STOCHASTIC AND STATE SPACE MODELS OF CARCINOGENESIS: SOME NEW MODELING APPROACHES - Quantitative Medical Data Analysis Using Mathematical Tools and Statistical Techniques - page 67

or mutated, E2F is unleashed to push the cell cycle from the G 1 phase to
the S phase. The protein products of the suppressor gene p16 INK4 at 9p21
inhibit the function of cyclin D1 and CDk4 proteins which phosphorylate
the RB gene product to release E2F. The inactivation of many suppressor
genes such as the p53 gene abrogates or suppresses the apoptosis process.
In colon cancer, the mutation or deletion of both copies of the suppressor
gene APC at 5q lead to increased expression level of the myc gene and D1
gene in the nucleus. Recent studies have shown that the APC gene may
also aect the G 2 checking point dominantly by interfering with the mi-
crotube and hence centrosome causing aberrant chromosomal segregation
and hence aneuploidy and polyploidy daughter cells 19;21 . (In this sense, the
APC gene in chromosome 5q act both as a recessive gene and a dominant
gene.)
2.3. Epigenetic and Cancer
Cancer initiation and progression are achieved and controlled by gene mu-
tations and genetic changes. However, these genetic eects can also be
achieved by changes of functions of these gene products through non-genetic
avenues without aecting the nucleotide sequences in DNA molecules (see
[2, 3, 7, 14, 17, 30, 32, 40, 43, 49, 64]). These are called epigenetic
changes which mainly involve activation of oncogenes products or silencing
of suppressor genes proteins through DNA methylation of cytosine at C p G
base pair islands (see [2, 3, 7, 14, 17, 30, 32, 40, 43, 49, 64]) or histone
acetylation 43 , or loss of imprinting (LOI) 49 , or tissue disorganization and
gap junction disruption 40;43 . For example, Ferreira et al 16 have showed that
besides genetic inactivation or mutation of the RB gene, the process that
the RB gene represses E2F-regulated genes in dierentiated cells can also
be achieved by an epigenetic mechanism linked to heterochromatin and in-
volving histone H3 and promoter DNA methylation. In human colon cancer,
Breivik and Gaudernack 7 showed that either methylating carcinogens or hy-
permethylation at C p G islands would lead to G/T mismatch which in turn
leads to Mis-match Repair (MMR) gene deciency or epigenetic silencing
of the MMR genes and hence MSI (Microsatellite Instability); alternatively,
either hypo-methylation, or bulky-adduct forming (BAF) carcinogens such
as alkylating agents, UV radiation and oxygen species promote chromo-
somal rearrangement via activation of mitotic check points (MCP), thus
promoting CIS (Chromosomal Instability). These data clearly suggest that
the epigenetic changes and/or interaction between genetic and epigenetic