Basic Cytogenetics and the Role of Genetics in Cancer Development
r *
Promotor A
Promotor B
Fig. 2.7 Main molecular mechanisms
subsequent to chromosomal translocations encountered in cancer. (A) In the first mechanism, breakpoints on both
chromosomes will spare the coding sequence of the targeted genes. The translocation will lead to the juxtaposition of strong promoter/enhancers elements
(blue lozenge) from one gene
with the entire intact coding sequence of another gene
leading to overexpression of this latter. In the classical example,
promoter/enhancers are brought by
coding genes and the targeted coding sequence is oncogenes such as
(B) the second mechanism
is characterized by chromosomal breakpoints occurring within the coding sequence of both genes involved in the translocation, leading to a chimeric gene
translated into a hybrid protein with altered function. White vertical bars denote chromosomal breakpoints.
]Gene A
] Gene B
tumors is now recognized as a component of the current sub-
classifications in the World Health Organization (WHO) fasci-
cules dealing with classification of tumors of hematopoietic and
lymphoid tissues and soft-tissue tumors.12,13
Nowadays, the well-accepted opinion is that cancer is a genetic
disease with two main genetic events triggering cancer initiation:
the activation or deregulation of oncogenes as a consequence
of point mutation, amplification, or chromosomal transloca-
tion; and the inactivation of tumor suppressor genes due to
chromosomal deletion, mutation, or epigenetic mechanisms. In
malignant epithelial tumors, the prevailing view is that they do
not exhibit tumor-specific genetic alteration but rather complex
karyotypes with multiple abnormalities shared by carcinoma of
different histological subtypes and origins. However, single and
specific chromosomal translocations are encountered in some
epithelial malignancies such as thyroid carcinoma, kidney car-
cinoma of childhood and young adult, aggressive midline carci-
noma, and a surprisingly great number of prostate cancer.14
Recurrent and specific chromosome abnormalities can be
easily investigated by FISH at diagnosis. The method originally
used on metaphase plates is also applicable on nondividing
cells (interphase cells) provided by smears, cytospins, or paraf-
fin-embedded tissues. It has proved to be suitable for the detec-
tion of numerical deviations on previously stained slides or
fresh smears and to be feasible for improving the sensitivity of
conventional cytology yielding "atypical cells" in cell suspen-
sions.15 As it will be illustrated below, FISH may be more sensi-
tive than conventional cytology. FISH combined with cytology
can improve the diagnostic sensitivity of detecting malignancy
in bronchial brushing and washing specimens.16 FISH has many
more applications in all fields of diagnostic cancer cytology,
with significant improvement in tumor classification and a criti-
cal value in selection of patients who will benefit from targeted
therapies (see Chap. 36).
In the following sections, we will review the chromosomal
abnormalities observed in lymphoma and sarcoma with their
relationship to tumor development. We will mainly focus on
specific aberrations that can be used as diagnostic tools in
complement to cytology. In the same way, the examples of
chromosomal markers in carcinoma will be limited to thyroid
carcinoma. In a second part, we will discuss the applications
of FISH in the field of cytology, again limiting our comments
to lymphoma and sarcoma. The contribution of FISH in multi-
ple myeloma will also be mentioned because of the novel and
promising FICTION technique used to detect chromosomal
abnormalities in selected nondividing plasma cells.
Recurrent chromosomal abnormalities in lymphoma are mainly
represented by balanced chromosomal translocations that exert
their tumorigenic action by two alternative molecular mecha-
nisms (Fig. 2.7). In the first mechanism, the breakpoints on
both chromosomes will occur adjacent to two genes and bring
them close together but will not alter the protein produced by
one of the targeted genes, mainly an oncogene. This latter is
translocated close to strong promoter/enhancer elements of the
other gene involved, hence the immunoglobulin
or T-cell
genes. The functional consequences are consti-
tutive activation of the oncogene through its overexpression
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