NUAK1 (ARK5) is Associated with Poor Prognosis in Ovarian Cancer.

Background and Objective: Nua kinase 1 (NUAK1) was identified in multigene signatures of survival and suboptimal debulking in high grade serous ovarian cancer (HGSOC). This study investigates the individual clinical and biologic contributions of NUAK1 in HGSOC patients and cell lines.Methods: Public transcript expression, clinical, and outcome data were used to interrogate the relationship between NUAK1 and clinicopathologic factors and patient outcomes including progression-free survival (PFS) and molecular subtypes using logistic and Cox modeling. Analysis of NUAK1 transcript expression was performed in primary tumors from 34 HGSOC patients with < or ≥ 2 years PFS. The impact of silencing NUAK1 by RNA interference on the migratory potential and chemosensitivity of SOC cells was assessed in vitro.Results: Elevated NUAK1 transcript expression was associated with worse PFS (hazard ratio=1.134), advanced stage (odds ratio, OR=1.7), any residual disease (OR=1.58), and mesenchymal disease subtype (OR=7.79 ± 5.89). Elevated NUAK1 transcript expression was observed in HGSOC patients with < vs. ≥ 2 years PFS (p<0.045). RNA interference (RNAi)-mediated silencing of NUAK1 expression attenuated migration of OV90 and E3 HGSOC cells in vitro, but did not modulate sensitivity to cisplatin or paclitaxel.Conclusions. Elevated NUAK1 was associated with poor survival as well as advanced stage, residual disease after cytoreductive surgery and mesenchymal molecular subtype. NUAK1 impacted migration, but not chemosensitivity in vitro. Additional studies are needed to further develop the concept of NUAK1 as a clinically deployable biomarker and therapeutic target in HGSOC

Immuno-Molecular Targeted Therapy Use and Survival Benefit in Patients with Stage IVB Cervical Carcinoma in Commission on Cancer^®-Accredited Facilities in the United States

Purpose: To investigate IMT use and survival in real-world stage IVB cervical cancer patients outside randomized clinical trials. Methods: Patients diagnosed with stage IVB cervical cancer during 2013–2019 in the National Cancer Database and treated with chemotherapy (CT) ± external beam radiation (EBRT) ± intracavitary brachytherapy (ICBT) ± IMT were studied. The adjusted hazard ratio (AHR) and 95% confidence interval (CI) for risk of death were estimated in patients treated with vs. without IMT after applying propensity score analysis to balance the clinical covariates. Results: There were 3164 evaluable patients, including 969 (31%) who were treated with IMT. The use of IMT increased from 11% in 2013 to 46% in 2019. Age, insurance, facility type, sites of distant metastasis, and type of first-line treatment were independently associated with using IMT. In propensity-score-balanced patients, the median survival was 18.6 vs. 13.1 months for with vs. without IMT (p < 0.001). The AHR was 0.72 (95% CI = 0.64–0.80) for adding IMT overall, 0.72 for IMT + CT, 0.66 for IMT + CT + EBRT, and 0.69 for IMT + CT + EBRT + ICBT. IMT-associated survival improvements were suggested in all subgroups by age, race/ethnicity, comorbidity score, facility type, tumor grade, tumor size, and site of metastasis. Conclusions: IMT was associated with a consistent survival benefit in real-world patients with stage IVB cervical cancer

Peptide ancestry informative markers in uterine neoplasms from women of European, African, and Asian ancestry

Characterization of ancestry-linked peptide variants in disease-relevant patient tissues represents a foundational step to connect patient ancestry with disease pathogenesis. Nonsynonymous single-nucleotide polymorphisms encoding missense substitutions within tryptic peptides exhibiting high allele frequencies in European, African, and East Asian populations, termed peptide ancestry informative markers (pAIMs), were prioritized from 1000 genomes. In silico analysis identified that as few as 20&nbsp;pAIMs can determine ancestry proportions similarly to &gt;260K SNPs (R2&nbsp;= 0.99). Multiplexed proteomic analysis of &gt;100 human endometrial cancer cell lines and uterine leiomyoma tissues combined resulted in the quantitation of 62&nbsp;pAIMs that correlate with patient race and genotype-confirmed ancestry. Candidates include a D451E substitution in GC vitamin D-binding protein previously associated with altered vitamin D levels in African and European populations. pAIMs will support generalized proteoancestry assessment as well as efforts investigating the impact of ancestry on the human proteome and how this relates to the pathogenesis of uterine neoplasms

Improving Risk Assessment for Metastatic Disease in Endometrioid Endometrial Cancer Patients Using Molecular and Clinical Features: An NRG Oncology/Gynecologic Oncology Group Study

Objectives: A risk assessment model for metastasis in endometrioid endometrial cancer (EEC) was developed using molecular and clinical features, and prognostic association was examined. Methods: Patients had stage I, IIIC, or IV EEC with tumor-derived RNA-sequencing or microarray-based data. Metastasis-associated transcripts and platform-centric diagnostic algorithms were selected and evaluated using regression modeling and receiver operating characteristic curves. Results: Seven metastasis-associated transcripts were selected from analysis in the training cohorts using 10-fold cross validation and incorporated into an MS7 classifier using platform-specific coefficients. The predictive accuracy of the MS7 classifier in Training-1 was superior to that of other clinical and molecular features, with an area under the curve (95% confidence interval) of 0.89 (0.80–0.98) for MS7 compared with 0.69 (0.59–0.80) and 0.71 (0.58–0.83) for the top evaluated clinical and molecular features, respectively. The performance of MS7 was independently validated in 245 patients using RNA sequencing and in 81 patients using microarray-based data. MS7 + MI (myometrial invasion) was preferrable to individual features and exhibited 100% sensitivity and negative predictive value. The MS7 classifier was associated with lower progression-free and overall survival (p ≤ 0.003). Conclusion: A risk assessment classifier for metastasis and prognosis in EEC patients with primary tumor derived MS7 + MI is available for further development and optimization as a companion clinical support tool

Elevated AKAP12 in Paclitaxel-Resistant Serous Ovarian Cancer Cells Is Prognostic and Predictive of Poor Survival in Patients

A majority of high-grade (HG) serous ovarian cancer (SOC) patients develop resistant disease despite high initial response rates to platinum/paclitaxel-based chemotherapy. We identified shed/secreted proteins in preclinical models of paclitaxel-resistant human HGSOC models and correlated these candidate proteins with patient outcomes using public data from HGSOC patients. Proteomic analyses of a HGSOC cell line secretome was compared to those from a syngeneic paclitaxel-resistant variant and from a line established from an intrinsically chemorefractory HGSOC patient. Associations between the identified candidate proteins and patient outcome were assessed in a discovery cohort of 545 patients and two validation cohorts totaling 795 independent SOC patients. Among the 81 differentially abundant proteins identified (<i>q</i> < 0.05) from paclitaxel-sensitive vs -resistant HGSOC cell secretomes, AKAP12 was verified to be elevated in all models of paclitaxel-resistant HGSOC. Furthermore, elevated AKAP12 transcript expression was associated with worse progression-free and overall survival. Associations with outcome were observed in three independent cohorts and remained significant after adjusted multivariate modeling. We further provide evidence to support that differential gene methylation status is associated with elevated expression of AKAP12 in taxol-resistant ovarian cancer cells and ovarian cancer patient subsets. Elevated expression and shedding/secretion of AKAP12 is characteristic of paclitaxel-resistant HGSOC cells, and elevated AKAP12 transcript expression is a poor prognostic and predictive marker for progression-free and overall survival in SOC patients