The immunopeptidomic landscape of ovarian carcinomas Schuster, Heiko; Peper, Janet K.; Bösmüller, Hans-Christian ...
Proceedings of the National Academy of Sciences - PNAS,
11/2017, Letnik:
114, Številka:
46
Journal Article
Recenzirano
Odprti dostop
Immunotherapies, particularly checkpoint inhibitors, have set off a revolution in cancer therapy by releasing the power of the immune system. However, only little is known about the antigens that are ...essentially presented on cancer cells, capable of exposing them to immune cells. Large-scale HLA ligandome analysis has enabled us to exhaustively characterize the immunopeptidomic landscape of epithelial ovarian cancers (EOCs). Additional comparative profiling with the immunopeptidome of a variety of benign sources has unveiled a multitude of ovarian cancer antigens (MUC16, MSLN, LGALS1, IDO1, KLK10) to be presented by HLA class I and class II molecules exclusively on ovarian cancer cells. Most strikingly, ligands derived from mucin 16 and mesothelin, a molecular axis of prognostic importance in EOC, are prominent in a majority of patients. Differential gene-expression analysis has allowed us to confirm the relevance of these targets for EOC and further provided important insights into the relationship between gene transcript levels and HLA ligand presentation.
The SRY-related HMG-box family of transcription factors member SOX2 has been mainly studied in embryonic stem cells as well as early foregut and neural development. More recently, SOX2 was shown to ...participate in reprogramming of adult somatic cells to a pluripotent stem cell state and implicated in tumorigenesis in various organs. In breast cancer, SOX2 expression was reported as a feature of basal-like tumors. In this study, we assessed SOX2 expression in 95 primary tumors of postmenopausal breast cancer patients.
Samples from 95 patients diagnosed and treated at the University of Tuebingen Institute of Pathology and Women's Hospital were analyzed by immunohistochemistry for SOX2 expression in the primary tumor samples and in corresponding lymph node metastasis, where present. Furthermore, SOX2 amplification status was assessed by FISH in representative samples. In addition, eighteen fresh frozen samples were analyzed for SOX2, NANOG and OCT4 gene expression by real-time PCR.
SOX2 expression was detected in 28% of invasive breast carcinoma as well as in 44% of ductal carcinoma in situ (DCIS) lesions. A score of SOX2 expression (score 0 to 3) was defined in order to distinguish SOX2 negative (score 0) from SOX2 positive samples (score 1-3) and among latter the subgroup of SOX2 high expressors (score 3 > 50% positive cells). Overall, the incidence of SOX2 expression (score 1-3) was higher than previously reported in a cohort of lymph node negative patients (28% versus 16.7%). SOX2 expression was detected across different breast cancer subtypes and did not correlate with tumor grading. However, high SOX2 expression (score 3) was associated with larger tumor size (p = 0.047) and positive lymph node status (0.018). Corresponding metastatic lymph nodes showed higher SOX2 expression and were significantly more often SOX2 positive than primary tumors (p = 0.0432).
In this report, we show that the embryonic stem cell factor SOX2 is expressed in a variety of early stage postmenopausal breast carcinomas and metastatic lymph nodes. Our data suggest that SOX2 plays an early role in breast carcinogenesis and high expression may promote metastatic potential. Further studies are needed to explore whether SOX2 can predict metastatic potential at an early tumor stage.
Many women with ovarian endometrioid carcinoma present with concurrent endometrial carcinoma. Organ-confined and low-grade synchronous endometrial and ovarian tumors (SEOs) clinically behave as ...independent primary tumors rather than a single advanced-stage carcinoma. We used 18 SEOs to investigate the ancestral relationship between the endometrial and ovarian components. Based on both targeted and exome sequencing, 17 of 18 patient cases of simultaneous cancer of the endometrium and ovary from our series showed evidence of a clonal relationship, ie, primary tumor and metastasis. Eleven patient cases fulfilled clinicopathological criteria that would lead to classification as independent endometrial and ovarian primary carcinomas, including being of FIGO stage T1a/1A, with organ-restricted growth and without surface involvement; 10 of 11 of these cases showed evidence of clonality. Our observations suggest that the disseminating cells amongst SEOs are restricted to physically accessible and microenvironment-compatible sites yet remain indolent, without the capacity for further dissemination.
The proper communication between gut and brain is pivotal for the maintenance of health and, dysregulation of the gut-brain axis can lead to several clinical disorders. In Parkinson's disease (PD) ...85% of all patients experienced constipation many years before showing any signs of motor phenotypes. For differential diagnosis and preventive treatment, there is an urgent need for the identification of biomarkers indicating early disease stages long before the disease phenotype manifests. DJ-1 is a chaperone protein involved in the protection against PD and genetic mutations in this protein have been shown to cause familial PD. However, how the deficiency of DJ-1 influences the risk of PD remains incompletely understood. In the present study, we provide evidence that DJ-1 is implicated in shaping the gut microbiome including; their metabolite production, inflammation and innate immune cells (ILCs) development. We revealed that deficiency of DJ-1 leads to a significant increase in two specific genera/species, namely Alistipes and Rikenella. In DJ-1 knock-out (DJ-1
) mice the production of fecal calprotectin and MCP-1 inflammatory proteins were elevated. Fecal and serum metabolic profile showed that malonate which influences the immune system was significantly more abundant in DJ-1
mice. DJ-1 appeared also to be involved in ILCs development. Further, inflammatory genes related to PD were augmented in the midbrain of DJ-1
mice. Our data suggest that metabolites and inflammation produced in the gut could be used as biomarkers for PD detection. Perhaps, these metabolites and inflammatory mediators could be involved in triggering inflammation resulting in PD pathology.
One of the basic prerequisites for generating evidence-based data is the availability of classification systems. Attempts to date to classify breast cancer operations have focussed on specific ...problems, e.g. the avoidance of secondary corrective surgery for surgical defects, rather than taking a generic approach.
Starting from an existing, simpler empirical scheme based on the complexity of breast surgical procedures, which was used in-house primarily in operative report-writing, a novel classification of ablative and breast-conserving procedures initially needed to be developed and elaborated systematically. To obtain proof of principle, a prospectively planned analysis of patient records for all major breast cancer-related operations performed at our breast centre in 2005 and 2006 was conducted using the new classification. Data were analysed using basic descriptive statistics such as frequency tables.
A novel two-type, six-tier classification system comprising 12 main categories, 13 subcategories and 39 sub-subcategories of oncological, oncoplastic and reconstructive breast cancer-related surgery was successfully developed. Our system permitted unequivocal classification, without exception, of all 1225 procedures performed in 1166 breast cancer patients in 2005 and 2006.
Breast cancer-related surgical procedures can be generically classified according to their surgical complexity. Analysis of all major procedures performed at our breast centre during the study period provides proof of principle for this novel classification system. We envisage various applications for this classification, including uses in randomised clinical trials, guideline development, specialist surgical training, continuing professional development as well as quality of care and public health research.
The role of circulating tumor cells (CTCs) in blood of primary breast cancer patients is still under investigation. We evaluated the incidence of CTCs in blood, we evaluated the correlation between ...CTCs and disseminated tumor cells (DTCs) in the bone marrow (BM), and we characterized CTCs for the expression of HER2, the estrogen receptor (ER) and the progesterone receptor (PR).
Blood of 431 patients with primary breast cancer were analyzed for EpCAM, MUC1 and HER2 transcripts with the AdnaTest BreastCancer (AdnaGen AG, Germany). Expression of the ER and PR was assessed in an additional RT-PCR. BM aspirates from 414 patients were analyzed for DTCs by immunocytochemistry using the pan-cytokeratin antibody A45-B/B3.
DTCs were found in 107/414 patients (24%), CTCs were detected in 58/431 (13%) patients. DTCs were associated with PR status of the primary tumor (P = 0.04) and CTCs significantly correlated with nodal status (P = 0.04), ER (P = 0.05), and PR (P = 0.01). DTCs in the BM weakly correlated with CTCs (P = 0.05) in blood. Interestingly, the spread of CTCs was mostly found in triple-negative tumors (P = 0.01) and CTCs in general were mostly found to be triple-negative regardless of the ER, PR and HER2 status of the primary tumor.
(1) Due to the weak concordance between CTCs and DTCs the clinical relevance may be different. (2) The biology of the primary tumor seems to direct the spread of CTCs. (3) Since the expression profile between CTCs and the primary tumor differs, the consequence for the selection of adjuvant treatment has to be evaluated.
Treatment with CDK4/6 inhibitors and endocrine therapy (CDK4/6i + ET) is a standard for patients with advanced hormone receptor–positive, HER2-negative (HR + HER2–) breast cancer (BC). However, ...real-world data on the implementation of therapy usage, efficacy, and toxicity have not yet been reported.
The PRAEGNANT registry was used to identify advanced HR + HER2– BC patients (n = 1136). The use of chemotherapy, ET, everolimus + ET, and CDK4/6i + ET was analyzed for first-line, second-line, and third-line therapy. Progression-free survival (PFS) and overall survival (OS) were also compared between patients treated with CDK4/6i + ET and ET monotherapy. Also toxicity was assessed.
CDK4/6i + ET use increased from 38.5% to 62.7% in the first 2 years after CDK4/6i treatment became available (November 2016). Chemotherapy and ET monotherapy use decreased from 2015 to 2018 from 42.2% to 27.2% and from 53% to 9.5%, respectively. In this early analysis no statistically significant differences were found comparing CDK4/6i + ET and ET monotherapy patients with regard to PFS and OS. Leukopenia was was seen in 11.3% of patients under CDK4/6i + ET and 0.5% under ET monotherapy.
In clinical practice, CDK4/6i + ET has been rapidly implemented. A group of patients with a more unfavorable prognosis was possibly treated in the real-world setting than in the reported randomized clinical trials. The available data suggest that longer follow-up times and a larger sample size are required in order to identify differences in survival outcomes. Studies should be supported that investigate whether chemotherapy can be avoided or delayed in this patient population by using CDK4/6i + ET.
•CDK4/6i + ET use increased from 39% to 63% after becoming available.•Chemotherapy and ET monotherapy use decreased from 42% to 27% and 53%–10%.•There was no difference between CDK4/6i + ET and ET monotherapy regarding PFS and OS.
Scope
Urolithin A (UA) is a gut‐derived bacterial metabolite from ellagic acid found in pomegranates, berries, and nuts can downregulate cell proliferation and migration. Cell proliferation and cell ...motility require actin reorganization, which is under control of ras‐related C3 botulinum toxin substrate 1 (Rac1) and p21 protein‐activated kinase 1 (PAK1). The present study explores whether UA can modify actin cytoskeleton in cancer cells.
Methods
The effect of UA on globular over filamentous actin ratio is determined utilizing Western blotting, immunofluorescence, and flow cytometry. Rac1 and PAK1 levels are measured by quantitative RT‐PCR and immunoblotting. As a result, a 24 h treatment with UA (20 µm) significantly decreased Rac1 and PAK1 transcript levels and activity, depolymerized actin and wound healing. The effect of UA on actin polymerization is mimicked by pharmacological inhibition of Rac1 and PAK1. The effect is also mirrored by knock down using siRNA.
Conclusion
UA leads to disruption of Rac1 and Pak1 activity with subsequent actin depolymerization and migration. Thus, use of dietary UA in cancer prevention or as adjuvant therapy is promising.
Ellagic acid, from red berries or fruits, is metabolized in the intestine to produce urolithins. It is shown specifically that Urolithin A reduces the Rac1 and PAK1 activity that leads to a decrease in actin polymerization, thus leading to reduced cell migration in human endometrial carcinoma cells.
Patients with estrogen receptor- and/or progesterone receptor-positive, early breast cancer benefit from hormonal treatment, yet high global death burdens due to high prevalence and long-term ...recurrence risk call for biomarkers to guide additional treatment approaches.
From a prospective, observational study of postmenopausal early breast cancer patients treated with tamoxifen or aromatase inhibitors, gene expression analyses of 612 tumors was performed using the NanoString Breast Cancer 360 panel to interrogate 23 breast cancer pathways. Candidate signatures associated with disease subtype and event-free survival (EFS) were obtained by cluster analysis, Cox modeling, and conditional inference trees, and were independently tested in 613 patients from BreastMark. Tumor-infiltrating lymphocytes (TIL) were assessed on tissue sections, and mutational burden was assessed in 36 tumors by whole-exome sequencing.
PAM50-derived classification distinguished lower-risk (Luminal A) from higher-risk subtypes (Luminal B,
= 0.04; HER2,
= 0.006; Basal,
= 0.008). In higher-risk patients, shorter EFS was associated with low androgen receptor HR = 3.61; 95% confidence interval (CI), 1.72-7.56;
= 0.001 or high BRCAness signature expression (HR = 3.58; 95% CI, 1.19-10.7;
= 0.023). BRCAness was independently confirmed as a predictor of shorter EFS (HR = 2.64; 95% CI, 1.31-5.34;
= 0.007). About 13%-15% of patients, enriched for high-grade, higher-risk subtypes (
≤ 0.0001), had strong expression of the Tumor Inflammation Signature (TIS) suggestive of an inhibited antitumor immune response. TIS scores were strongly associated with TIL numbers (
< 1e-30) but not with tumor mutation status.
BRCA-related DNA repair deficiency and suppressed tumor immune responses may be clinically relevant predictors of endocrine therapy complementing treatment options in subgroups of hormone-sensitive early breast cancer.
Breast cancer is the leading cause of cancer-related mortality among women in Germany and worldwide. This retrospective claims data analysis utilizing data from AOK Baden-Wuerttemberg, a major ...statutory German health insurance provider, aimed to construct and assess a real-world data breast cancer disease model. The study included 27,869 female breast cancer patients and 55,738 age-matched controls, analyzing data from 2010 to 2020. Three distinct breast cancer stages were analyzed: Stage A (early breast cancer without lymph node involvement), Stage B (early breast cancer with lymph node involvement), and Stage C (primary distant metastatic breast cancer). Tumor subtypes were estimated based on the prescription of antihormonal or HER2-targeted therapy. The study established that 77.9% of patients had HR+ breast cancer and 9.8% HER2+; HR+/HER2- was the most common subtype (70.9%). Overall survival (OS) analysis demonstrated significantly lower survival rates for stages B and C than for controls, with 5-year OS rates ranging from 79.3% for stage B to 35.4% for stage C. OS rates were further stratified by tumor subtype and stage, revealing varying prognoses. Distant recurrence-free survival (DRFS) analysis showed higher recurrence rates in stage B than in stage A, with HR-/HER2- displaying the worst DRFS. This study, the first to model breast cancer subtypes, stages, and outcomes using German claims data, provides valuable insights into real-world breast cancer epidemiology and demonstrates that this breast cancer disease model has the potential to be representative of treatment outcomes.
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