Aberrant methylation of TMS1 in small cell, non small cell lung cancer and breast cancer.
TMS1 (target of methylation-induced silencing) is a CpG island-associated gene that functions in the regulation of apoptosis and encodes a caspase recruitment domain, a recently described motif found in apoptotic signaling molecules. Recent evidence suggests that silencing of genes in the apoptotic pathway contribute to human carcinogenesis. We examined the DNA methylation status of the TMS1 promoter in lung and breast tumor tissues, tumor cell lines and nonmalignant tissues by methylation-specific polymerase chain reaction (MSP) and its mRNA expression by reverse transcription PCR. Aberrant methylation of TMS1 was present in 70% (40 of 57) of small cell lung cancer (SCLC) cell lines and 41% (13 of 32) of SCLC tumor tissues, 48% (29 of 61) of non small cell lung cancer (NSCLC) cell lines and 40% (28 of 70) of NSCLC tumor tissues and 46% (12 of 26) of breast cancer cell lines and 32% (20 of 63) of breast tumor tissues. Methylation was absent in the peripheral blood lymphocytes and buccal epithelium from healthy volunteers, as well as in nonmalignant lung tissues and was rare in nonmalignant breast tissues 7% (2 of 30). DNA methylation was confirmed by sequence analysis and the methylation status correlated inversely with TMS1 RNA expression in 18 cell lines tested. RNA expression was restored by treatment with the demethylating agent 5-aza-2'-deoxycytidine, in 4 of 4 methylated cell lines that lacked the TMS1 transcript. Our results suggest that methylation of TMS1 may play a role in the pathogenesis of small cell and non small lung and breast cancers.
Virmani
Arvind
A
Hamon Center for Therapeutic Oncology Research, University of Texas Southwestern Medical Center, Dallas, TX, USA. arvind@geneticassays.com
Rathi
Asha
A
Sugio
Kenji
K
Sathyanarayana
Ubaradka G
UG
Toyooka
Shinichi
S
Kischel
Frank C
FC
Tonk
Vijay
V
Padar
Asha
A
Takahashi
Takashi
T
Roth
Jack A
JA
Euhus
David M
DM
Minna
John D
JD
Gazdar
Adi F
AF
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D017209:Apoptosis; D001483:Base Sequence; D001943:Breast Neoplasms / Q000235:genetics* / Q000378:metabolism; D053468:CARD Signaling Adaptor Proteins; D002289:Carcinoma, Non-Small-Cell Lung / Q000235:genetics* / Q000378:metabolism; D018288:Carcinoma, Small Cell / Q000235:genetics* / Q000378:metabolism; D016022:Case-Control Studies; D018899:CpG Islands; D003598:Cytoskeletal Proteins; D004248:DNA (Cytosine-5-)-Methyltransferases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D019175:DNA Methylation; D004273:DNA, Neoplasm / Q000235:genetics; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008175:Lung Neoplasms / Q000235:genetics* / Q000378:metabolism; D008214:Lymphocytes / Q000097:blood / Q000378:metabolism; D008875:Middle Aged; D008969:Molecular Sequence Data; D011506:Proteins / Q000235:genetics* / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014407:Tumor Cells, Cultured
D053468:CARD Signaling Adaptor Proteins; D003598:Cytoskeletal Proteins; D004273:DNA, Neoplasm; D004791:Enzyme Inhibitors; C402202:PYCARD protein, human; D011506:Proteins; D004248:DNA (Cytosine-5-)-Methyltransferases