Clonality studies can establish the single cell origin of tumors and differentiate nonmalignant from malignant states. Detection of clonal cells may be genotype-based relying on somatic mutations to mark the clonal population (e.g. 9q+:22q– translocation in CML), or phenotype-based, where the clonal population is identified by expression of surrogate genes which facilitate tracking the clonal process. Methods for determining phenotypic clonality rely on the principle of X chromosome inactivation (XCIP), unique to women, and are based on differentiating transcriptionally active from inactive X-chromosomal genes. Detection of the polymorphic state of genes subjected to inactivation may be done by either:
discrimination of DNA methylation status,
detection of mRNA transcripts, or
polymorphic isozyme protein products.
Extreme skewing of X-chromosome allelic usage by methylation-based clonality assay has been reported in ∼30% of healthy elderly females precluding clonality studies in this population. In contrast, by X-chromosome quantitative transcriptional clonality assay (TCA), we previously reported a normal skewing range based on our determination of random X-chromosome inactivation in 8 progenitors of pluripotent hematopoietic stem cells at the time of inactivation during the blastocyst stage of development (
Disclosure:Research Funding: 1) R01HL5007-13 and 2) 1P01CA108671-O1A2 (NCI) Myeloproliferative Disorders (MPD) Consortium.