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

<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

Morbidity associated with "self-rated health" in epithelial ovarian cancer survivors

<p>Abstract</p> <p>Background</p> <p>Epithelial ovarian cancer survivors (EOCSs) frequently report multiple complaints after their treatment. The objective was to study somatic and mental morbidity in EOCSs associated with their Self- Rated Health (SRH) assessed by a single item.</p> <p>Findings were compared to age-matched controls from the general population.</p> <p>Methods</p> <p>In a cross -sectional follow-up design 189/287 (66%) EOCSs treated at The Norwegian Radiumhospital 1979–2003 responded to a mailed questionnaire on demographic data, and somatic and mental morbidity. SRH last week was rated on item #29 of the European Organization and Treatment of Cancer Quality of Life Questionnaire in 84/189 (97%) of responding EOCSs. For comparisons "good" and "poor" SRH groups were defined by the median score on the SRH item.</p> <p>Results</p> <p>EOCSs with "poor SRH" had higher level of somatic symptoms, anxiety, depression and fatigue than those with "good SRH" (p < .001). In multivariate analyses somatic symptoms, age and fatigue, were significantly associated with the SRH score in EOCSs, but not the cancer-related variables (FIGO stage, recurrence in < 6 months or chemotherapy ever). The model explained 70% of the variance in SRH in linear and 77% in logistic regression analyses. The distribution of the SRH scores in EOCSs did not differ significantly from that of normative controls; however a higher proportion of controls recorded a high SRH score.</p> <p>Conclusion</p> <p>SRH is strongly related to common somatic complaints, impairment and fatigue but not to cancer-related variables. A single question concerning SRH last week might be a quick screening method for collecting important information on symptoms in EOCSs, in addition to cancer – related questions.</p

Epithelial–Mesenchymal Transition in Ovarian Carcinoma

Ovarian cancer is the most lethal gynecologic malignancy, with the majority of patients dying within 5 years of diagnosis. This poor survival of patients diagnosed with this malignancy is attributed to diagnosis at advanced stage, when the tumor has metastasized, and to chemotherapy resistance, either primary or developing along tumor progression. However, ovarian carcinomas, constituting the vast majority of ovarian cancers, additionally have unique biology, one aspect of which is the ability to co-express epithelial and mesenchymal determinants. Epithelial-mesenchymal transition (EMT), a physiological process by which mesenchymal cells are formed and migrate to target organs during embryogenesis, is involved in cancer cell invasion and metastasis. However, these changes do not fully occur in ovarian carcinoma, and are even reversed in tumor cells present in malignant peritoneal and pleural effusions. This review summarizes current knowledge in this area, including the characteristics of EMT related to adhesion, transcriptional regulation and chemoresistance, and their clinical relevance, as well as the recently observed regulation of EMT by microRNA

Genomic profile of ovarian carcinomas

Background It is known that all tumors studied in sufficient number to draw conclusions show characteristic/specific chromosomal rearrangements, and the identification of these chromosomes and the genes rearranged behind the aberrations may ultimately lead to a tailor-made therapy for each cancer patient. Knowledge about the acquired genomic aberrations of ovarian carcinomas is still unsatisfactory. Methods We cytogenetically analyzed 110 new cases of ovarian carcinoma of different histological subtypes using karyotyping of G-banded chromosomes and high-resolution comparative genomic hybridization. We first compared the aberration patterns identified by the two genomic screening techniques using the so-called “classical” pathological classification in which the carcinomas are grouped as tumors of types I and II. We also broke down our findings according to the more “modern” classification which groups the carcinomas in five different categories. Results The chromosomal breakpoints identified by karyotyping tended to cluster to 19p/q and to 11q, but no unquestionably recurrent rearrangement could be seen. Common imbalances were scored as gains from 1q, 3q, 7q, and 8q and losses from 17p, 19q, and 22q. Gain of material from 8q23 and losses from 19q and 22q have previously been described at high frequencies in bilateral and borderline ovarian carcinomas. The fact that they were present both in “precursor” lesions, i.e., borderline tumors, as well as in tumors of more advanced stages, i.e., carcinomas, highlights the possibility of an adenoma-carcinoma sequence in ovarian carcinogenesis. Conclusion Based on the relatively simple genomic changes we identified in the low-grade serous carcinomas examined (n = 7) and which largely corresponded to the aberration pattern formerly identified in borderline tumors, one can interpret the cytogenetic data as supporting the view that the low-grade carcinomas represent a phenotypically more advanced stage of borderline tumors. Whether transition from low-grade to high-grade carcinoma also occurs, is a question about which the genomic data is still inconclusive

CIAPIN1 and ABCA13 are markers of poor survival in metastatic ovarian serous carcinoma

Background The objective of this study was to investigate the expression and clinical role of 14 genes previously shown to be associated with chemotherapy response and/or progression-free survival in a smaller series of ovarian serous carcinoma effusions. Methods Advanced-stage serous ovarian carcinoma effusions (n = 150) were analyzed for mRNA expression of AKR1C1, ABCA4, ABCA13, ABCB10, BIRC6, CASP9, CIAPIN1, FAS, MGMT, MUTYH, POLH, SRC, TBRKB and XPA using quantitative real-time PCR. mRNA expression was studied for association with clinicopathologic parameters, including chemotherapy response and survival. Results ABCA4 mRNA expression was significantly related to better (complete) chemotherapy response at diagnosis in the entire cohort (p = 0.018), whereas higher POLH mRNA levels were significantly related to better chemoresponse at diagnosis in analysis to 58 patients with pre-chemotherapy effusions treated with standard chemotherapy (carboplatin + paclitaxel; p = 0.023). In univariate survival analysis for patients with pre-chemotherapy effusions (n = 77), CIAPIN1 mRNA expression was significantly related to shorter overall (p = 0.007) and progression-free (p = 0.038) survival, whereas ABCA13 mRNA expression was significantly related to shorter OS (p = 0.024). Higher CIAPIN1 mRNA expression was an independent marker of poor overall survival in Cox multivariate analysis (p = 0.044). Conclusions Our data identify ABCA4 and POLH as markers of better chemotherapy response in metastatic serous carcinoma. CIAPIN1 and ABCA13 may be novel markers of poor outcome in pre-chemotherapy serous carcinoma effusions