Studies have often demonstrated that these tumour-specific alterations are associated with activation of cellular proto-oncogenes or the inactivation of tumour suppressor genes.

2.  Studies have often demonstrated that these tumour-
specific alterations are associated with activation of cellular
proto-oncogenes or the inactivation of tumour suppressor
genes.
 Ionizing radiation induces a broad range of neoplasms in
both man and experimental animals. Point mutations and
chromosome translocations that activate proto-oncogenes
and deletions that lead to a loss of function of tumour
suppressor genes all probably play a role in the initiation
(and progression) of these diseases.
 The DNA of a cell is damaged by ionizing radiation that
may principally, but not exclusively, initiate oncogenesis
through mechanisms involving deletion ,rearrangement of
segments of DNA or both.

3.  The activation of proto-oncogenes seems to occur
through two mechanisms. For example, in proto-
oncogenes such as RAS, the DNA base pair (bp)
changes needed for activation are limited thus
providing a small molecular target of may be only a
few base pairs.
 For the gene-specific translocations involving
juxtaposition of proto-oncogenes such as ABL or BSL-2
with other genes, the target would be larger (maybe up
to 10' bp) although it could, in principle, be necessary
to damage the DNA at two specific sites rather than
one.

4.  However, with the loss-of-function mutations
characteristic of tumour suppressor genes, such as Rb, APC
or p53, the situation is different.
 Inactivation may occur through point mutation, small
deletions within the gene or larger deletions involving
whole chromosome segments (about 107 bp), the principal
limit to the size of such DNA deletions being the extent to
which the cell can sustain viability following large losses of
genetic material.
 Thus, on simple biophysical arguments it would seem that
radiation induced loss-of-function mutations, since they
appear to offer the larger target size by perhaps two or three
orders of magnitude, may dominate the spectrum of
initiating events for radiation-induced carcinogenesis

5.  Support for this concept comes from molecular studies
with radiation-induced mutations where the main
mechanism has been shown to be through gross
genetic change - usually DNA deletions. Although
such studies in no way exclude radiation mutagenesis
through point mutation, they indicate ionizing
radiation to be a rather weak point mutagen

6.  Many chemical agents also induce gross chromosomal
damage, but the mechanisms are fundamentally different
from those of radiation as the majority of chemicals
principally act to produce point mutations.
 Thus, the major mechanistic difference at the cellular level
between radiation-induced and chemical-induced
oncogenesis is probably related to their relative efficiencies
at inducing point mutations or activation of proto-
oncogenes, and some variations in the spectrum of
neoplasms induced by radiation and chemical carcinogens
are, therefore, possible.
 Moreover, it is feasible that specific point mutations in
tumour genes may serve as a signature of prior exposure to
chemical carcinogens

7.  The commonest and most extensively characterized genetic
abnormalities that are associated with leukaemia are the
chromosomal translocations that give rise to fusion genes
encoding oncogenic proteins. The classical example, found
in CML, gives rise to the Philadelphia (Ph) chromosome
which involves a translocation between chromosomes 9
and 22 and results in the juxtaposition of the BCR gene and
the ABL proto-oncogene
 several other types of chromosomal aberrations exist and
their fusion genes have been identified in acute leukaemia.
These include the DEK-CAN (chromosomes 6 and 9) and
AML1-ETO (chromosomes 8 and 21) genes in AML, and the
TEL AML1 (chromosomes 12 and 21) and MLL-AF1P genes
(chromosomes 1 and 11) in ALL. Also trisomy and polysomy
of chromosome 21 are frequent anomalies in ALL

8.  High doses of ionizing radiation are capable of
generating such fusion genes in haemopoetic cell lines
in vitro. The genes are generally induced at different
frequencies - AML1-ETO having the highest frequency
and differ for the different cell lines

9.  Typically in these secondary leukaemias, loss of part or all of
chromosomes 5 and/or 7 is observed with the frequency of
abnormalities of both chromosomes being more prevalent in
patients who receive both types of therapy.
 In the case of secondary AML following treatment with
chemotherapeutic drugs, there are some significant genotypic
and phenotypic differences between, for example, AML
associated with alkylating agents and the epipodophyllotoxins.
 While non-balanced abnormalities of chromosomes 5 and 7 are
again the most frequently observed in neoplastic processes
arising after alkylating agent therapy, leukaemias occurring after
treatment that includes epipodophyllotoxins often feature
balanced chromosomal translocations. These latter leukaemias
often have a latency period of about 2 years compared with
typically 6 years following treatment with alkylating agents.

10.  Chromosome rearrangements and deletions are major
features of the oncogenic process and there is an ongoing
debate about the significance of specific sites of instability-
the so-called fragile sites.
 Some fragile sites are believed to be preferential targets for
the clastogenic action of DNA-damaging agents such as
ionizing radiation, although no overall association between
common fragile sites and cancer-associated breakpoints
has yet been shown-except possibly with respect to certain
leukaemias.
 The molecular structures of fragile sites are not known,
but it seems likely that they contain certain repeat DNA
sequences in particular telomere-like repeat (TLR)
sequences which may recombine at high frequency.

11. THANK YOU