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J Med Genet. Jan 2002; 39(1): 30–33.
PMCID: PMC1734952

High frequency of skewed X inactivation in young breast cancer patients


Introduction: Patients with invasive ovarian cancer were recently shown to have a higher frequency of skewed X chromosome inactivation in peripheral blood cells compared to patients with borderline cancer and controls. In this study, we analysed the X inactivation pattern in peripheral blood from 216 breast cancer patients.

Methods: X inactivation analysis was performed using HpaII predigestion of DNA followed by PCR of the highly polymorphic CAG repeat of the androgen receptor gene (AR), which amplifies the undigested inactive X chromosome only. The X inactivation pattern was classified as skewed when 90% or more of the cells preferentially used one X chromosome.

Results: Young breast cancer patients (27-45 years) had a higher frequency of skewed X inactivation than young controls (13 and 1%, respectively) (p=0.009), whereas no difference was found for middle aged and older patients compared to controls of a similar age.

Conclusions: A germline mutation in an X linked tumour suppressor gene may give a proliferative advantage to cells with this mutation on the active X chromosome, thus causing skewed X inactivation and an increased risk for developing cancer. Another possible explanation could be that females with a constitutionally skewed X inactivation pattern are more susceptible to develop breast cancer because of an X linked low penetrance susceptibility allele that is affected by the inactivation pattern.

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Selected References

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  • Puck JM, Willard HF. X inactivation in females with X-linked disease. N Engl J Med. 1998 Jan 29;338(5):325–328. [PubMed]
  • Belmont JW. Genetic control of X inactivation and processes leading to X-inactivation skewing. Am J Hum Genet. 1996 Jun;58(6):1101–1108. [PMC free article] [PubMed]
  • Fearon ER, Kohn DB, Winkelstein JA, Vogelstein B, Blaese RM. Carrier detection in the Wiskott Aldrich syndrome. Blood. 1988 Nov;72(5):1735–1739. [PubMed]
  • Nyhan WL, Bakay B, Connor JD, Marks JF, Keele DK. Hemizygous expression of glucose-6-phosphate dehydrogenase in erythrocytes of heterozygotes for the Lesch-Nyhan syndrome. Proc Natl Acad Sci U S A. 1970 Jan;65(1):214–218. [PMC free article] [PubMed]
  • Orstavik KH, Orstavik RE, Naumova AK, D'Adamo P, Gedeon A, Bolhuis PA, Barth PG, Toniolo D. X chromosome inactivation in carriers of Barth syndrome. Am J Hum Genet. 1998 Nov;63(5):1457–1463. [PMC free article] [PubMed]
  • Allen RC, Nachtman RG, Rosenblatt HM, Belmont JW. Application of carrier testing to genetic counseling for X-linked agammaglobulinemia. Am J Hum Genet. 1994 Jan;54(1):25–35. [PMC free article] [PubMed]
  • Busque L, Mio R, Mattioli J, Brais E, Blais N, Lalonde Y, Maragh M, Gilliland DG. Nonrandom X-inactivation patterns in normal females: lyonization ratios vary with age. Blood. 1996 Jul 1;88(1):59–65. [PubMed]
  • Christensen K, Kristiansen M, Hagen-Larsen H, Skytthe A, Bathum L, Jeune B, Andersen-Ranberg K, Vaupel JW, Orstavik KH. X-linked genetic factors regulate hematopoietic stem-cell kinetics in females. Blood. 2000 Apr 1;95(7):2449–2451. [PubMed]
  • Brown CJ, Robinson WP. The causes and consequences of random and non-random X chromosome inactivation in humans. Clin Genet. 2000 Nov;58(5):353–363. [PubMed]
  • Buller RE, Sood AK, Lallas T, Buekers T, Skilling JS. Association between nonrandom X-chromosome inactivation and BRCA1 mutation in germline DNA of patients with ovarian cancer. J Natl Cancer Inst. 1999 Feb 17;91(4):339–346. [PubMed]
  • Chamberlain NL, Driver ED, Miesfeld RL. The length and location of CAG trinucleotide repeats in the androgen receptor N-terminal domain affect transactivation function. Nucleic Acids Res. 1994 Aug 11;22(15):3181–3186. [PMC free article] [PubMed]
  • Yu H, Bharaj B, Vassilikos EJ, Giai M, Diamandis EP. Shorter CAG repeat length in the androgen receptor gene is associated with more aggressive forms of breast cancer. Breast Cancer Res Treat. 2000 Jan;59(2):153–161. [PubMed]
  • Rebbeck TR, Kantoff PW, Krithivas K, Neuhausen S, Blackwood MA, Godwin AK, Daly MB, Narod SA, Garber JE, Lynch HT, et al. Modification of BRCA1-associated breast cancer risk by the polymorphic androgen-receptor CAG repeat. Am J Hum Genet. 1999 May;64(5):1371–1377. [PMC free article] [PubMed]
  • Allen RC, Zoghbi HY, Moseley AB, Rosenblatt HM, Belmont JW. Methylation of HpaII and HhaI sites near the polymorphic CAG repeat in the human androgen-receptor gene correlates with X chromosome inactivation. Am J Hum Genet. 1992 Dec;51(6):1229–1239. [PMC free article] [PubMed]
  • Gale RE, Wheadon H, Linch DC. X-chromosome inactivation patterns using HPRT and PGK polymorphisms in haematologically normal and post-chemotherapy females. Br J Haematol. 1991 Oct;79(2):193–197. [PubMed]
  • Zhu X, Daffada AA, Chan CM, Dowsett M. Identification of an exon 3 deletion splice variant androgen receptor mRNA in human breast cancer. Int J Cancer. 1997 Aug 7;72(4):574–580. [PubMed]
  • Birrell SN, Hall RE, Tilley WD. Role of the androgen receptor in human breast cancer. J Mammary Gland Biol Neoplasia. 1998 Jan;3(1):95–103. [PubMed]
  • Spurdle AB, Dite GS, Chen X, Mayne CJ, Southey MC, Batten LE, Chy H, Trute L, McCredie MR, Giles GG, et al. Androgen receptor exon 1 CAG repeat length and breast cancer in women before age forty years. J Natl Cancer Inst. 1999 Jun 2;91(11):961–966. [PubMed]
  • Bishop DT. BRCA1 and BRCA2 and breast cancer incidence: a review. Ann Oncol. 1999;10 (Suppl 6):113–119. [PubMed]

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