Publications
152 results found
Rambau PF, Vierkant RA, Intermaggio MP, et al., 2018, Association of p16 expression with prognosis varies across ovarian carcinoma histotypes: an Ovarian Tumor Tissue Analysis consortium study, Journal of Pathology: Clinical Research, Vol: 4, Pages: 250-261, ISSN: 2056-4538
We aimed to validate the prognostic association of p16 expression in ovarian high-grade serous carcinomas (HGSC) and to explore it in other ovarian carcinoma histotypes. p16 protein expression was assessed by clinical-grade immunohistochemistry in 6,525 ovarian carcinomas including 4,334 HGSC using tissue microarrays from 24 studies participating in the Ovarian Tumor Tissue Analysis (OTTA) consortium. p16 expression patterns were interpreted as abnormal (either overexpression referred to as block expression or absence) or normal (heterogeneous). CDKN2A (which encodes p16) mRNA expression was also analyzed in a subset (N=2,280) mostly representing HGSC (N=2,010). Association of p16 expression with overall survival (OS) was determined within histotypes as was CDKN2A expression for HGSC only. p16 block expression was most frequent in HGSC (56%) but neither protein nor mRNA expression was associated with OS. However, relative to heterogeneous expression, block expression was associated with shorter OS in endometriosis-associated carcinomas, clear cell (HR: 2.02, 95%CI 1.47-2.77, p< 0.001) and endometrioid (HR: 1.88, 95%CI 1.30- 2.75, p=0.004), while absence was associated with shorter OS in low-grade serous carcinomas (HR: 2.95, 95%CI 1.61-5.38, p=0.001). Absence was most frequent in mucinous carcinoma (50%), and was not associated with OS in this histotype. The prognostic value of p16 expression is histotype-specific and pattern dependent. We provide definitive evidence against an association of p16 expression with survival in ovarian HGSC as previously suggested. Block expression of p16 in clear cell and endometrioid carcinoma should be further validated as a prognostic marker, and absence in low-grade serous carcinoma justifies CDK4 inhibition. This article is protected by copyright. All rights reserved.
Blagden SP, Rizzuto I, Suppiah P, et al., 2018, Anti-tumour activity of a first-in-class agent NUC-1031 in patients with advanced cancer: results of a phase I study, British Journal of Cancer, Vol: 119, Pages: 815-822, ISSN: 0007-0920
BackgroundGemcitabine is used to treat a wide range of tumours, but its efficacy is limited by cancer cell resistance mechanisms. NUC-1031, a phosphoramidate modification of gemcitabine, is the first anti-cancer ProTide to enter the clinic and is designed to overcome these key resistance mechanisms.MethodsSixty-eight patients with advanced solid tumours who had relapsed after treatment with standard therapy were recruited to a dose escalation study to determine the recommended Phase II dose (RP2D) and assess the safety of NUC-1031. Pharmacokinetics and anti-tumour activity was also assessed.ResultsSixty-eight patients received treatment, 50% of whom had prior exposure to gemcitabine. NUC-1031 was well tolerated with the most common Grade 3/4 adverse events of neutropaenia, lymphopaenia and fatigue occurring in 13 patients each (19%). In 49 response-evaluable patients, 5 (10%) achieved a partial response and 33 (67%) had stable disease, resulting in a 78% disease control rate. Cmax levels of the active intracellular metabolite, dFdCTP, were 217-times greater than those reported for equimolar doses of gemcitabine, with minimal toxic metabolite accumulation. The RP2D was determined as 825 mg/m2 on days 1, 8 and 15 of a 28-day cycle.ConclusionsNUC-1031 was well tolerated and demonstrated clinically significant anti-tumour activity, even in patients with prior gemcitabine exposure and in cancers not traditionally perceived as gemcitabine-responsive.
Montinaro A, Hartwig T, von Karstedt S, et al., 2018, Characterization and therapeutic harnessing of TRAIL's pro-tumorigenic and pro-apoptotic functions in cancer, Publisher: AMER ASSOC CANCER RESEARCH, ISSN: 1078-0432
Zubiaur IA, Montinaro A, von Karstedt S, et al., 2018, The impact of combined CDK9 inhibition and TRAIL treatment on NSCLC, Publisher: AMER ASSOC CANCER RESEARCH, ISSN: 1078-0432
Stronach EA, Paul J, Timms KM, et al., 2018, Biomarker assessment of HR deficiency, tumor BRCA1/2 mutations and CCNE1 copy number in ovarian cancer: associations with clinical outcome following platinum monotherapy, Molecular Cancer Research, Vol: 16, Pages: 1103-1111, ISSN: 1541-7786
The current study evaluated three biomarkers [homologous recombination deficiency (HRD), tumor BRCA1/2 (tBRCA) mutations, and CCNE1 copy number variation (CNV)] in ovarian tumors from patients enrolled on the SCOTROC4 clinical trial for associations with outcome following carboplatinum monotherapy. Ovarian tumors (n=250), with high-grade serous (HGSOC) subgroup analysis (n=179), were classified as HRD positive (HRD score ≥42 or tBRCA mutation) and as CCNE1 amplification positive (CCNE1 CNV score >2.4). Seventy-four (30%) tumors were HRD positive, including 34 (14%) with tBRCA mutations. Forty-seven (19%) were CCNE1 amplification positive, all of which were tBRCA wild-type. HRD and tBRCA, but not CCNE1 amplification, were significantly associated with CA125 complete response in the entire cohort (HRD, p=0.00015; tBRCA p=0.0096), and the HGSOC subgroup (HRD, p= 0.0016; tBRCA p=0.032). HRD and lack of CCNE1 amplification were associated with improved progression free survival (PFS) and overall survival (OS) in the full cohort and HGSOC subgroup (HRD, p=0.00021; CCNE1 status p=0.038). HRD remained significant for OS and PFS after adjusting for clinical factors, while CCNE1 status only remained significant for PFS. Patients with HRD positive tumors had greater PFS and OS benefit from platinum dose intensification than HRD negative tumors (p=0.049 and p=0.035, respectively). An alternative exploratory HRD score threshold (≥33 or tBRCA mutation) was also significantly associated with both PFS and OS in the HGSOC subset. IMPLICATIONS: HRD, tumor BRCA1/2 mutations and absence of CCNE1 amplification are associated with improved survival of ovarian cancer patients treated with platinum monotherapy and HRD positive patients may benefit from platinum dose intensification.
Phelps DL, Balog J, Gildea LF, et al., 2018, The surgical intelligent knife distinguishes normal, borderline and malignant gynaecological tissues using rapid evaporative ionisation mass spectrometry (REIMS), British Journal of Cancer, Vol: 118, Pages: 1349-1358, ISSN: 0007-0920
BackgroundSurvival from ovarian cancer (OC) is improved with surgery, but surgery can be complex and tumour identification, especially for borderline ovarian tumours (BOT), is challenging. The Rapid Evaporative Ionisation Mass Spectrometric (REIMS) technique reports tissue histology in real-time by analysing aerosolised tissue during electrosurgical dissection.MethodsAerosol produced during diathermy of tissues was sampled with the REIMS interface. Histological diagnosis and mass spectra featuring complex lipid species populated a reference database on which principal component, linear discriminant and leave-one-patient-out cross-validation analyses were performed.ResultsA total of 198 patients provided 335 tissue samples, yielding 3384 spectra. Cross-validated OC classification vs separate normal tissues was high (97·4% sensitivity, 100% specificity). BOT were readily distinguishable from OC (sensitivity 90.5%, specificity 89.7%). Validation with fresh tissue lead to excellent OC detection (100% accuracy). Histological agreement between iKnife and histopathologist was very good (kappa 0.84, P < 0.001, z = 3.3). Five predominantly phosphatidic acid (PA(36:2)) and phosphatidyl-ethanolamine (PE(34:2)) lipid species were identified as being significantly more abundant in OC compared to normal tissue or BOT (P < 0.001, q < 0.001).ConclusionsThe REIMS iKnife distinguishes gynaecological tissues by analysing mass-spectrometry-derived lipidomes from tissue diathermy aerosols. Rapid intra-operative gynaecological tissue diagnosis may improve surgical care when histology is unknown, leading to personalised operations tailored to the individual.
Moulla A, Magdy N, El-Bahrawy M, 2017, Ovarian leiomyoma with myxoid stroma, Pathologica, Vol: 109, Pages: 389-391, ISSN: 0031-2983
Ovarian smooth muscle tumours are rare. Notable myxoid change in smooth muscle tumours is uncommon, and raises diagnostic issues that need to be considered on evaluating a spindle cell lesion with notable myxoid change. There is only one case of myxoid leiomyoma of the ovary previously reported. We here report a case of ovarian leiomyoma with areas of myxoid stroma and discuss the relevant differential diagnosis and histological features to be assessed in such a lesion.
Jones BP, Saso S, Farren J, et al., 2017, Ultrasound-Guided Laparoscopic Ovarian Wedge Resection in Recurrent Serous Borderline Ovarian Tumours, INTERNATIONAL JOURNAL OF GYNECOLOGICAL CANCER, Vol: 27, Pages: 1813-1818, ISSN: 1048-891X
Zanini E, Louis LS, Antony J, et al., 2017, The tumor suppressor protein OPCML potentiates anti-EGFR and anti-HER2 targeted therapy in HER2-positive ovarian and breast cancer., Molecular Cancer Therapeutics, Vol: 16, Pages: 2246-2256, ISSN: 1535-7163
OPCML is a tumor suppressor gene that is frequently inactivated in ovarian cancer and many other cancers by somatic methylation. We have previously shown that OPCML exerts its suppressor function by negatively regulating a spectrum of receptor tyrosine kinases (RTKs), such as ErbB2/HER2, FGFR1 and EphA2, thus attenuating their related downstream signaling. The physical interaction of OPCML with this defined group of RTKs is a prerequisite for their downregulation. Overexpression/gene amplification of EGFR and HER2 is a frequent event in multiple cancers including ovarian and breast cancers. Molecular therapeutics against EGFR/HER2 or EGFR only, such as lapatinib and erlotinib respectively, were developed to target these receptors but resistance often occurs in relapsing cancers. Here we show that, though OPCML interacts only with HER2 and not with EGFR, the interaction of OPCML with HER2 disrupts the formation of the HER2-EGFR heterodimer and this translates into a better response to both lapatinib and erlotinib in HER2-expressing ovarian and breast cancer cell lines. Also, we show that high OPCML expression is associated with better response to lapatinib therapy in breast cancer patients and better survival in HER2-overexpressing ovarian cancer patients, suggesting that OPCML co-therapy could be a valuable sensitizing approach to RTK inhibitors.
Westaby JD, Magdy N, Fisher C, et al., 2017, Primary ovarian malignant PEComa: a case report, International Journal of Gynecological Pathology, Vol: 36, Pages: 400-404, ISSN: 0277-1691
Perivascular epithelioid cell tumor (PEComa) is a rare mesenchymal neoplasm characterized by expression of both melanocytic and smooth muscle markers. PEComas are rarely encountered in the female genital tract. We report a case of malignant primary PEComa of the ovary, and discuss the differential diagnosis. This represents the first case of primary typical malignant PEComa of the ovary.
El-Masry ANS, El-Bahrawy MA, 2017, The impact of extensive cytoreductive surgery for ovarian cancer on thehistopathology laboratory workload, Journal of Cytology & Histology, Vol: 8, ISSN: 2157-7099
Objectives: Cytoreductive surgery is the principal management for ovarian cancer. Recently there has been progressive change to more extensive cytoreductive surgery (ECS) as evidence shows this improves patient prognosis. The aim of this study is to investigate the change in histopathology work load with change in surgical practice for the treatment of ovarian cancer patients at Hammersmith Hospital, UK.Materials and methods: Specimens for patients with ovarian cancer (n=116) were selected and classified into three groups: (i) standard debulking surgery; (ii) a mix of standard debulking and ECS and (iii) ECS only. The types of specimens and numbers of blocks in each group were studied.Results: Post-hoc analysis demonstrates a statistically significant increase in the number of specimens per case from standard debulking to the mixed group (p<0.0001) and to the ECS group (p<0.0001). There is also a statistically significant increase in the number of blocks from standard debulking to the mixed (p<0.0001) and to the ECS groups (p<0.0001).Conclusion: The study shows there is a significant increase in the histopathology workload with the shift from standard to extensive cytoreductive surgery, as well as increase in the complexity and range of specimens sent for histopathological examination. It is essential that centres opting for a shift to ECS ensure that adequate provisions and resources are in place to accommodate these changes.
Olusoji MJ, Van Noorden S, Magdy N, et al., 2017, Expression of Mel-CAM and HSD3B1 in Cervical Carcinoma, 207th Winter Meeting of the Pathological-Society-of-Great-Britain-and-Ireland, Publisher: Wiley, Pages: S5-S5, ISSN: 0022-3417
Hartwig T, Montinaro A, von Karstedt S, et al., 2017, The TRAIL-Induced Cancer Secretome Promotes a Tumor-Supportive Immune Microenvironment via CCR2, Molecular Cell, Vol: 65, Pages: 730-742.e5, ISSN: 1097-2765
Tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) is known for specifically killing cancer cells, whereas in resistant cancers, TRAIL/TRAIL-R can promote metastasis via Rac1 and PI3K. It remains unknown, however, whether and to what extent TRAIL/TRAIL-R signaling in cancer cells can affect the immune microenvironment. Here we show that TRAIL-triggered cytokine secretion from TRAIL-resistant cancer cells is FADD dependent and identify the TRAIL-induced secretome to drive monocyte polarization to myeloid-derived suppressor cells (MDSCs) and M2-like macrophages. TRAIL-R suppression in tumor cells impaired CCL2 production and diminished both lung MDSC presence and tumor growth. In accordance, the receptor of CCL2, CCR2, is required to facilitate increased MDSC presence and tumor growth. Finally, TRAIL and CCL2 are co-regulated with MDSC/M2 markers in lung adenocarcinoma patients. Collectively, endogenous TRAIL/TRAIL-R-mediated CCL2 secretion promotes accumulation of tumor-supportive immune cells in the cancer microenvironment, thereby revealing a tumor-supportive immune-modulatory role of the TRAIL/TRAIL-R system in cancer biology.
Magdy N, Lee D, Masood M, et al., 2017, The expression of prolactin receptor and its ligands in ovarian epithelial tumours, ECCO European Cancer Congress, Publisher: Elsevier, Pages: S89-S89, ISSN: 0959-8049
Rzepecka IK, Szafron LM, Stys A, et al., 2016, Prognosis of patients with BRCA1-associated ovarian carcinomas depends on TP53 accumulation status in tumor cells., Gynecologic Oncology, Vol: 144, Pages: 369-376, ISSN: 0090-8258
ObjectiveTP53 mutation is the most frequent molecular event in BRCA1-associated ovarian carcinomas. TP53 status may be a confounding factor in the evaluation of clinical importance of other proteins. We aimed to evaluate the clinical significance of BRCA1 mutations with respect to the TP53 accumulation status in 159 high-grade ovarian carcinomas.MethodsStatistical analyses were done with the Kaplan-Meier method, log-rank test, the Cox's and logistic regression models for all patients, and in subgroups with and without TP53 accumulation (TP53 + and TP53 −, respectively).ResultsForty of 159 ovarian carcinomas (25.2%) were diagnosed in patients with BRCA1 germline mutations; 102 tumors (64.2%) were TP53 + and 57 (37.8%) were TP53 −. Among patients with TP53 + carcinomas, BRCA1 carriers had increased odds of recurrence compared with sporadic cases (HR 2.25, P = 0.003; median disease-free survival time 7.7 vs. 18.4 months, respectively). In the smaller TP53 − subgroup, BRCA1 mutation reduced the risk of death by 46% (HR 0.54, P = 0.099, median overall survival time 42.7 vs. 28.1 months), but beyond the border of significance. When the TP53 status was not taken into account, BRCA1 mutations did not show any significance, however, there was a trend toward increased odds of complete remission for women with BRCA1 mutations compared to non-carriers (OR 2.47, P = 0.064). Taxane-platinum therapy showed advantage over the platinum-cyclophosphamide one in the entire group of patients and in the TP53 + subgroup.ConclusionsOur results suggest that the TP53 accumulation status determines the prognosis of BRCA1 mutation carriers with high-grade ovarian carcinomas.
Jones BP, Saso S, Farren J, et al., 2016, Intraoperative ultrasound-guided laparoscopic ovarian-tissue-preserving surgery for recurrent borderline ovarian tumor., Ultrasound in Obstetrics and Gynecology, Vol: 50, Pages: 405-406, ISSN: 0960-7692
Wang J, Trivedi P, El-Bahrawy M, 2016, Positivity rate of TTF-1 on immunohistochemistry in pancreatic neuroendocrine tumors, Pathology International, Vol: 66, Pages: 708-709, ISSN: 1320-5463
Phelps DL, Balog J, El-Bahrawy M, et al., 2016, Diagnosis of borderline ovarian tumours by rapid evaporative ionisation mass spectrometry (REIMS) using the surgical intelligent knife (iKnife), Royal College of Obstetricians and Gynaecologists - Blair Bell Academic Meeting, Publisher: Wiley, Pages: e4-e4
Konopka B, Szafron LM, Kwiatkowska E, et al., 2016, The significance of c.690G>T polymorphism (rs34529039) and expression of the CEBPA gene in ovarian cancer outcome, Oncotarget, Vol: 7, Pages: 67412-67424, ISSN: 1949-2553
The CEBPA gene is known to be mutated or abnormally expressed in several cancers. This is the first study assessing the clinical impact of CEBPA gene status and expression on the ovarian cancer outcome. The CEBPA gene sequence was analyzed in 118 ovarian cancer patients (44 platinum/cyclophosphamide (PC)-treated and 74 taxane/platinum (TP)-treated), both in tumors and blood samples, and in blood from 236 healthy women, using PCR-Sanger sequencing and Real-Time quantitative PCR (qPCR)-based genotyping methods, respectively. The CEBPA mRNA level was examined with Reverse Transcription quantitative PCR (RT-qPCR). The results were correlated to different clinicopathological parameters. Thirty of 118 (25.4%) tumors harbored the CEBPA synonymous c.690G>T polymorphism (rs34529039), that we showed to be related to up-regulation of CEBPA mRNA levels (p=0.0059). The presence of the polymorphism was significantly associated with poor prognosis (p=0.005) and poor response to the PC chemotherapy regimen (p=0.024). In accordance, elevated CEBPA mRNA levels negatively affected patient survival (p<0.001) and tumor response to the PC therapy (p=0.014). The rs34529039 SNP did not affect the risk of developing ovarian cancer. This is the first study providing evidence that the c.690G>T, p.(Thr230Thr) (rs34529039) polymorphism of the CEBPA gene, together with up-regulation of its mRNA expression, are negative factors worsening ovarian cancer outcome. Their adverse clinical effect depends on a therapeutic regimen used, which might make them potential prognostic and predictive biomarkers for response to DNA-damaging chemotherapy.
Abdulgawad N, Masood M, van Noorden S, et al., 2016, The expression of prolactin and prolactin receptors in ovarian epithelial tumours, Publisher: SPRINGER, Pages: S100-S100, ISSN: 0945-6317
Abdulgawad N, Masood M, van Noorden S, et al., 2016, The expression of prolactin and prolactin receptors in ovarian epithelial tumours, XXXI International Congress of the IAP and 28th Congress of the ESP, Publisher: Springer Verlag, Pages: S100-S100, ISSN: 0945-6317
Moulla AA, Magdy N, Francis N, et al., 2016, Rare Skin Adnexal and Melanocytic Tumors Arising in Ovarian Mature Cystic Teratomas: A Report of 3 Cases and Review of the Literature, INTERNATIONAL JOURNAL OF GYNECOLOGICAL PATHOLOGY, Vol: 35, Pages: 448-455, ISSN: 0277-1691
Mature teratoma of the ovary is the most common primary ovarian tumor accounting for 15% (10%–20%) of all ovarian neoplasms. Skin and skin adnexal structures are the most common elements identified in mature teratomas. Benign and malignant skin tumors can arise in ovarian teratomas, the most common being epithelial tumors. Melanocytic and adnexal tumors developing in a teratoma are rare and can be easily overlooked. We report 3 cases and review melanocytic and skin adnexal tumors encountered in ovarian teratomas.
Stavrinou S, Clark A, Irving J, et al., 2016, Differential expression of E-cadherin and catenins in ovarian sex cord stromal tumours, Histopathology, Vol: 69, Pages: 298-306, ISSN: 0309-0167
AimsSex cord stromal tumours (SCSTs) of the ovary encompass several histological tumour subtypes that are defined by characteristic histological features. Some can show morphological overlap with other subtypes of SCSTs, as well as with non-SCSTs. The E-cadherin/catenin complex constitutes the adherens junction, which is well developed in epithelial tissue, but the constituent molecules are also expressed in several non-epithelial tumours. The aim of this study was to determine whether the expression patterns of E-cadherin and catenins in ovarian SCSTs can be of diagnostic utility.Methods and resultsWe studied the expression of E-cadherin, α-, β- and γ-catenin in 55 tumours using immunohistochemistry. We found that all tumour subtypes showed nuclear expression of E-cadherin, while only microcystic stromal tumours (MCSTs) displayed a distinct profile, with nuclear localization of all three catenins in almost all cases.ConclusionsWe conclude that the E-cadherin expression profile in SCSTs can assist in distinguishing between SCSTs and non-SCSTs in which there is no nuclear expression of E-cadherin. The nuclear localization of catenins may be of potential use in distinguishing MCST from other subtypes of SCST.
Alzoubi S, Brody L, Rahman S, et al., 2016, Synergy between histone deacetylase inhibitors and DNA-damaging agents is mediated by histone deacetylase 2 in colorectal cancer, Oncotarget, Vol: 7, Pages: 44505-44521, ISSN: 1949-2553
Previous studies have associated the overexpression of histone deacetylase 2 (HDAC2) and the presence of TP53 mutations with the progression to advanced stage drug resistant colorectal cancer (CRC). However, the mechanistic link between HDAC2 expression and the TP53 mutational status has remained unexplored. Here, we investigated the function of HDAC2 in drug resistance by assessing the synergistic effects of DNA-targeted chemotherapeutic agents and HDAC inhibitors (HDACis) on two TP53-mutated colorectal adenocarcinoma CRC cell lines (SW480 and HT-29) and on the TP53-wild type carcinoma cell line (HCT116 p53+/+) and its TP53 deficient sub-line (HCT116 p53-/-). We showed that in the untreated SW480 and HT-29 cells the steady-state level of HDAC2 was low compared to a TP53-wild type carcinoma cell line (HCT116 p53+/+). Increased expression of HDAC2 correlated with drug resistance, and depletion by shRNA sensitised the multi-drug resistance cell line HT-29 to CRC chemotherapeutic drugs such as 5-fluorouracil (5-FU) and oxaliplatin (Oxa). Combined treatment with the HDACi suberoylanilide hydroxamic acid plus 5-FU or Oxa reduced the level of HDAC2 expression, modified chromatin structure and induced mitotic cell death in HT-29 cells. Non-invasive bioluminescence imaging revealed significant reductions in xenograft tumour growth with HDAC2 expression level reduced to <50% in treated animals. Elevated levels of histone acetylation on residues H3K9, H4K12 and H4K16 were also found to be associated with resistance to VPA/Dox or SAHA/Dox treatment. Our results suggest that HDAC2 expression rather than the p53 mutation status influences the outcome of combined treatment with a HDACi and DNA-damaging agents in CRC.
Hopkins TG, Blagden S, Mura M, et al., 2016, The RNA-binding protein LARP1 is a post-transcriptional regulator of survival and tumorigenesis in ovarian cancer, Nucleic Acids Research, Vol: 44, Pages: 1227-1246, ISSN: 1362-4962
RNA-binding proteins (RBPs) are increasingly identifiedas post-transcriptional drivers of cancer progression.The RBP LARP1 is an mRNA stability regulator,and elevated expression of the protein in hepatocellularand lung cancers is correlated with adverseprognosis. LARP1 associates with an mRNA interactomethat is enriched for oncogenic transcripts.Here we explore the role of LARP1 in epithelial ovariancancer, a disease characterized by the rapid acquisitionof resistance to chemotherapy through theinduction of pro-survival signalling. We show, usingovarian cell lines and xenografts, that LARP1 is requiredfor cancer cell survival and chemotherapy resistance.LARP1 promotes tumour formation in vivoand maintains cancer stem cell-like populations. Usingtranscriptomic analysis following LARP1 knockdown,cross-referenced against the LARP1 interactome,we identify BCL2 and BIK as LARP1 mRNAtargets. We demonstrate that, through an interactionwith the 3 untranslated regions (3 UTRs) of BCL2and BIK, LARP1 stabilizes BCL2 but destabilizes BIKwith the net effect of resisting apoptosis. Together,our data indicate that by differentially regulating thestability of a selection of mRNAs, LARP1 promotesovarian cancer progression and chemotherapy resistance.
Showeil R, Romano C, Valganon M, et al., 2016, The status of epidermal growth factor receptor in borderline ovarian tumours, Oncotarget, Vol: 7, Pages: 10568-10577, ISSN: 1949-2553
Flower KJ, Shenker NS, el-Bahrawy M, et al., 2016, DNA methylation profiling to assess pathogenicity of BRCA1 unclassified variants in breast cancer, Epigenetics, Vol: 10, Pages: 1121-1132, ISSN: 1559-2308
Germline pathogenic mutations in BRCA1 increase risk of developing breast cancer. Screening for mutations in BRCA1 frequently identifies sequence variants of unknown pathogenicity and recent work has aimed to develop methods for determining pathogenicity. We previously observed that tumor DNA methylation can differentiate BRCA1-mutated from BRCA1-wild type tumors. We hypothesized that we could predict pathogenicity of variants based on DNA methylation profiles of tumors that had arisen in carriers of unclassified variants. We selected 150 FFPE breast tumor DNA samples [47 BRCA1 pathogenic mutation carriers, 65 BRCAx (BRCA1-wild type), 38 BRCA1 test variants] and analyzed a subset (n=54) using the Illumina 450K methylation platform, using the remaining samples for bisulphite pyrosequencing validation. Three validated markers (BACH2, C8orf31, and LOC654342) were combined with sequence bioinformatics in a model to predict pathogenicity of 27 variants (independent test set). Predictions were compared with standard multifactorial likelihood analysis. Prediction was consistent for c.5194-12G>A (IVS 19-12 G>A) (P>0.99); 13 variants were considered not pathogenic or likely not pathogenic using both approaches. We conclude that tumor DNA methylation data alone has potential to be used in prediction of BRCA1 variant pathogenicity but is not independent of estrogen receptor status and grade, which are used in current multifactorial models to predict pathogenicity.
Kyriakides M, Rama N, Sidhu J, et al., 2016, Metabonomic analysis of ovarian tumour cyst fluid by proton nuclear magnetic resonance spectroscopy, Oncotarget, Vol: 7, Pages: 7216-7226, ISSN: 1949-2553
The majority of ovarian tumours are of the epithelial type, which can be sub classified as benign, borderline or malignant. Epithelial tumours usually have cystic spaces filled with cyst fluid, the metabolic profile of which reflects the metabolic activity of the tumour cells, due to their close proximity. The approach of metabonomics using 1H-NMR spectroscopy was employed to characterize the metabolic profiles of ovarian cyst fluid samples (n = 23) from benign, borderline and malignant ovarian tumours in order to shed more light into ovarian tumour and cancer development. The analysis revealed that citrate was elevated in benign versus malignant tumours, while the amino acid lysine was elevated in malignant versus non-malignant tumours, both at a 5% significance level. Choline and lactate also had progressively increasing levels from benign to borderline to malignant samples. Finally, hypoxanthine was detected exclusively in a sub-cohort of the malignant tumours. This metabonomic study demonstrates that ovarian cyst fluid samples have potential to be used to distinguish between the different types of ovarian epithelial tumours. Furthermore, the respective metabolic profiles contain mechanistic information which could help identify biomarkers and therapeutic targets for ovarian tumours.
Gungor H, Saleem A, Babar S, et al., 2015, Dose-finding quantitative F-18-FDG PET imaging study with the oral pan-AKT inhibitor GSK2141795 in patients with gynecologic malignancies, Journal of Nuclear Medicine, Vol: 56, Pages: 1828-1835, ISSN: 1535-5667
AKT (a serine/threonine-specific protein kinase) regulates many cellular processes contributing to cytotoxic drug resistance. This study’s primary objective examined the relationship between GSK2141795, an oral, pan-AKT inhibitor, and 18F-FDG PET markers of glucose metabolism in tumor tissue to determine whether 18F-FDG PET could be used to guide personalized dosing of GSK2141795. Biomarker analysis of biopsies was also undertaken. Methods: Twelve patients were enrolled in 3 cohorts; all underwent dynamic 18F-FDG PET scans and serial pharmacokinetic sampling at baseline, week 2, and week 4 with tumor biopsies before treatment and at week 4. Response was evaluated by RECIST v1.1 and Gynecologic Cancer Intergroup criteria. Biopsy samples were analyzed for mutations and protein expression. Results: GSK2141795 did not significantly influence blood glucose levels. No dose–response relationship was observed between GSK2141795 pharmacokinetics and 18F-FDG PET pharmacodynamic measures; however, an exposure–response relationship was seen between maximum drug concentrations and maximal decrease in 18F-FDG uptake in the best-responding tumor. This relationship also held for pharmacokinetic parameters of exposure and 1,5-anhydroglucitol (a systemic measure of glucose metabolism). Phospho-AKT upregulation at week 4 in biopsies confirmed AKT inhibition by GSK2141795. Single-agent activity was observed with a clinical benefit rate of 27% (3/11) and 30% (3/10) CA125 response in the study’s platinum-resistant ovarian patients. AKT pathway activation by PIK3CA/PIK3R1 mutation did not correlate with clinical activity, whereas RAS/RAF pathway mutations did segregate with resistance to AKT inhibition. Conclusion: GSK2141795 demonstrated an exposure–response relationship with decreased 18F-FDG uptake and is active and tolerable. This study’s design integrating 18F-FDG PET, pharmacokinetics, and biomarker analyses demonstrates the potential for clinical
Shenker NS, Flower KJ, Wilhelm-Benartzi C, et al., 2015, Transcriptional implications of intragenic DNA methylation in the estrogen receptor alpha gene in breast cancer cells and tissues, 106th Annual Meeting of the American-Association-for-Cancer-Research (AACR), Publisher: American Association for Cancer Research, ISSN: 1538-7445
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