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Transcriptomic and genomic profiling of early-stage ovarian carcinomas associated with histotype and overall survival.

ABSTRACT: Ovarian cancer is the most lethal gynecological malignancy in the western world. Despite recent efforts to characterize ovarian cancer using molecular profiling, few targeted treatment options are currently available. Here, we examined genetic variants, fusion transcripts, SNP genotyping, and gene expression patterns for early-stage (I and II) ovarian carcinomas (n=96) in relation to clinicopathological characteristics and clinical outcome, thereby identifying novel genetic features of ovarian carcinomas. Furthermore, mutation frequencies of specific genetic variants and/or their gene expression patterns were associated with histotype and overall survival, e.g. SLC28A2 (mucinous ovarian carcinoma histotype), ARCN1 (low expression in 0-2 year survival group), and tumor suppressor MTUS1 (mutation status and overall survival). The long non-coding RNA MALAT1 was identified as a highly promiscuous fusion transcript in ovarian carcinoma. Moreover, gene expression deregulation for 23 genes was associated with tumor aggressiveness. Taken together, the novel biomarkers identified here may improve ovarian carcinoma subclassification and patient stratification according to histotype and overall survival.

SUBMITTER: Engqvist H

PROVIDER: S-EPMC6205557 | biostudies-literature | 2018 Oct

REPOSITORIES: biostudies-literature

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Transcriptomic and genomic profiling of early-stage ovarian carcinomas associated with histotype and overall survival.

Engqvist Hanna H Parris Toshima Z TZ Rönnerman Elisabeth Werner EW Söderberg Elin M V EMV Biermann Jana J Mateoiu Claudia C Sundfeldt Karin K Kovács Anikó A Karlsson Per P Helou Khalil K

Oncotarget 20181012 80

Ovarian cancer is the most lethal gynecological malignancy in the western world. Despite recent efforts to characterize ovarian cancer using molecular profiling, few targeted treatment options are currently available. Here, we examined genetic variants, fusion transcripts, SNP genotyping, and gene expression patterns for early-stage (I and II) ovarian carcinomas (n=96) in relation to clinicopathological characteristics and clinical outcome, thereby identifying novel genetic features of ovarian c ...[more]

PMID: 30416686

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Project description:Background:The understanding of ovarian cancer pathogenesis has recently shifted to recognize distinct changes in how ovarian cancer histotypes are defined. Using the 2014 World Health Organization (WHO) diagnostic guidelines, we classified ovarian cancer histotypes in Surveillance, Epidemiology, and End Results (SEER) cancer registry data and examined survival patterns by histotype and disease stage. Methods:We extracted data on 28 118 incident epithelial ovarian cancer cases diagnosed in 2004-2014 from SEER and defined histotype using the 2014 WHO guidelines (high-grade serous, low-grade serous, endometrioid, clear cell, mucinous, carcinosarcoma, and malignant Brenner tumors). By histotype and disease stage, we estimated Kaplan-Meier survival curves and calculated age-adjusted overall and cause-specific survival estimates. Cox proportional hazards regression models were used to estimate histotype-specific hazard ratios (HRs) and 95% confidence intervals (CIs) by disease stage while adjusting for age at diagnosis, region, race/ethnicity, and receipt of surgery. Results:Within two years after diagnosis, localized/regional-stage carcinosarcoma and distant-stage mucinous, clear cell, and carcinosarcoma had a higher risk of mortality compared with high-grade serous, with the most pronounced association for localized/regional carcinosarcoma (>1-2-year time period: HR = 3.81, 95% CI = 2.74 to 5.30) and distant-stage mucinous (0-1-year time period: HR = 3.87, 95% CI = 3.45 to 4.34). In the time period more than four to 10 years after diagnosis, hazard ratios for all histotypes relative to high-grade serous, irrespective of disease stage, were less than 1.00. Cumulatively, both localized/regional and distant-stage low-grade serous and endometrioid carcinomas had the most favorable outcomes. Conclusions:Our large study, which is representative of the United States population and incorporates the most current knowledge of ovarian cancer pathogenesis, highlights the need to recognize ovarian cancer as a set of distinct diseases and not a single entity. Only then will we be able to effectively target the unique features of each histotype to reduce ovarian cancer mortality.

Project description:ObjectiveTo identify predictors of ovarian conservation at hysterectomy and to examine the association of ovarian conservation and survival of young women with early-stage cervical cancer.MethodsThis is a retrospective cohort study using the Surveillance, Epidemiology, and End Results Program to identify hysterectomy-based surgically treated patients with stage I cervical cancer diagnosed between 1983 and 2012 (N=16,511). Multivariable models were used to identify independent factors associated with ovarian conservation. Among the subgroup of 9,419 women younger than 50 years of age with stage I disease, survival outcomes and causes of death were examined for 3,908 (41.5%) women who underwent ovarian conservation at hysterectomy without radiotherapy.ResultsOn multivariable analysis, age younger than 50 years, stage IA disease, and squamous histology were independent factors associated with ovarian conservation (all, P<.001). Among 5,526 women younger than 50 years of age with stage IA disease who underwent hysterectomy without radiotherapy, overall survival was significantly higher in patients undergoing ovarian conservation than in those undergoing oophorectomy (20-year rate, 93.5% compared with 86.8%, P<.001); cervical cancer-specific survival was similar between the patients who underwent ovarian conservation and those who underwent oophorectomy (98.8% compared with 97.8%, P=.12). On multivariable analysis, ovarian conservation remained an independent prognostic factor for improved overall survival (adjusted hazard ratio 0.63, 95% confidence interval [CI] 0.49-0.82, P=.001) and was independently associated with lower cumulative risks of death resulting from cardiovascular disease (20-year cumulative rate, 1.2% compared with 3.3%, adjusted hazard ratio 0.47, 95% CI 0.26-0.86, P=.014) and other chronic disease (0.5% compared with 1.4%, adjusted hazard ratio 0.24, 95% CI 0.09-0.65, P=.005) compared with oophorectomy. Both cervical cancer-specific survival (20-year rate, 93.1% compared with 92.0%, P=.37) and overall survival (86.7% compared with 84.6%, P=.12) were similar between ovarian conservation and oophorectomy among 3,893 women younger than 50 years of age with stage IB disease who underwent hysterectomy without radiotherapy.ConclusionAmong young women with stage IA cervical cancer, ovarian conservation at hysterectomy is associated with decreased all-cause mortality including death resulting from cardiovascular disease and other chronic diseases.

Project description:ObjectiveTo characterize contributing factors for ovarian conservation during surgical treatment for endometrial cancer and to examine the association of ovarian conservation on survival of young women with early-stage, low-grade tumors.MethodsThis was a population-based study using the Surveillance, Epidemiology, and End Results program to identify surgically treated stage I type I (grade 1-2 endometrioid histology) endometrial cancer cases diagnosed between 1983 and 2012 (N=86,005). Multivariable models were used to identify independent factors for ovarian conservation. Survival outcomes and cause of death were examined for women aged younger than 50 with stage I type I endometrial cancer who underwent ovarian conservation (1,242 among 12,860 women [9.7%]).ResultsOn multivariable analysis, age younger than 50 years, grade 1 endometrioid histology, and tumor size 2.0 cm or less were noted to be independent factors for ovarian conservation (all, P<.001). For 9,110 women aged younger than 50 years with stage I grade 1 tumors, cause-specific survival was similar between ovarian conservation and oophorectomy cases (20-year rates 98.9% compared with 97.7%, P=.31), whereas overall survival was significantly higher in ovarian conservation cases than oophorectomy cases (88.8% compared with 82.0%, P=.011). On multivariable analysis, ovarian conservation remained an independent prognostic factor for improved overall survival (adjusted hazard ratio 0.73, 95% confidence interval [CI] 0.54-0.98, P=.036) and was independently associated with a lower cumulative risk of death resulting from cardiovascular disease compared with oophorectomy (20-year rates, 2.3% compared with 3.7%, adjusted hazard ratio 0.40, 95% CI 0.17-0.91, P=.029). Contrary, cause-specific survival (20-year rates 94.6% compared with 96.1%, P=.68) and overall survival (81.0% compared with 80.6%, P=.91) were similar between ovarian conservation and oophorectomy among 3,750 women aged younger than 50 years with stage I grade 2 tumors.ConclusionOvarian conservation is performed in less than 10% of young women with stage I type I endometrial cancer. Ovarian conservation is associated with decreased mortality in young women with stage I grade 1 tumors.

Project description: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.

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Transcriptomic and genomic profiling of early-stage ovarian carcinomas associated with histotype and overall survival.

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Transcriptomic and genomic profiling of early-stage ovarian carcinomas associated with histotype and overall survival.

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