The Principles of Clinical Cytogenetics - Extra Materials - Springer

Fluorescence In Situ Hybridization 475
PLASMA CELL MYELOMA (MULTIPLE MYELOMA)/PLASMOCYTOMA
Chromosomal abnormalities have been reported in approximately 30–50% of disorders of plasma
cells, and interphase FISH detects deletions and translocations in at least 90% of cases studied (59).
Identification of the cytogenetic aberrations has led to the identification of subgroups of plasma cell
myeloma with unique clinical and biologic features (60). Translocations involving the Ig heavychain
locus (IGH) at 14q32 are frequent and appear to represent early genetic changes. The most
common translocations include t(4;14)(p16.3;q32), t(11;14)(q13;q32) (Chapter 15, Fig. 1v), and
t(14;16)(q13;q21). Patients with t(4;14) and t(14;16) fall within a poor prognosis subgroup, whereas
those with t(11;14) have a good prognosis (60). A FISH analysis with a break-apart probe specific for
the 3' and 5' ends of the IGH gene provides an efficient screen for these rearrangements. Given that
each of the translocations has prognostic implications, specific probes for each of the translocations
are of great value. FISH-detected 13q14 deletions, using a probe for the locus D13S319, are found in
approximately 40% of cases and loss of an as yet unidentified tumor suppressor gene is an independent
adverse prognostic factor (61). FISH is also useful for detecting deletions of TP53 at 17p13 (see
Fig. 9) that are associated with a poor prognosis (62). As with B-CLL, a panel of probes can be useful
for defining the subgroup of myeloma and for staging of disease in patients with plasma cell diseases,
as the frequency and extent of genetic aberrations appears to correlate with clinical disease state (60).
(See Fig. 12B). It should be noted, however, that detection rates for FISH panels directed at diagnosing
plasma cell myeloma are often lower in practice than suggested by the literature. This is due to
many of the patients being assessed for a monoclonal gammopathy of unspecified significance
(MGUS) that do not actually have myeloma. The results of a FISH panel in such cases will be negative.
Non-Hodgkin’s Lymphoma
The genetic hallmarks of many non-Hodgkin’s lymphoma (NHLs) are translocations involving
the immunoglobulin (Ig) and T-cell receptor (TCR) genes resulting in inappropriate expression of
genes at the reciprocal breakpoints, and FISH presents an effective test for rearrangement assessment.
A break-apart probe can be used to screen for recurrent chromosomal aberrations associated with
the tumorigenesis of subtypes of B-cell lymphomas involving the immunoglobulin heavy-chain (IGH)
gene at 14q32. Several translocations represent the primary event producing the initial disease state.
t(14;18)(q32;q21) (see Chapter 15, Fig. 1y) that juxtaposes the IGH locus with the BCL2 gene is
virtually pathognomonic for follicular lymphoma and can also be seen in a percentage of diffuse
large cell lymphomas. For mantle cell lymphoma, IGH is positioned next to the BCL1 gene by a
t(11;14)(q13;q32) (see Chapter 15, Fig. 1v). FISH with DCDF probes provides the most sensitive
diagnostic assay for these rearrangements, detecting the specific gene fusions in an estimated 95–100%
of cases (59). Burkitt’s lymphoma (BL), an aggressive disease of B-cell origin, harbors a t(8;14)(q24;
q32) or variant translocation [t(8;22)(q24;q11), t(2;8)(p11;q24)] in all cases. Juxtaposition of IGH
and the MYC gene (8q24) results in overexpression of the transcription factor c-myc (see Chapter 15,
Fig. 1q,e). The utility of FISH with a DCDF probe for high grade lymphomas is in the rapid diagnosis
of the (8;14) translocation, particularly because treatment strategies differ between BL and other
high-grade lymphomas. A dual-color break-apart probe for the ALK gene at 2p23 can be used to
detect the t(2;5) or variant translocations involving ALK that are characteristic of anaplastic large cell
lymphoma. FISH is useful for establishing the diagnosis for NHLs on primary lymph node tissue,
both in cultured cells and with touch preparations, paraffin-embedded tissues, and bone marrow to
assess for involvement of this tissue.
Sex-Mismatched Bone Marrow or Stem Cell Transplant
For many hematologic malignancies, bone marrow or stem cell transplantation can be a reasonable
treatment and/or the only hope to cure the patient of disease. FISH is particularly useful for