Molecular Pathogenesis Of Multiple Myeloma (Plasma Cell Tumors)
Tags: Cancer, Fish, Cytogenetics, Plasma Cells, Myeloma

Multiple myeloma is a malignant proliferation of plasma cells and plasmacytoid (collection of monoclonal plasma cells) in bone marrow. In active multiple myeloma must be distinguished from other disorder and characterized by monoclonal gammopathies, both are malignant and otherwise, in particular monoclonal gammopathy undetermined significance (MGUS) and smoldering multiple myeloma. In some cases gammopathy undetermined significanc can be associated with symptoms and that requiring therapy is plasma exchange appears to be efficacious in neuropathy associated with IgG or IgA MGUS. In this significance, a potential risk factor for the development of myeloma includes exposure to irradiation or petroleum product. In different type of leukemia, there is no increased risk of MM with benzene Exposure.

Cells and their associated antigens in Multiple myeloma

The cells that accumulate in the BM of patients with MM have plasma cells or plasmablast morphology. However, it has been known since the 1970s, based on studies using anti-idiotypic antibodies, that a unique idiotypic determinant can identify clones of peripheral blood lymphocytes in patients with macroglobulinemia, MM, MGUS, CLL.

Multiple myeloma share cell surface expression of some antigens, for example, CD38 and PCA-1 (prostate cancer antigen-1) that is also present on normal plasma cells.

The malignant plasma cells in MM are localized to the bone marrow in close association with bone marrow stromal cells (BMSCs). They are long-lived cells with a very low labeling index that provides a measure percentage of bone marrow plasma cells.

MM cells have significantly lower rate of Ig secretion than normal plasma cells, Thus it appears in critical oncogenic event in MM.

Clinical and pathological significance in Multiple Myeloma

Active multiple myeloma in both clinical and pathological diagnosis that is defined by the presence of monoclonal protein in the serum/ or urine with >10% plasma cells in bone marrow and associated hypercalcemia, renal dysfunction, anemia and/or bone marrow disease related to the multiple myeloma. Symptoms of bone pain and anemia are the most common presenting features in multiple myeloma.

Biological technique used to rule out aberrations in genetics material-

Gene expression profiling has been utilized to characterized change associate with the progression from normal plasma cells to MGUS to MM.

By conventional cytogenetic analysis, karyotypic abnormalities are detected in MM at a frequency of 30–50% in large studies of MM tumors. The frequency and extent of karyotypic abnormalities correlate with the stage, prognosis, and response to therapy. Although convention karyotyping is not routinely reported of MGUS. The Characteristic numerical abnormalities are monosomy 13 and trisomies of chromosomes 3, 5, 7, 9, 11, 15, and 19. Nonrandom structural abnormalities most frequently involve in chromosome 1.

By Fluorescence in situ hybridization, MM is a plasma cell dyscrasia that can evolve from premalignant monoclonal gammopathy. Plasma cells are isolated from bone marrow aspirate using CD138 and microbeads. Interphase FISH analysis for relevant markers del(13q14.3), t(4;14), t(11;14), t(14;16) and Del(17p13.1)(TP53 gene) has performed upon diagnosis and in low-risk individuals at the time of relapse to aid in risk stratification.

Chromosomal abnormalities and/or gene variation of Multiple Myeloma

The majority of MM tumors have chromosomal abnormalities are broadly classified into hyperdiploid or nonhyperdiploid tumors. The nonhyperdiploid tumors have been associated with a poorer prognosis.

11q13 (Cyclin D) — Induces growth

4p16 (FGFR3)- Growth Factor

8q24 (MYC)- Growth/ Apoptosis

16q23 (MAF)- Transcription factor

6p25 (IRF4)- Transcription factor

Chromosome 13 deletion is present in over 15% of patients having MM and is associated with poor prognosis. However these deletion are also associated with MGUS, and their role in transformation to MM is therefore at present undefined.

The deletion of chromosome 17p involving TP53 locus are more common in relapsed and refractory cases and are associated with negative prognosis.

1p21 amplification is detected by FISH and that is more common in relapsed cases. It can serve a negative impact on overall survival.

The most common genetic Lesion in Mutliple Myeloma

· Hyperdiploid

· t(4;14)

· t(11;14)

· t(14;16)

· del (13q)/ Monosomy 13

· del(1p)/ chromosome 1q21 amplification

· TP53 inactivaton[mutation and del(17p)]

· RAS mutation

· IGH and MYC rearrangements

. FAM46C, DIS3

· Rb inactivation

· PTEN(phosphtase and tensin homolog) loss

The biological function of FAM46C is non-canonical poly(A) polymerase, which is frequently mutated in MM. The loss of function of FAM46C promotes cell survival of multiple myeloma, suggesting a tumor-suppression role.

MYC rearrangement involving unbalanced translocation and insertion, small duplication, amplification, inversion on chromosome 8p24.

Homozygous deletions of 11q22 locus resulting in loss of YAP1, BIRC3, and BIRC2 genomic region.

Chromosome 4, 14, and 16 aberrations disrupting FGFR3, WWOX, CYLD, and deletion or amplification of chromosome 6 and homozygous deletions of Xp11.2 locus.

Conclusions

Despite significant advance in the management of MM, the disease remains incurable. Virtually some patient having MM will develop relapsed disease, although strides in the field have provided opportunities for longer term remission. There are a multitude of strategies that are under investigation, and further studies are needed to establish their role in the treatment of patient with multiple myeloma.

References

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International Myeloma Working Group. Criteria for the classification of monoclonal gammopathies, multiple myeloma and related disorders: a report of the International Myeloma Working Group. Br J Haematol. 2003.

Dyck PJ, Low PA, Windebank AJ, et al. Plasma exchange in polyneuropathy associated with monoclonal gammopathy of undetermined significance. N Engl J Med. 1991;325:1482–1486.

Dewald GW, Kyle RA, Hicks GA, Greipp PR. The clinical significance of cytogenetic studies in 100 patients with multiple myeloma, plasma cell leukemia, or amyloidosis. Blood. 1985.

Sawyer JR, Waldron JA, Jagannath S, Barlogie B. Cytogenic findings in 200 patients with multiple myeloma. Cancer Genet Cytogenet. 1995.

Fonseca R, Bailey RJ, Ahmann GJ, et al. Genomic abnormalities in monoclonal gammopathy of undetermined significance. Blood. 2002.