Page 321 - 20dynamics of cancer

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division during development may, on average, suffer a high probability
of creating at least one heritable change. Among the trillions of cells in
a human, each of billions of different heritable changes forms its own
distinct mosaic pattern.
Gottlieb et al. (2001) list 30 diseases with reported mosaicism. I briefly
discuss skin disorders with visible phenotypes, because the altered skin
markings provide the easiest examples for study (Happle 1993).
The spatial distribution of the mosaic cells traces the tips of the cell
lineage trees. If descendant cells remain together, then the mosaics form
patches of distinct cells. In some cases, the descendant cell lineages
trace distinctive patterns that reflect the movement of cells during de-
velopment. For example, several visible skin diseases follow the lines
of Blaschko (Figure 14.6). Other distinct patterns also occur in skin dis-
eases (Chuong et al. 2006). Speckled lentiginous naevus and Becker’s
naevus follow a mosaic checkerboard pattern; mosaic trisomy of chro-
mosome 13 causes scattered leaf-like shapes of hypopigmentation.
Familial glomuvenous malformations provide an excellent system to
study the process of developmental mosaicism. These venous malfor-
mations appear on the skin as blue-red nodules (Vikkula et al. 2001;
Brouillard and Vikkula 2003).
Individuals who inherit a mutation to one of the two alleles at the
glomulin locus develop multiple independent nodules distributed ran-
domly across their skin. By contrast, noninherited cases typically arise
as a single, isolated nodule (Rudolph 1993; Boon et al. 1999; Happle and
Konig 1999; Brouillard et al. 2002).
These patterns suggest that nodules form when both alleles of the
glomulin locus have lost function. In inherited cases, the spatial pat-
tern of nodules likely marks the multiple independent inactivations of
the second allele at different locations during development (Happle and
Konig 1999; Happle 1999; Brouillard et al. 2005). Study of individuals
who inherit one nonfunctional allele would provide interesting data on
developmental mosaicism. The number, spatial distribution, and size
of nodules would describe the loss of the second allele, either by direct
mutation, loss of heterozygosity, or epigenetic silencing.
The nodules of glomuvenous malformations record mutational events
in the cell lineage history of the developing organism. Those events fo-
cus on a single locus. Independent heritable changes also accumulate