Page 57 - 20dynamics of cancer

42 CHAPTER 3

The strong tendency for APC mutations to appear in early morphologi-
cal stages and RAS mutations to occur only in later morphological stages
suggests that the order of the mutational steps plays an important role
in colorectal carcinogenesis.

DEVELOPMENT OF LATE ADENOMAS
As adenomas continue to grow and begin to show great histological
disorder, they tend to lose parts of 18q, the long arm of chromosome
18 (Kinzler and Vogelstein 2002). Only about 10 percent of early and
intermediate adenomas have 18q chromosomal loss, whereas about 50
percent of late adenomas and 75 percent of carcinomas have 18q loss.
These observations suggest one or more additional genetic events asso-
ciated with continuing morphological progression through late adenoma
and early carcinoma stages.
Limited evidence points to one or more of the genes DCC, SMAD4, and
SMAD2 in 18q21 as playing a role in carcinogenesis. DCC is a surface
protein with extensive homology to other cell adhesion and surface gly-
coprotein molecules. Loss of DCC often occurs in cancers, suggesting
DCC acts as a tumor suppressor. SMAD4 and SMAD2 may interact with
the transforming growth factor beta (TGFβ) pathway. The TGFβ path-
way often suppresses normal cellular growth, so loss of response to this
pathway may release developing tumors from suppressive signals.

TRANSITION TO CANCER
Loss of functional p53 by damage to both alleles drives progression to
carcinomas (Kinzler and Vogelstein 2002). p53 suppresses cell division
or induces apoptosis in response to stress or damage. Cancerous growth
usually requires release from p53’s protective control over cellular birth
and death. p53 is on the short arm of chromosome 17, region 17p13.
Allelic losses on 17p occur in less than 10 percent of early or interme-
diate stage adenomas, increasing to about 30 percent in late adenomas
and rising to about 75 percent in cancers.
Other genetic changes probably arise during progression. During
metastasis, adaptation of cancerous tissues likely occurs as the tissues
become aggressive, migrate, and greatly alter the environment in which
they live. Such adaptations must often depend on genetic changes.