Project: Research project

Project Details


DESCRIPTION (adapted from the investigator's abstract): Background; Multiple
myeloma (MM) is an incurable plasma cell malignancy. Most investigators believe
that progression and outcome in MM is secondary to specific genetic alterations
of the malignant cells. Translocations at 14q32 are thought to be the genetic
hallmark of MM. By conventional cytogenetic analysis (CC), others and Dr.
Fonseca have determined that the presence of chromosomal abnormalities is
associated with an adverse outcome. Structural abnormalities of the long arm of
chromosomes 11 (mostly translocations), and 13 and the short arm of 17 have
special prognostic significance. However, CC is fraught with many difficulties
including inability to detect abnormalities in non-proliferating cells.
Fluorescent in situ hybridization (FISH) can detect chromosomal abnormalities
in interphase cells. The prognostic significance of FISH is not yet known.
Preliminary data suggest that chromosomal abnormalities as detected by FISH are
of significance as well. Understanding the genetic mechanisms of MM cell
proliferation, disease progression and outcome is important to eventually
overcoming the disease. Furthermore these abnormalities may identify
biologically different subgroups of MM.

Hypothesis: 1) Specific chromosomal structural and numerical abnormalities will
have prognostic significance in patients with MM (overall survival and event
free survival). 2) Translocations will result in gene overexpression as
detected by RNA analysis (reverse transcriptase polymerase chain reaction,
TR-PCR) and immunohistochemistry. 3) These chromosomal abnormalities will have
correlations with known biological and prognostic factors. 4) Specific
chromosomal abnormalities at two years after initiation of treatment may result
in development of therapy-related myelodysplasia or acute leukemia (tMDS/AML).

Objectives: 1) Determine the frequency and prognostic significance (overall
survival and event free survival) of translocations between 14q32 and other
donors chromosomes (11q13, 4q16.3, 16q23), deletions (13q and 17p13) and
numerical chromosomal abnormalities (chromosomes 6, 7, 9, 11, 15,17). 2)
Correlate the presence of specific chromosomal translocations with resulting
gene overexpression by RT-PCR (cyclin D1, FGFR3, MMSET, and c-maf) and
immunohistochemistry (cyclin D1 only). 3) Correlate chromosomal abnormalities
with tumor biological markers (plasma cell labeling index, B-2 microglobulin,
C-reactive protein, soluble IL-6 receptor, DNA content S-phase, DNA aneuploidy,
and plasmablastic morphologic). 4) Assess for specific chromosomal
abnormalities associated to myelodysphasia and therapy related leukemia and
relate these findings to clinical development of tMDS/AML.

Material and Methods; To detect chromosomal abnormalities he will perform
dual-color FISH using locus-specific and chromosome-specific probes on archival
samples of 250 patients collected for E9487 (associated ancillary laboratory
trial to clinical trial E9486). To precisely identify monotypic plasma cells he
will couple FISH with fluorescent staining for the cytoplasmic immunoglobulin.
Additionally, he will do RT-PCR for RNA analysis and immunohistochemistry for
protein overexpression (cyclin D1). He will perform biological correlations
with other markers, and perform an overall survival and event free survival
analysis according to the presence or absence of specific abnormalities.
Variables will also be studied using a multiple-variable model to test them as
independent predictors.
Effective start/end date4/1/007/31/14


  • Medicine(all)