DNA methylation profiles of lymphoid and hematopoietic malignancies.
OBJECTIVE
Aberrant methylation of the 5' gene promoter regions is an epigenetic phenomenon that is the major mechanism for silencing of tumor suppressor genes in many cancer types. The aims of our study were (a) to compare the methylation profiles of the major forms of hematological malignancies and (b) to determine the methylation profile of monoclonal gammopathy of undetermined significance (MGUS) and compare it with that of multiple myeloma (MM).


METHODS
We compared the aberrant promoter methylation profile of 14 known or suspected tumor suppressor genes in leukemias (n = 48), lymphomas (n = 42), and MMs (n = 40). We also examined the methylation profile of MGUS (n = 20), a premalignant plasma cell dyscrasia. The genes studied represent five of the six "hallmarks of cancer."


RESULTS
Peripheral blood lymphocytes (n = 14) from healthy volunteers were negative for methylation of all genes, and methylation percentages in 41 nonmalignant tissues (peripheral blood mononuclear cells, bone marrows, and lymph nodes) from hematological patients were low (0-9%) for all 14 genes, confirming that methylation was tumor specific. Ten of the genes were methylated at frequencies of 29-68% in one or more tumor types, and the methylation indices (an indicator of overall methylation) varied from 0.25 to 0.34. With two exceptions, the methylation patterns of leukemias and lymphomas were similar. However, the pattern of MMs varied from the other tumor types for six genes. In general, the methylation pattern of MGUS was similar to that of MM, although the methylation frequencies were lower (the methylation index of MGUS was 0.15, and that of MM was 0.3). However, the methylation frequencies of six genes were significantly higher in MGUS than in control tissues. The relatively high frequencies of methylation in MGUS are consistent with it being a premalignant condition.


CONCLUSIONS
The three major forms of lymphoid/hematopoietic malignancies show overlapping but individual patterns of methylation.
Takahashi
Takao
T
Hamon Center for Therapeutic Oncology Research, University of Texas Southwestern Medical Center, Dallas, Texas 75390, USA.
Shivapurkar
Narayan
N
Reddy
Jyotsna
J
Shigematsu
Hisayuki
H
Miyajima
Kuniharu
K
Suzuki
Makoto
M
Toyooka
Shinichi
S
Zöchbauer-Müller
Sabine
S
Drach
Johannes
J
Parikh
Gunjan
G
Zheng
Yingye
Y
Feng
Ziding
Z
Kroft
Steven H
SH
Timmons
Charles
C
McKenna
Robert W
RW
Gazdar
Adi F
AF
D000367:Age Factors; D000964:Antimetabolites, Antineoplastic / Q000494:pharmacology; D001374:Azacitidine / Q000031:analogs & derivatives* / Q000494:pharmacology; D045744:Cell Line, Tumor; D019175:DNA Methylation; D004273:DNA, Neoplasm / Q000235:genetics / Q000378:metabolism; D000077209:Decitabine; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D016147:Genes, Tumor Suppressor; D006801:Humans; D007938:Leukemia / Q000235:genetics* / Q000473:pathology; D016015:Logistic Models; D008223:Lymphoma / Q000235:genetics* / Q000473:pathology; D008297:Male; D008875:Middle Aged; D009101:Multiple Myeloma / Q000235:genetics / Q000473:pathology; D011401:Promoter Regions, Genetic / Q000235:genetics; D012737:Sex Factors
D000964:Antimetabolites, Antineoplastic; D004273:DNA, Neoplasm; D000077209:Decitabine; D001374:Azacitidine