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Editor—The process of X chromosome inactivation was identified as early as 1960 when Ohno and Hauschka1described the presence of a pyknotic X chromosome in both benign and malignant cell lines. Mary Lyon formalised the role of X inactivation and its relationship to dosage compensation of X chromosome genetic material in a letter to Nature in 1961.2 This phenomenon, now known as the Lyon hypothesis, states that only one X chromosome is transcriptionally active in a given female cell. While the Lyon hypothesis dictates that the X inactivation process is random, skewing of this process to the point of non-random X chromosome inactivation is a known mechanism associated with the development of X linked genetic diseases in females.3
Our laboratory has been interested in the association of non-random X chromosome inactivation (NRXI) with ovarian cancer.4 Not only does this process violate a basic biological principle, the Lyon hypothesis, but it also provides a mechanism to bypass one of two steps generally accepted as necessary for the development of a cancer phenotype, dictated by the Knudson two hit model.5 The process of X inactivation silences one of two alleles for a particular gene and hence creates a state of functional loss of heterozygosity. Thus, X linked tumour suppressor genes can require only a single mutational event (or “hit”) to contribute to the process of carcinogenesis. Furthermore, with NRXI, hypothetical germline mutation of tumour suppressor genes could contribute to early onset disease. We have hypothesised that the process of NRXI may provide a mechanism for some hereditary breast or ovarian cancers independent ofBRCA1/BRCA2associated disease because of its strong association with invasive ovarian cancers.4 More recently, data from our group suggest that this association extends to breast and endometrial, but not …