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Aberrant Methylation of Tumor Suppressor Genes (TSG) In Myeloma Multiple (MM) and Chronic Lymphocytic Leukemia (CLL)

Reviewer: John P. Plastaras, MD, PhD
Abramson Cancer Center of the University of Pennsylvania
Last Modified: March 22, 2007

Presenter: Chena, C. and Stanganelli, C.
Presenter's Affiliation: Academia Nacional de Medicina, Argentina
Type of Session: Scientific

Background

• Multiple myeloma (MM) is a clonal B-cell neoplasm that results from a number of mutations. Monoclonal gammopathy of unknown significance (MGUS) is considered to be a precursor of MM. Chronic lymphocytic leukemia Is characterized by the slow accumulation of neoplastic lymphocytes with a variable clinical course, possibly due to the step wise accumulation of genetic abnormalities.
• Aberrant gene promoter methylation is an epigenetic mechanism whereby gene expression can be silenced. It is a potential mechanism to silence tumor suppressor genes (TSGs) without the need for deletion or mutation.
• This study was undertaken to evaluate the methylation status of different TSGs involved in regulation of the cell cycle: p15INK4b, p16INK4a, p14ARF, SOCS-1, p27KIP1, RASSF1A and TP73, in MM, MGUS, and CLL patients.

Materials and Methods

• Design: Single institution, retrospective, laboratory based study.
• Patient samples:
  • 30 patients with MM (14 males; mean age 67.6 years; Durie-Salmon clinical stages: I: 24%, II: 12%, III: 64%)
  • 8 patients with MGUS (3 males; mean age 68.6 years)
  • 36 CLL patients (17 females; mean age 67 years; Rai clinical stages: 0: 32%, I-II: 38%, III-IV: 30%).
• Methylation status from DNA samples was performed using a Methylation Specific PCR (MSP) technique.
  • Methylation of SOCS-1, TP73, p14ARF, p15INK4b, p16INK4a and RASSF1A genes was studied.

Results

MM:

• At least one TSG was methylated in 83%
• 50% had 2 or more TSGs methylated
• SOCS-1 was methylated in 61%
• TP73 was methylated in 35%

MGUS:

• Only 50% had at least one TSG methylated (p<0.03 compared to MM)
• TP73 was methylated in 25%
• P14ARF was methylated in 25%
• There was a significant difference between the percentage of methylated
  SOCS-1 in MM vs. MGUS ( P<0.04)
• The presence of similar frequency of p14ARF methylation in both MM and MGUS suggests that it is an early event in MM and MGUS.

CLL:

• At least one TSG was methylated in 78%
• 11% had 2 or more TSGs methylated
• TP73 was methylated in 77%
• All patients had UNmethylated p27KIP1 implicating that this TSG is not critical for the development of CLL

Author's Conclusions

• A different methylation pattern was observed in MM and CLL. The genes most frequently affected by aberrant methylation were SOCS-1 in MM and TP73 in CLL.
• The high incidence of SOCS-1 and TP73 suggests that they would be potential targets for therapeutic intervention.

Clinical/Scientific Implications

• Promoter methylation is an important, but previously poorly characterized mechanism of gene inactivation. As techniques become available to understand epigenetic mechanisms of carcinogenesis, they will need to be applied to various malignancies to better understand the pathways of cancer development.
• This study would have been complemented by TSG deletion analysis to understand the necessary pathways of carcinogenesis in MM and CLL. Also, confirmation of decreased expression of these genes would have bolstered the conclusions of the authors.
• This is an interesting demonstration of TSG inactivation by methylation in MM, MGUS, and CLL. It suggests that there may be common pathways (SOCS-1 pathway in MM and TP73 pathway in CLL) that may be good targets for therapy.