Distinct hypermethylation profile of primary breast cancer is associated with sentinel lymph node metastasis.
OBJECTIVE
Gene promoter region hypermethylation is a significant event in primary breast cancer. However, its impact on tumor progression and potential predictive implications remain relatively unknown.


METHODS
We conducted hypermethylation profiling of 151 primary breast tumors with association to known prognostic factors in breast cancer using methylation-specific PCR for six known tumor suppressor and related genes: RASSF1A, APC, TWIST, CDH1, GSTP1, and RAR-beta2. Furthermore, correlation with sentinel lymph node (SLN) tumor status was assessed as it represents the earliest stage of metastasis that is readily detected. Hypermethylation for any one gene was identified in 147 (97%) of 151 primary breast tumors. The most frequently hypermethylated gene was RASSF1A (81%).


RESULTS
Hypermethylation of the CDH1 was significantly associated with primary breast tumors demonstrating lymphovascular invasion (P = 0.008), infiltrating ductal histology (P = 0.03), and negative for the estrogen receptor (P = 0.005), whereas RASSF1A and RAR-beta2 gene hypermethylation were significantly more common in estrogen receptor-positive (P < 0.001) and human epidermal growth factor receptor 2-positive (P < 0.001) tumors, respectively. In multivariate analysis, hypermethylation of GSTP1 and/or RAR-beta2 was significantly associated with patients having macroscopic SLN metastasis compared with those with microscopic or no sentinel node metastasis (odds ratio, 4.59; 95% confidence interval, 2.02-10.4; P < 0.001). In paired SLN metastasis, CDH1 was the most frequently methylated gene (90%) and provides evidence in patients corroborating its role in the clinical development of metastasis.


CONCLUSIONS
Hypermethylation profiling of primary breast tumors is significantly associated with known pathologic prognostic factors and may have additional clinical and pathologic utility for assessing patient prognosis and predicting early regional metastasis.
Shinozaki
Masaru
M
Department of Molecular Oncology, John Wayne Cancer Institute and St. John's Health Center, 2200 Santa Monica Boulevard, Santa Monica, CA 90404, USA.
Hoon
Dave S B
DS
Giuliano
Armando E
AE
Hansen
Nora M
NM
Wang
He-Jing
HJ
Turner
Roderick
R
Taback
Bret
B
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D001943:Breast Neoplasms / Q000175:diagnosis / Q000235:genetics*; D018270:Carcinoma, Ductal, Breast / Q000175:diagnosis / Q000235:genetics; D018275:Carcinoma, Lobular / Q000175:diagnosis / Q000235:genetics; D019175:DNA Methylation; D005260:Female; D006801:Humans; D008198:Lymph Nodes / Q000473:pathology*; D008207:Lymphatic Metastasis; D008875:Middle Aged; D016133:Polymerase Chain Reaction; D011379:Prognosis; D011401:Promoter Regions, Genetic; D011960:Receptors, Estrogen / Q000378:metabolism; D021701:Sentinel Lymph Node Biopsy; D025521:Tumor Suppressor Proteins / Q000235:genetics*
D011960:Receptors, Estrogen; D025521:Tumor Suppressor Proteins