A similar cell-specific pattern of HOXA methylation in normal and in cancer tissues.
HOX genes are developmental genes that determine anterior-posterior embryonic pattern and govern the process of differentiation. Inappropriate expression of HOX genes has been implicated in developmental abnormalities and hematopoietic malignancies. In addition, HOX genes silencing by DNA methylation has been reported in cancers and related to disease aggressiveness and outcome. On the other hand, accumulating evidence suggests that epigenetic changes at HOX genes are linked to normal development and differentiation. To better understand the relationship between HOXA methylation and cancer, we analyzed the methylation pattern of HOXA genes in human primary breast and colon carcinomas, normal tissues, and normal white blood cells. Genome-wide methylation arrays of breast cancers and white blood cells demonstrated similar methylation patterns. Quantitative methylation analysis of seven representative HOXA genes revealed various levels of methylation in both normal tissues and cancers. Analysis of epithelial-enriched normal breast tissue and stroma indicated that the stroma was the major origin of HOXA methylation. Furthermore, in selected dense breast cancers, minimal increase in methylation of several HOXA genes did not correlate with the predominance of malignant epithelial cells in these tumors. Our results suggest that methylation of the HOXA cluster may be a normal developmental and cell type specific process rather than a cancer specific mechanism.
Avraham
Ayelet
A
Department of Oncology, Assaf Harofeh Medical Center affiliated with Tel-Aviv University, Zerifin, Israel. ayeleta@asaf.health.gov.il
Sandbank
Judith
J
Yarom
Nirit
N
Shalom
Avshalom
A
Karni
Tami
T
Pappo
Itzhak
I
Sella
Avishay
A
Fich
Alexander
A
Walfisch
Shlomo
S
Gheber
Larisa
L
Evron
Ella
E
D001940:Breast / Q000378:metabolism; D001943:Breast Neoplasms / Q000097:blood / Q000235:genetics* / Q000378:metabolism; D002454:Cell Differentiation; D018899:CpG Islands; D019175:DNA Methylation; D004848:Epithelium / Q000378:metabolism; D015972:Gene Expression Regulation, Neoplastic; D020868:Gene Silencing; D015894:Genome, Human; D018398:Homeodomain Proteins / Q000235:genetics* / Q000502:physiology; D006801:Humans; D007962:Leukocytes / Q000378:metabolism; D008957:Models, Genetic; D005810:Multigene Family; D011379:Prognosis
D018398:Homeodomain Proteins; C088144:HoxA protein