Browsing by Subject "ovarian cancer"

Sort by: Order: Results:

Now showing items 1-11 of 11
  • Salminen, Liina; Braicu, Elena Ioana; Laaperi, Mitja; Jylha, Antti; Oksa, Sinikka; Hietanen, Sakari; Sehouli, Jalid; Kulbe, Hagen; du Bois, Andreas; Mahner, Sven; Harter, Philipp; Carpen, Olli; Huhtinen, Kaisa; Hynninen, Johanna; Hilvo, Mika (2021)
    Simple Summary Most ovarian cancer patients initially show a response to primary treatments, but the development of refractory disease is a major problem. Currently, there are no blood-based prognostic biomarkers, and the prognosis of a patient is determined by the International Federation of Gynecology and Obstetrics (FIGO) stage and residual disease after cytoreductive surgery. In this study, we developed and validated a novel test based on the ratio of two circulatory lipids that enables the prognostic stratification of ovarian cancer patients at the time of diagnosis, prior to any oncological treatments. The translational relevance of this test is to find those patients with poor prognosis early on, and to identify patients that are at high risk of recurrence despite complete cytoreduction. Thus, the test enables the early direction of novel targeted therapies to those ovarian cancer patients at greatest risk of recurrence and death. Epithelial ovarian cancer (EOC) generally responds well to oncological treatments, but the eventual development of a refractory disease is a major clinical problem. Presently, there are no prognostic blood-based biomarkers for the stratification of EOC patients at the time of diagnosis. We set out to assess and validate the prognostic utility of a novel two-lipid signature, as the lipidome is known to be markedly aberrant in EOC patients. The study consisted of 499 women with histologically confirmed EOC that were prospectively recruited at the university hospitals in Turku (Finland) and Charite (Berlin, Germany). Lipidomic screening by tandem liquid chromatography-mass spectrometry (LC-MS/MS) was performed for all baseline serum samples of these patients, and additionally for 20 patients of the Turku cohort at various timepoints. A two-lipid signature, based on the ratio of the ceramide Cer(d18:1/18:0) and phosphatidylcholine PC(O-38:4), showed consistent prognostic performance in all investigated study cohorts. In the Turku cohort, the unadjusted hazard ratios (HRs) per standard deviation (SD) (95% confidence interval) were 1.79 (1.40, 2.29) for overall and 1.40 (1.14, 1.71) for progression-free survival. In a Charite cohort incorporating only stage III completely resected patients, the corresponding HRs were 1.59 (1.08, 2.35) and 1.53 (1.02, 2.30). In linear-mixed models predicting progression of the disease, the two-lipid signature showed higher performance (beta per SD increase 1.99 (1.38, 2.97)) than cancer antigen 125 (CA-125, 1.78 (1.13, 2.87)). The two-lipid signature was able to identify EOC patients with an especially poor prognosis at the time of diagnosis, and also showed promise for the detection of disease relapse.
  • Kaipio, Katja; Chen, Ping; Roering, Pia; Huhtinen, Kaisa; Mikkonen, Piia; Östling, Päivi; Lehtinen, Laura; Mansuri, Naziha; Korpela, Taina; Potdar, Swapnil; Hynninen, Johanna; Auranen, Annika; Grénman, Seija; Wennerberg, Krister; Hautaniemi, Sampsa; Carpén, Olli (2020)
    Poor chemotherapy response remains a major treatment challenge for high-grade serous ovarian cancer (HGSC). Cancer stem cells are the major contributors to relapse and treatment failure as they can survive conventional therapy. Our objectives were to characterise stemness features in primary patient-derived cell lines, correlate stemness markers with clinical outcome and test the response of our cells to both conventional and exploratory drugs. Tissue and ascites samples, treatment-naive and/or after neoadjuvant chemotherapy, were prospectively collected. Primary cancer cells, cultured under conditions favouring either adherent or spheroid growth, were tested for stemness markers; the same markers were analysed in tissue and correlated with chemotherapy response and survival. Drug sensitivity and resistance testing was performed with 306 oncology compounds. Spheroid growth condition HGSC cells showed increased stemness marker expression (including aldehyde dehydrogenase isoform I; ALDH1A1) as compared with adherent growth condition cells, and increased resistance to platinum and taxane. A set of eight stemness markers separated treatment-naive tumours into two clusters and identified a distinct subgroup of HGSC with enriched stemness features. Expression of ALDH1A1, but not most other stemness markers, was increased after neoadjuvant chemotherapy and its expression in treatment-naive tumours correlated with chemoresistance and reduced survival. In drug sensitivity and resistance testing, five compounds, including two PI3K-mTOR inhibitors, demonstrated significant activity in both cell culture conditions. Thirteen compounds, including EGFR, PI3K-mTOR and aurora kinase inhibitors, were more toxic to spheroid cells than adherent cells. Our results identify stemness markers in HGSC that are associated with a decreased response to conventional chemotherapy and reduced survival if expressed by treatment-naive tumours. EGFR, mTOR-PI3K and aurora kinase inhibitors are candidates for targeting this cell population. (c) 2019 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.
  • Mende, Anna-Maria (Helsingin yliopisto, 2020)
    Ovarian cancer is the fifth most common cause of cancer death among women in Europe; high-grade serous ovarian carcinoma (HGSC) is the most common subtype of ovarian cancer. This report describes the construction and preliminary analysis of a retrospective cohort of HGSC patients. Tissue samples were obtained from Helsinki Biobank, and clinical data was retrieved from several electronic data bases as well as from the paper archives of the HUS Women’s hospital. Over 900 patients were identified for potential inclusion in the cohort. The process of confirming diagnoses is still ongoing. Challenges with the collection and categorization of clinical data are reported and possible solutions discussed. As the confirmation of which patients will be included in the final cohort is not yet complete, analyses in this report are limited to some preliminary descriptions. These initial findings seem to be in concordance with other reports: patients with stage I or II disease and/or complete surgical cytoreduction (R0) have a better 5-year overall survival than those with stage III or IV disease and/or suboptimal surgical outcome. Once the cohort is ready, it will be a unique tool for studying the biology of high-grade ovarian carcinoma.
  • Pelttari, L. M.; Shimelis, H.; Toiminen, H.; Kvist, A.; Törngren, T.; Borg, Å.; Blomqvist, C.; Bützow, R.; Couch, F.; Aittomäki, K.; Nevanlinna, H. (2018)
    Gene-panel sequencing allows comprehensive analysis of multiple genes simultaneously and is now routinely used in clinical mutation testing of high-risk breast and ovarian cancer patients. However, only BRCA1 and BRCA2 are often analyzed also for large genomic changes. Here, we have analyzed 10 clinically relevant susceptibility genes in 95 breast or ovarian cancer patients with gene-panel sequencing including also copy number variants (CNV) analysis for genomic changes. We identified 12 different pathogenic BRCA1, BRCA2, TP53, PTEN, CHEK2, or RAD51C mutations in 18 of 95 patients (19%). BRCA1/2 mutations were observed in 8 patients (8.4%) and CHEK2 protein-truncating mutations in 7 patients (7.4%). In addition, we identified a novel duplication encompassing most of the RAD51C gene. We further genotyped the duplication in breast or ovarian cancer families (n=1149), in unselected breast (n=1729) and ovarian cancer cohorts (n=553), and in population controls (n=1273). Seven additional duplication carries were observed among cases but none among controls. The duplication associated with ovarian cancer risk (3/590 of all ovarian cancer patients, 0.5%, P=.032 compared with controls) and was found to represent a large fraction of all identified RAD51C mutations in the Finnish population. Our data emphasizes the importance of comprehensive mutation analysis including CNV detection in all the relevant genes.
  • Braicu, Elena Ioana; Darb-Esfahani, Silvia; Schmitt, Wolfgang D.; Koistinen, Kaisa M.; Heiskanen, Laura; Pöhö, Päivi; Budczies, Jan; Kuhberg, Marc; Dietel, Manfred; Frezza, Christian; Denkert, Carsten; Sehouli, Jalid; Hilvo, Mika (2017)
    Ovarian cancer is a very severe type of disease with poor prognosis. Treatment of ovarian cancer is challenging because of the lack of tests for early detection and effective therapeutic targets. Thus, new biomarkers are needed for both diagnostics and better understanding of the cellular processes of the disease. Small molecules, consisting of metabolites or lipids, have shown emerging potential for ovarian cancer diagnostics. Here we performed comprehensive lipidomic profiling of serum and tumor tissue samples from high-grade serous ovarian cancer patients to find lipids that were altered due to cancer and also associated with progression of the disease. Ovarian cancer patients exhibited an overall reduction of most lipid classes in their serum as compared to a control group. Despite the overall reduction, there were also specific lipids showing elevation, and especially alterations in ceramide and triacylglycerol lipid species were dependent on their fatty acyl side chain composition. Several lipids showed progressive alterations in patients with more advanced disease and poorer overall survival, and outperformed CA-125 as prognostic markers. The abundance of many serum lipids correlated with their abundance in tumor tissue samples. Furthermore, we found a negative correlation of serum lipids with 3-hydroxybutyric acid, suggesting an association between decreased lipid levels and fatty acid oxidation. In conclusion, here we present a comprehensive analysis of lipid metabolism alterations in ovarian cancer patients, with clinical implications.
  • Fortner, Renée T.; Poole, Elizabeth M.; Wentzensen, Nicolas A.; Trabert, Britton; White, Emily; Arslan, Alan A.; Patel, Alpa V.; Setiawan, V. Wendy; Visvanathan, Kala; Weiderpass, Elisabete; Adami, Hans-Olov; Black, Amanda; Bernstein, Leslie; Brinton, Louise A.; Buring, Julie; Clendenen, Tess V.; Fournier, Agnès; Fraser, Gary; Gapstur, Susan M.; Gaudet, Mia M.; Giles, Graham G.; Gram, Inger T.; Hartge, Patricia; Hoffman-Bolton, Judith; Idahl, Annika; Kaaks, Rudolf; Kirsh, Victoria A.; Knutsen, Synnove; Koh, Woon-Puay; Lacey Jr., James V.; Lee, I-Min; Lundin, Eva; Merritt, Melissa A.; Milne, Roger L.; Onland-Moret, N. Charlotte; Peters, Ulrike; Poynter, Jenny N.; Rinaldi, Sabina; Robien, Kim; Rohan, Thomas; Sánchez, Maria-José; Schairer, Catherine; Schouten, Leo J.; Tjonneland, Anne; Townsend, Mary K.; Travis, Ruth C.; Trichopoulou, Antonia; van den Brandt, Piet A.; Vineis, Paolo; Wilkens, Lynne; Wolk, Alicja; Yang, Hannah P.; Zeleniuch-Jacquotte, Anne; Tworoger, Shelley S. (2019)
    Ovarian cancer risk factors differ by histotype; however, within subtype, there is substantial variability in outcomes. We hypothesized that risk factor profiles may influence tumor aggressiveness, defined by time between diagnosis and death, independent of histology. Among 1.3 million women from 21 prospective cohorts, 4,584 invasive epithelial ovarian cancers were identified and classified as highly aggressive (death in = 35 vs. 20 to <25 kg/m(2), 1.93 [1.46-2.56] and current smoking (vs. never, 1.30 [1.07-1.57]) were associated with increased risk of highly aggressive disease. Results were similar within histotypes. Ovarian cancer risk factors may be directly associated with subtypes defined by tumor aggressiveness, rather than through differential effects on histology. Studies to assess biological pathways are warranted.
  • Farkkila, Anniina; Haltia, Ulla-Maija; Tapper, Johanna; McConechy, Melissa K.; Huntsman, David G.; Heikinheimo, Markku (2017)
    Adult-type granulosa cell tumor is a clinically and molecularly unique subtype of ovarian cancer. These tumors originate from the sex cord stromal cells of the ovary and represent 3-5% of all ovarian cancers. The majority of adult-type granulosa cell tumors are diagnosed at an early stage with an indolent prognosis. Surgery is the cornerstone for the treatment of both primary and relapsed tumor, while chemotherapy is applied only for advanced or non-resectable cases. Tumor stage is the only factor consistently associated with prognosis. However, every third of the patients relapse, typically in 4-7 years from diagnosis, leading to death in 50% of these patients. Anti-Mullerian Hormone and inhibin B are currently the most accurate circulating biomarkers. Adult-type granulosa cell tumors are molecularly characterized by a pathognomonic somatic missense point mutation 402C->G (C134W) in the transcription factor FOXL2. The FOXL2 402C->G mutation leads to increased proliferation and survival of granulosa cells, and promotes hormonal changes. Histological diagnosis of adult-type granulosa cell tumor is challenging, therefore testing for the FOXL2 mutation is crucial for differential diagnosis. Large international collaborations utilizing molecularly defined cohorts are essential to improve and validate new treatment strategies for patients with high-risk or relapsed adult-type granulosa cell tumor.Key Messages:Adult-type granulosa cell tumor is a unique ovarian cancer with an indolent, albeit unpredictable disease course.Adult-type granulosa cell tumors harbor a pathognomonic somatic missense mutation in transcription factor FOXL2.The key challenges in the treatment of patients with adult-type granulosa cell tumor lie in the identification and management of patients with high-risk or relapsed disease.
  • GEMO Study Collaborators; EMBRACE Collaborators; kConFab Investigators; HEBON Investigators; GENEPSO Investigators; Consortium Investigators Modifiers; Barnes, Daniel R.; Rookus, Matti A.; McGuffog, Lesley; Aittomäki, Kristiina (2020)
    Purpose We assessed the associations between population-based polygenic risk scores (PRS) for breast (BC) or epithelial ovarian cancer (EOC) with cancer risks forBRCA1andBRCA2pathogenic variant carriers. Methods Retrospective cohort data on 18,935BRCA1and 12,339BRCA2female pathogenic variant carriers of European ancestry were available. Three versions of a 313 single-nucleotide polymorphism (SNP) BC PRS were evaluated based on whether they predict overall, estrogen receptor (ER)-negative, or ER-positive BC, and two PRS for overall or high-grade serous EOC. Associations were validated in a prospective cohort. Results The ER-negative PRS showed the strongest association with BC risk forBRCA1carriers (hazard ratio [HR] per standard deviation = 1.29 [95% CI 1.25-1.33],P = 3x10(-72)). ForBRCA2, the strongest association was with overall BC PRS (HR = 1.31 [95% CI 1.27-1.36],P = 7x10(-50)). HR estimates decreased significantly with age and there was evidence for differences in associations by predicted variant effects on protein expression. The HR estimates were smaller than general population estimates. The high-grade serous PRS yielded the strongest associations with EOC risk forBRCA1(HR = 1.32 [95% CI 1.25-1.40],P = 3x10(-22)) andBRCA2(HR = 1.44 [95% CI 1.30-1.60],P = 4x10(-12)) carriers. The associations in the prospective cohort were similar. Conclusion Population-based PRS are strongly associated with BC and EOC risks forBRCA1/2carriers and predict substantial absolute risk differences for women at PRS distribution extremes.
  • Nurmi, Anna; Muranen, Taru A.; Pelttari, Liisa M.; Kiiski, Johanna I.; Heikkinen, Tuomas; Lehto, Sini; Kallioniemi, Anne; Schleutker, Johanna; Bützow, Ralf; Blomqvist, Carl; Aittomäki, Kristiina; Nevanlinna, Heli (2019)
    Mutations in BRCA1 and BRCA2 genes predispose to breast and ovarian cancer (BC/OC) with a high lifetime risk, whereas mutations in PALB2, CHEK2, ATM, FANCM, RAD51C and RAD51D genes cause a moderately elevated risk. In the Finnish population, recurrent mutations have been identified in all of these genes, the latest being CHEK2 c.319+2T>A and c.444+1G>A. By genotyping 3,156 cases and 2,089 controls, we estimated the frequencies of CHEK2 c.319+2T>A and c.444+1G>A in Finnish BC patients. CHEK2 c.319+2T>A was detected in 0.7% of the patients, and it was associated with a high risk of BC in the unselected patient group (OR = 5.40 [95% CI 1.58-18.45], p = 0.007) and similarly in the familial patient group. CHEK2 c.444+1G>A was identified in 0.1% of all patients. Additionally, we evaluated the combined prevalence of recurrent moderate-risk gene mutations in 2,487 BC patients, 556 OC patients and 261 BRCA1/2 carriers from 109 families. The overall frequency of the mutations was 13.3% in 1,141 BRCA1/2-negative familial BC patients, 7.5% in 1,727 unselected BC patients and 7.2% in 556 unselected OC patients. At least one moderate-risk gene mutation was found in 12.5% of BRCA1 families and 7.1% of BRCA1 index patients, as well as in 17.0% of BRCA2 families and 11.3% of BRCA2 index patients, and the mutations were associated with an additional risk in the BRCA1/2 index patients (OR = 2.63 [1.15-5.48], p = 0.011). These results support gene panel testing of even multiple members of BC families where several mutations may segregate in different individuals.
  • Dominguez-Valentin, Mev; Seppälä, Toni T.; Engel, Christoph; Aretz, Stefan; Macrae, Finlay; Winship, Ingrid; Capella, Gabriel; Thomas, Huw; Hovig, Eivind; Nielsen, Maartje; Sijmons, Rolf H.; Bertario, Lucio; Bonanni, Bernardo; Tibiletti, Maria Grazia; Cavestro, Giulia Martina; Mints, Miriam; Gluck, Nathan; Katz, Lior; Heinimann, Karl; Vaccaro, Carlos A.; Green, Kate; Lalloo, Fiona; Hill, James; Schmiegel, Wolff; Vangala, Deepak; Perne, Claudia; Strauss, Hans-Georg; Tecklenburg, Johanna; Holinski-Feder, Elke; Steinke-Lange, Verena; Mecklin, Jukka-Pekka; Plazzer, John-Paul; Pineda, Marta; Navarro, Matilde; Vidal, Joan Brunet; Kariv, Revital; Rosner, Guy; Alejandra Pinero, Tamara; Laura Gonzalez, Maria; Kalfayan, Pablo; Sampson, Julian R.; Ryan, Neil A. J.; Evans, D. Gareth; Moller, Pal; Crosbie, Emma J. (2020)
    Purpose: To survey risk-reducing hysterectomy and bilateral salpingo-oophorectomy (BSO) practice and advice regarding hormone replacement therapy (HRT) in women with Lynch syndrome. Methods: We conducted a survey in 31 contributing centers from the Prospective Lynch Syndrome Database (PLSD), which incorporates 18 countries worldwide. The survey covered local policies for risk-reducing hysterectomy and BSO in Lynch syndrome, the timing when these measures are offered, the involvement of stakeholders and advice regarding HRT. Results: Risk-reducing hysterectomy and BSO are offered to path_MLH1 and path_MSH2 carriers in 20/21 (95%) contributing centers, to path_MSH6 carriers in 19/21 (91%) and to path_PMS2 carriers in 14/21 (67%). Regarding the involvement of stakeholders, there is global agreement (similar to 90%) that risk-reducing surgery should be offered to women, and that this discussion may involve gynecologists, genetic counselors and/or medical geneticists. Prescription of estrogen-only HRT is offered by 15/21 (71%) centers to women of variable age range (35-55 years). Conclusions: Most centers offer risk-reducing gynecological surgery to carriers of path_MLH1, path_MSH2 and path_MSH6 variants but less so for path_PMS2 carriers. There is wide variation in how, when and to whom this is offered. The Manchester International Consensus Group developed recommendations to harmonize clinical practice across centers, but there is a clear need for more research.
  • Boussios, Stergios; Mikropoulos, Christos; Samartzis, Eleftherios; Karihtala, Peeter; Moschetta, Michele; Sheriff, Matin; Karathanasi, Afroditi; Sadauskaite, Agne; Rassy, Elie; Pavlidis, Nicholas (2020)
    Epithelial ovarian cancer (EOC) is the fifth leading cause of cancer mortality among women. Two-thirds of patients present at advanced stage at diagnosis, and the estimated 5 year survival rate is 20-40%. This heterogeneous group of malignancies has distinguishable etiology and molecular biology. Initially, single-gene sequencing was performed to identify germline DNA variations associated with EOC. However, hereditary EOC syndrome can be explained by germline pathogenic variants (gPVs) in several genes. In this regard, next-generation sequencing (NGS) changed clinical diagnostic testing, allowing assessment of multiple genes simultaneously in a faster and cheaper manner than sequential single gene analysis. As we move into the era of personalized medicine, there is evidence that poly (ADP-ribose) polymerase (PARP) inhibitors exploit homologous recombination (HR) deficiency, especially in breast cancer gene 1 and 2 (BRCA1/2) mutation carriers. Furthermore, extensive preclinical data supported the development of aurora kinase (AURK) inhibitors in specific tumor types, including EOC. Their efficacy may be optimized in combination with chemotherapeutic or other molecular agents. The efficacy of metformin in ovarian cancer prevention is under investigation. Certain mutations, such as ARID1A mutations, and alterations in the phosphatidylinositol 3-kinase (PI3K)/AKT/mTOR pathway, which are specific in ovarian clear cell carcinoma (OCCC) and endometrioid ovarian carcinoma (EnOC), may offer additional therapeutic targets in these clinical entities. Malignant ovarian germ cell tumors (MOGCTs) are rare and randomized trials are extremely challenging for the improvement of the existing management and development of novel strategies. This review attempts to offer an overview of the main aspects of ovarian cancer, catapulted from the molecular mechanisms to therapeutic considerations.