Tumor suppressor genes are frequently methylated in lymph node metastases of breast cancers.
BACKGROUND
Metastasis represents a major adverse step in the progression of breast carcinoma. Lymph node invasion is the most relevant prognostic factor; however little is known on the molecular events associated with lymph node metastasis process. This study is to investigate the status and role of methylation in lymph node metastatic tumors.


METHODS
Bisulfite pyrosequencing is used to screen 6 putative tumor suppressor genes (HIN-1, RASSF1A, RIL, CDH13, RARbeta2 and E-cadherin) in 38 pairs of primary breast tumors and lymph node metastases.


RESULTS
We found that HIN-1, CDH13, RIL, RASSF1A and RARbeta2 were frequently methylated both in primary and metastatic tissues (range: 55.3% approximately 89.5%). E-cadherin was not frequently methylated in either setting (range: 18.4% approximately 23.7%). The methylation status of HIN-1, CDH13, RIL, and RARbeta2 in lymph nodes metastasis were correlated with that in primary tumors. The Pearson correlation values ranged from 0.624 to 0.472 (p values < 0.01 to 0.001). Interestingly, we observed an association between HIN-1 methylation and hormone status in metastatic lymph nodes. Hypermethylation of HIN-1 in metastasis lymph nodes was significantly associated with expression of ER (odds ratio, 1.070; P = 0.024) and with PR (odds ratio, 1.046; P = 0.026).


CONCLUSIONS
This study suggests that hypermethylation of tumor suppressor genes is extended from primary to metastatic tumors during tumor progression.
Feng
Weiwei
W
Obstetrics and Gynecology Hospital of Fudan University, Shanghai, China.
Orlandi
Rosaria
R
Zhao
Naiqing
N
Carcangiu
Maria Luisa
ML
Tagliabue
Elda
E
Xu
Jia
J
Bast
Robert C
RC
Yu
Yinhua
Y
D000328:Adult; D000368:Aged; D001940:Breast / Q000378:metabolism / Q000473:pathology; D001943:Breast Neoplasms / Q000235:genetics* / Q000473:pathology; D015820:Cadherins / Q000235:genetics; D018270:Carcinoma, Ductal, Breast / Q000235:genetics* / Q000556:secondary; D018275:Carcinoma, Lobular / Q000235:genetics* / Q000556:secondary; D016022:Case-Control Studies; D016207:Cytokines / Q000235:genetics; D019175:DNA Methylation; D004268:DNA-Binding Proteins / Q000235:genetics; D005260:Female; D016147:Genes, Tumor Suppressor; D006801:Humans; D007124:Immunoenzyme Techniques; D060588:LIM Domain Proteins; D008875:Middle Aged; D009367:Neoplasm Staging; D016133:Polymerase Chain Reaction; D011379:Prognosis; D011401:Promoter Regions, Genetic / Q000235:genetics; D011960:Receptors, Estrogen / Q000378:metabolism; D018168:Receptors, Retinoic Acid / Q000235:genetics; D025521:Tumor Suppressor Proteins / Q000235:genetics
D015820:Cadherins; D016207:Cytokines; D004268:DNA-Binding Proteins; C099972:H-cadherin; D060588:LIM Domain Proteins; C486247:PDLIM4 protein, human; C533416:RARB2 protein, human; C411762:RASSF1 protein, human; D011960:Receptors, Estrogen; D018168:Receptors, Retinoic Acid; C434732:SCGB3A1 protein, human; D025521:Tumor Suppressor Proteins