X chromosome inactivation is an essential process that compensates for gene dosage differences between men and women. During early embryogenesis, one of the two X chromosomes in females is randomly selected for transcriptional silencing, inactivating either the maternal or paternal chromosome. This process makes the functional genetic information in females equivalent to a single X chromosome, as in males. Usually, X inactivation occurs in approximately 50% of maternal and 50% of paternal X chromosomes. However, deviations from this ratio can occur, resulting in skewed X inactivation. In women carrying pathogenic variants on the X chromosome—thus presenting X-linked syndromes—such skewing can lead to a wide range of phenotypic manifestations, making X inactivation an important subject of study. Moreover, several X-linked syndromes have been associated with an increased risk of various types of cancer. This risk is influenced not only by specific pathogenic variants but also by mechanisms such as defective X inactivation, which has itself been linked to tumor development. This review compiles both historical and recent findings on X inactivation and its relationship with cancer. It provides an updated overview of the X chromosome inactivation mechanism, a summary of X-linked disorders associated with cancer risk, a discussion of X chromosome involvement in tumorigenesis, an examination of cancer-related genes on the X chromosome, and information on sexual dimorphism in cancer.
Salas‐Labadía et al. (Wed,) studied this question.