Page 292 - 20dynamics of cancer

STEM CELLS: POPULATION GENETICS 277

EXCESS RISK FROM DEVELOPMENTAL PREDISPOSITION
A significant fraction of adult-onset cancers may arise from mutations
that occur during the short period of development early in life (Frank
and Nowak 2003). In this section, I briefly summarize Meza et al.’s (2005)
thorough quantitative analysis of this problem.
Meza et al. (2005) evaluated the role of developmental mutations in
the context of colorectal cancer. They began with a model of progression
and incidence that they had previously studied (Luebeck and Moolgavkar
2002). In that model, carcinogenesis progresses through four stages:
two initial transitions, followed by a third transition that triggers clonal
expansion, and then a final transition to the malignant stage.
In their new study, Meza et al. (2005) began with the same four-stage
model. They then added a Luria-Delbrück process to obtain the prob-
ability distribution for the number of stem cells mutated at the end of
development. The stochasticity in the Luria-Delbrück process causes a
wide variation between individuals in the number of mutated stem cells.
Meza et al. (2005) first calculated the probability that an individual car-
ries Nx initially mutated stem cells at the end of development. To obtain
overall population incidence, they summed the probability for each Nx
multiplied by the incidence for individuals with Nx mutations.
Meza et al. (2005) summed incidence in their four-stage model over
the number of initially mutated stem cells to fit the model’s predicted in-
cidence curve to the observed incidence of colorectal cancer in the USA.
From their fitted model, they then estimated the proportion of cancers
attributable to mutations that arise during development. Figure 13.4
shows that a high proportion of cancers may arise from mutations dur-
ing the earliest stage of life.
Cancers at unusually young ages are often attributed to inheritance.
However, Figure 13.4 suggests that early-onset cancers may often arise
from developmental mutations. Developmental mutations act similarly
to inherited mutations: if the developmental mutation happens in one
of the first rounds of post-zygotic cell division, then many stem cells
start life with the mutation. Inheritance is, in effect, a mutation that
happened before the first zygotic division.