Page 322 - 20dynamics of cancer

CELL LINEAGE HISTORY 307

at thousands of other genes. Of those thousands of genes, several hun-
dred affect DNA repair and chromosomal maintenance; probably several
hundred other loci control the cell cycle and cell death.
Heritable changes in any of those hundreds of DNA repair or cell-cycle
genes may advance cancer progression through the first stages. Simple
calculations suggest that such developmental mosaicism may contribute
significantly to the incidence of cancer (Frank and Nowak 2003; Meza
et al. 2005).

FIELDS DERIVED FROM CLONAL EXPANSIONS

Mutations during development can create a population of descendant
cells that have progressed toward cancer. Alternatively, in a fully devel-
oped individual, a single mutated cell may expand clonally to create a
local patch or field of tissue that has progressed through an early stage
of carcinogenesis. Most reported cases of a precancerous field do not
distinguish between developmental mutations and clonal expansions in
the fully developed organism.
Slaughter et al. (1953) introduced the idea that localized tumors may
emerge from a broader precancerous field. Subsequent work on “field
cancerization” almost always assumes that the field grows by clonal ex-
pansion of a mutated cell in the fully developed organism (Braakhuis
et al. 2003, 2005; Hunter et al. 2005).
Several different lines of evidence may indicate a broader field sur-
rounding a localized tumor: neighboring tissue may be histologically
abnormal; genetic analysis may directly measure the spatial distribu-
tion of a mutated gene; and multiple independent tumors may develop
from the same tissue patch. Improved genomic technologies make it
increasingly easy to use direct genetic analysis. Those genetic analyses
often demonstrate a broad field containing the same clonally derived
mutation in tissue that appears normal.
Fields of p53 mutants have been observed in the bladder (Simon et al.
2001), oral cavity (Braakhuis et al. 2003), and skin (Jonason et al. 1996;
Brash 2006). Fields have also been observed in the lung, esophagus,
vulva, cervix, colon, and breast (reviewed by Braakhuis et al. 2003). The
importance of fields in progression depends on the fraction of cells in
the expanded clone that retain the ability to progress further. It may be