Springer, Encyclopedic Reference Of Cancer (2001) Ocr 7.0 Lotb.pdf

604 Multistep Development
and RB mutations are correlated with poor
prognosis. Multiple primary tumors may be
generated by the spread and further progression
of a single progenitor clone.
Hepatocellular carcinoma [! liver cancer, molecular
biology] is initiated by the DNA virus hepatitis
B virus (HBV). Sequential changes include
p53 losses. The virally encoded transactivator
HBV-X is believed to induce the overexpression
of several oncogenes.
Hemopoetic tumors [! hematological malignancies]
are often initiated by chromosomal
translocations, leading to gene fusions (in
CML and a wide variety of childhood leukemias),
juxtaposition of an oncogene to an Ig locus
(B-cell lymphomas) or to a TCR locus (T-
ALL). Sequential events affect mainly the apoptosis
regulating systems, with up-regulation of
bcl-2 or inactivation of p53, p19 ARF or BAX. In
T-ALL, p16 may remain unaffected, whereas
ARF is disrupted or deleted. In the absence
of ARF, p53 usually remains in wild type configuration.
A similar alternative mutational relationship
has been found between p16 and RB,
as in other tumors.
Clinical relevance
For diagnosis, oncogene activation by chromosomal
translocation, with or without gene fusion,
is diagnostic for certain leukemias, lymphomas
and sarcomas. For prognosis, the identity
of the activated oncogene may be decisive for
the biological behavior of the tumor. Oncogene
amplification, a well defined step in the progression
of carcinomas and gliomas, may be a bad
prognostic sign; it is being used clinically to determine
prognosis in ! neuroblastoma and is a
parameter for therapy design.
! Micrometastasis detection by antibodies
and/or by molecular techniques, and the identification
of residual, translocation carrying
leukemia or sarcoma cells by polymerase chain
reaction (PCR) are useful for the diagnosis of
residual disease and for predicting the probability
of recurrence. These parameters may
also provide surrogate endpoints for the evaluation
of new therapies.
Therapeutic choices are decisively influenced
by the molecular findings. This can be
exemplified by the identification of the genes
involved in the translocations found in ALL
and APML. Current therapeutic experimentation
aims at the inhibition of pathologically activated
signal transduction chains with small
peptides, antibodies or DNA constructs. Faulty
protein-protein interactions provide other important
targets. It is not necessary to correct all
genetic aberrations in tumors that have evolved
by multiple steps. Inhibition of a dominating
driving mechanism or, alternatively, induction
of apoptosis may be sufficient.
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