DNA methylation profiling of ovarian carcinomas and their <it>in vitro </it>models identifies <it>HOXA9</it>, <it>HOXB5</it>, <it>SCGB3A1</it>, and <it>CRABP1 </it>as novel targets

• Main Authors: Tropé Claes G, Silins Ilvars, Ahlquist Terje, Lothe Ragnhild A, Wu Qinghua, Micci Francesca, Nesland Jahn M, Suo Zhenhe, Lind Guro E
• Format: Article
• Language: English
• Published: BMC 2007-07-01
• Series: Molecular Cancer
• Online Access: http://www.molecular-cancer.com/content/6/1/45
• ISSN: 1476-4598

<p>Abstract</p> <p>Background</p> <p>The epigenetics of ovarian carcinogenesis remains poorly described. We have in the present study investigated the promoter methylation status of 13 genes in primary ovarian carcinomas (n = 52) and their <it>in vitro </it>models (n = 4; ES-2, OV-90, OVCAR-3, and SKOV-3) by methylation-specific polymerase chain reaction (MSP). Direct bisulphite sequencing analysis was used to confirm the methylation status of individual genes. The MSP results were compared with clinico- pathological features.</p> <p>Results</p> <p>Eight out of the 13 genes were hypermethylated among the ovarian carcinomas, and altogether 40 of 52 tumours were methylated in one or more genes. Promoter hypermethylation of <it>HOXA9</it>, <it>RASSF1A</it>, <it>APC</it>, <it>CDH13</it>, <it>HOXB5</it>, <it>SCGB3A1 (HIN-1)</it>, <it>CRABP1</it>, and <it>MLH1 </it>was found in 51% (26/51), 49% (23/47), 24% (12/51), 20% (10/51), 12% (6/52), 10% (5/52), 4% (2/48), and 2% (1/51) of the carcinomas, respectively, whereas <it>ADAMTS1</it>, <it>MGMT</it>, <it>NR3C1</it>, <it>p14</it>^<it>ARF</it>, and <it>p16</it>^{<it>INK</it>4<it>a </it>}were unmethylated in all samples. The methylation frequencies of <it>HOXA9 </it>and <it>SCGB3A1 </it>were higher among relatively early-stage carcinomas (FIGO I-II) than among carcinomas of later stages (FIGO III-IV; <it>P </it>= 0.002, <it>P </it>= 0.020, respectively). The majority of the early-stage carcinomas were of the endometrioid histotype. Additionally, <it>HOXA9 </it>hypermethylation was more common in tumours from patients older than 60 years of age (15/21) than among those of younger age (11/30; <it>P </it>= 0.023). Finally, there was a significant difference in <it>HOXA9 </it>methylation frequency among the histological types (<it>P </it>= 0.007).</p> <p>Conclusion</p> <p>DNA hypermethylation of tumour suppressor genes seems to play an important role in ovarian carcinogenesis and <it>HOXA9</it>, <it>HOXB5</it>, <it>SCGB3A1</it>, and <it>CRABP1 </it>are identified as novel hypermethylated target genes in this tumour type.</p>