Page 229 - 20dynamics of cancer

214 CHAPTER 11

cell that descended from the most recent zygote. Somatic variants drive
progression within an individual.
This chapter focuses on germline variants that may occur in differ-
ent individuals in the population: in a particular cell, germline variants
trace their origin back to an ancestral cell that preceded the most recent
zygote. Germline variants determine inherited predisposition to cancer.
The first section describes how inherited variants affect progression
and incidence—the causal pathway from genes to phenotypes. A classi-
cal Mendelian mutation is a single variant that strongly shifts age-onset
curves to earlier ages. Such mutations demonstrate the central role
of inherited variation in progression and the multistage nature of car-
cinogenesis. Other inherited variants may only weakly shift age-onset
curves; however, the combination of many such variants predisposes
individuals to early-onset disease.
The second section turns around the causal pathway: the phenotype
of a variant—progression and incidence—influences the rate at which
that variant increases or decreases within the population. The limited
data appear to match expectations: variants that cause a strong shift
of incidence to earlier ages occur at low frequency; variants that cause
a milder age shift occur at higher frequencies; and variants that only
sometimes lead to disease occur most frequently.
The final section addresses a central question of biomedical genetics:
Does inherited disease arise mostly from few variants that occur at rel-
atively high frequency in populations or from many variants that each
occur at relatively low frequency? The current data clarify the question
but do not give a clear answer. Inheritance of cancer provides the best
opportunity for progress on this key question.

11.1 Genetic Variants Affect Progression and Incidence

The first studies measured differences in progression and age of on-
set between variants at a single locus. Those first studies aggregated
all variants into two classes, wild type and mutant, and compared inci-
dences between those classes. Current studies measure differences at
a finer molecular scale, distinguishing between variants at a particular
nucleotide or amino acid site, or between variants that differ by single
insertions or deletions. Ultimately, one would like to know how variants
at multiple sites combine to affect incidence. So far, most studies have