X-inactivation patch size in human female tissue confounds the assessment of tumor clonality

Most models of tumorigenesis assume that tumors are monoclonal
in origin. This conclusion is based largely on studies using X
chromosome-linked markers in females. One important factor,
often ignored in such studies, is the distribution of X-inactivated
cells in tissues. Because lyonization occurs early in development,
many of the progeny of a single embryonic stem cell are grouped
together in the adult, forming patches. As polyclonality can be
demonstrated only at the borders of X-inactivation patches, the
patch size is crucial in determining the chance of demonstrating
polyclonality and hence the number of tumors that need to be
examined to exclude polyclonality. Previously studies using Xlinked
genes such as glucose-6-phosphate dehydrogenase have
been handicapped by the need to destroy the tissues to study the
haplotypes of glucose-6-phosphate dehydrogenase [Fialkow, P.-J.
(1976)Biochim. Biophys. Acta458, 283–321] or to determine the
restriction fragment length polymorphisms of X chromosomelinked
genes [Vogelstein, B., Fearon, E. R., Hamilton, S. R. &
Feinberg, A. P. (1985)Science227, 642–645]. Here we visualize
X-inactivation patches in human females directly. Results show
that the patch size is relatively large in both the human colon and
breast, confounding assessment of tumor clonality with traditional
X-inactivation studies.