Page 311 - 20dynamics of cancer

296 CHAPTER 14

(a) The common ancestor shifts with clonal succession

A
− C
MMR 1
ancestor C 2

(b) Early common ancestor preserved with multiple lineages

A 1
A 2
MMR − C
ancestor 1
C 2

Figure 14.3 Alternative hypotheses for the relative time to the common ances-
tor between cells from a colorectal adenoma and an adjacent cancer. Time is
measured relative to the ancestral loss of a component of DNA mismatch repair
−
(MMR ). Lightest gray shows the ancestry of cells sampled from the current ade-
noma. Black shows the ancestry of cells sampled from the current cancer. (a)
Successive clonal expansions during multistage progression continually move
the most recent common ancestor within the tissue to the recent past. Thus,
the divergence is recent between the samples of the remaining adenoma tissue
(A) and the developing cancer (C 1 and C 2 ) when compared with the time back
to the ancestral loss of MMR. (b) After the initial MMR event, the tissue retains
−
multiple independent lines of progression. At diagnosis, two samples from the
remaining adenoma (A 1 and A 2 ) derive from a relatively recent ancestor, and
similarly, two samples from the developing cancer (C 1 and C 2 ) also derive from
a recent ancestor. By contrast, cells from the adenoma and cancer derive from a
−
more distant common ancestor, relatively close to the original MMR mutation.
Redrawn from Tsao et al. (1999).

MITOTIC AGE
Mitosis is perhaps the greatest risk factor in carcinogenesis (Peto
1977; Preston-Martin et al. 1990; Ames and Gold 1990; Cairns 1998).