Page 294 - 20dynamics of cancer

STEM CELLS: POPULATION GENETICS 279

CELL GENERATIONS TO A COMMON PRECURSOR CELL
When will cases with early onset and multiple tumors be caused by
developmental mutations rather than inherited mutations? The answer
depends on the pattern of cellular lineages that produce a tissue.
All cells in a tissue trace their ancestry back to a precursor cell. That
common precursor would be the zygote if both cells from the first zy-
gotic division contribute descendants to the tissue. Alternatively, sev-
eral cell divisions derived from the zygote may occur before a precursor
cell begins to differentiate into a particular tissue.
Figure 13.1 shows the different phases in the ancestry of a tissue. In
that figure, n p rounds of cell division happen between the zygote and
the common precursor cell for the tissue. The precursor then seeds
an exponentially growing clone through n e cell generations. Once the
tissue is formed, the stem cells renew the tissue by proceeding through
n s cell divisions, where n s increases with age.
Consider an example to illustrate the potential importance of the
number of cell generations to a common precursor for a tissue. Sup-
pose a particular cancer syndrome has the characteristics of inherited
disease—early onset and multiple independent tumors. Assume that the
syndrome causes such severe early-onset disease that individuals who
suffer the disease rarely reproduce. Then each case must arise from a
new mutation.
The new mutation could occur in the parent: either in the germline or
in a precursor to the germline that does not give rise to the affected tis-
sue. A parental mutation would give rise to an inherited case, in which
the offspring carries the mutation in all somatic cells. Suppose the num-
ber of cell generations between the parental germline precursor and the
gamete is n g . Alternatively, the new mutation could occur in the off-
spring. The number of cell generations between the zygote and the
common precursor for the tissue is n p .
The probability that an observed case arose from a developmental
mutation rather than an inherited mutation would be approximately
n p /(n p + n g ). We could refine this approximation by adjusting for the
mutation rates in the maternal and paternal germlines and the somatic
precursor lineage and for the frequency of mutations carried by parents
that derived from an earlier generation. For example, if the mutation
rate per cell division is u, and the frequency of mutations carried by