - Waring, P.

AU - Loughrey, M.

AU - O'Callaghan, N.

AU - Murray, Bill

AU - Billson, V.

AU - Pyman, J.

AU - Neesham, D.

AU - Quinn, M.

AU - Underhill, C.

AU - Bell, R.

AU - Ng, L. F.

AU - Blum, R.

AU - Ganju, V.

AU - Hammond, I.

AU - McCartney, A.

AU - Leung, Y.

AU - Buck, M.

AU - Zeps, N.

PY - 2008/11/5

Y1 - 2008/11/5

N2 - 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: 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: 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: 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.

AB - 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: 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: 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: 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.

UR - http://www.scopus.com/inward/record.url?scp=55749112839&partnerID=8YFLogxK

U2 - 10.1093/jnci/djn345

DO - 10.1093/jnci/djn345

M3 - ???researchoutput.researchoutputtypes.contributiontojournal.article???

C2 - 18957670

AN - SCOPUS:55749112839

SN - 0027-8874

VL - 100

SP - 1519

EP - 1529

JO - Journal of the National Cancer Institute

JF - Journal of the National Cancer Institute

IS - 21

ER -

Skewed X chromosome inactivation and breast and ovarian cancer status: Evidence for X-linked modifiers of BRCA1

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