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Genetic and clinical correlates of entosis in pancreatic ductal adenocarcinoma.

ABSTRACT: Entosis is a type of regulated cell death that promotes cancer cell competition. Though several studies have revealed the molecular mechanisms that govern entosis, the clinical and genetic correlates of entosis in human tumors is less well understood. Here we reviewed entotic cell-in-cell (CIC) patterns in a large single institution sequencing cohort (MSK IMPACT clinical sequencing cohort) of more than 1600 human pancreatic ductal adenocarcinoma (PDAC) samples to identify the genetic and clinical correlates of this cellular feature. After case selection, 516 conventional PDACs and 21 ASCs entered this study and ~45,000 HPFs (median 80 HPFs per sample) were reviewed; 549 entotic-CICs were detected through our cohort. We observed that entotic-CIC occurred more frequently in liver metastasis compared with primary in PDAC. Moreover, poorly differentiated adenocarcinoma or adenosquamous carcinoma had more entotic-CIC than well or moderately differentiated adenocarcinoma. With respect to genetic features TP53 mutations, KRAS amplification, and MYC amplification were significantly associated with entosis in PDAC tissues. From a clinical standpoint entotic CICs were independently associated with a poor prognosis by multivariate Cox regression analysis when considering all cases or primary PDACs specifically. These results provide a contextual basis for understanding entosis in PDAC, a highly aggressive cancer for which molecular insights are needed to improve survival.

SUBMITTER: Hayashi A

PROVIDER: S-EPMC7452867 | biostudies-literature | 2020 Sep

REPOSITORIES: biostudies-literature

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Genetic and clinical correlates of entosis in pancreatic ductal adenocarcinoma.

Hayashi Akimasa A Yavas Aslihan A McIntyre Caitlin A CA Ho Yu-Jui YJ Erakky Amanda A Wong Winston W Varghese Anna M AM Melchor Jerry P JP Overholtzer Michael M O'Reilly Eileen M EM Klimstra David S DS Basturk Olca O Iacobuzio-Donahue Christine A CA

Modern pathology : an official journal of the United States and Canadian Academy of Pathology, Inc 20200429 9

Entosis is a type of regulated cell death that promotes cancer cell competition. Though several studies have revealed the molecular mechanisms that govern entosis, the clinical and genetic correlates of entosis in human tumors is less well understood. Here we reviewed entotic cell-in-cell (CIC) patterns in a large single institution sequencing cohort (MSK IMPACT clinical sequencing cohort) of more than 1600 human pancreatic ductal adenocarcinoma (PDAC) samples to identify the genetic and clinica ...[more]

PMID: 32350415

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Project description:PurposeHypodensity of pancreatic ductal adenocarcinoma (PDAC) during contrast-enhanced computed tomography (CECT) examination is common, but a minority of PDAC patients exhibit hyperdense images. The present study examined the clinical characteristics and protein landscape of PDAC with hyperdensity.Materials and methodsA total of 844 pathologically confirmed PDAC patients who underwent CECT before surgery were included. During the parenchymal phase of CECT, patients were assigned to the hyperdense or hypodense group based on CT values. Clinical and CT characteristics for predicting relapse-free survival (RFS) and overall survival (OS) were analyzed using the Kaplan-Meier method and Cox proportional hazards model. The expression of the tumor angiogenesis marker CD31 and stroma-related protein CTHRC1 were analyzed using immunohistochemistry (IHC) assay to evaluate differences between the two groups. Proteomics was performed to compare the possible mechanisms underlying the differential enhancement on CT scans.ResultsBased on CECT, 43 and 801 PDAC patients had hyperdense and hypodense lesions, respectively. All 43 patients presented a hyperdense lesion in the parenchymal phase. The mean CECT values of the hyperdense group were higher than the hypodense group (102.5 ± 17.4 and 53.7 ± 18.7, respectively, P < 0.001). The hyperdense group had a better prognosis than the hypodense group (median RFS, 19.97 vs. 12.34 months, P = 0.0176; median OS, 33.6 vs. 20.3 months, P = 0.047). Multivariate analysis showed that age, higher CA19-9 levels (> 300 U/ml), tumor stage, tumor differentiation, tumor CT density, and adjuvant chemotherapy were significant independent prognostic factors for OS. CD31 immunohistochemical staining showed that the hyperdense PDACs had a higher microvessel density than the hypodense group (P < 0.001). CTHRC1 expression was higher in the hypodense group (P = 0.019). Sixty-eight differentially expressed proteins were found using the tandem mass tag labeling-based quantification of the proteomes of PDAC tissue samples, and 7 proteins (POFUT1, PKP2, P0DOX4, ITPR1, HBG2, IGLC3, SAA2) were related to angiogenesis.ConclusionPatients who presented with a hyperdense mass on CECT had a higher microvessel density and better prognosis. Anti-angiogenic therapy may be suitable for these patients.

Project description:RATIONALE:Pancreatic ductal adenocarcinoma (PDAC) remains a tumor entity of exceptionally poor prognosis, and several biomarkers are under current investigation for the prediction of patient prognosis. Many studies focus on promoting newly developed imaging biomarkers without a rigorous comparison to other established parameters. To assess the true value and leverage the potential of all efforts in this field, a multi-parametric evaluation of the available biomarkers for PDAC survival prediction is warranted. Here we present a multiparametric analysis to assess the predictive value of established parameters and the added contribution of newly developed imaging features such as biomarkers for overall PDAC patient survival. METHODS:103 patients with resectable PDAC were retrospectively enrolled. Clinical and histopathological data (age, sex, chemotherapy regimens, tumor size, lymph node status, grading and resection status), morpho-molecular and genetic data (tumor morphology, molecular subtype, tp53, kras, smad4 and p16 genetics), image-derived features and the combination of all parameters were tested for their prognostic strength based on the concordance index (CI) of multivariate Cox proportional hazards survival modelling after unsupervised machine learning preprocessing. RESULTS:The average CIs of the out-of-sample data were: 0.63 for the clinical and histopathological features, 0.53 for the morpho-molecular and genetic features, 0.65 for the imaging features and 0.65 for the combined model including all parameters. CONCLUSIONS:Imaging-derived features represent an independent survival predictor in PDAC and enable the multiparametric, machine learning-assisted modelling of postoperative overall survival with a high performance compared to clinical and morpho-molecular/genetic parameters. We propose that future studies systematically include imaging-derived features to benchmark their additive value when evaluating biomarker-based model performance.

Dataset Information

Genetic and clinical correlates of entosis in pancreatic ductal adenocarcinoma.

Publications

Genetic and clinical correlates of entosis in pancreatic ductal adenocarcinoma.

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