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  • MiR‐29a, targeting caveolin 2 expression, is responsible for limitation of pancreatic cancer metastasis in patients with normal level of serum CA125
Title: MiR‐29a, targeting caveolin 2 expression, is responsible for limitation of pancreatic cancer metastasis in patients with normal level of serum CA125
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NSF-PAR ID:
10463117
Author(s) / Creator(s):
 ;  ;  ;  ;  ;  ;  ;  ;  ;  
Publisher / Repository:
Wiley Blackwell (John Wiley & Sons)
Date Published:
Journal Name:
International Journal of Cancer
Volume:
143
Issue:
11
ISSN:
0020-7136
Page Range / eLocation ID:
p. 2919-2931
Format(s):
Medium: X
Sponsoring Org:
National Science Foundation
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    Background

    CD8+T cell in pancreatic ductal adenocarcinoma (PDAC) is closely related to the prognosis and treatment response of patients. Accurate preoperative CD8+T‐cell expression can better identify the population benefitting from immunotherapy.

     Purpose

    To develop and validate a machine learning classifier based on noncontrast magnetic resonance imaging (MRI) for the preoperative prediction of CD8+T‐cell expression in patients with PDAC.

     Study Type

    Retrospective cohort study.

     Population

    Overall, 114 patients with PDAC undergoing MR scan and surgical resection; 97 and 47 patients in the training and validation cohorts.

     Field Strength/Sequence/3 T

    Breath‐hold single‐shot fast‐spin echo T2‐weighted sequence and noncontrast T1‐weighted fat‐suppressed sequences.

     Assessment

    CD8+T‐cell expression was quantified using immunohistochemistry. For each patient, 2232 radiomics features were extracted from noncontrast T1‐ and T2‐weighted images and reduced using the Wilcoxon rank‐sum test and least absolute shrinkage and selection operator method. Linear discriminative analysis was used to construct radiomics and mixed models. Model performance was determined by its discriminative ability, calibration, and clinical utility.

     Statistical Tests

    Kaplan–Meier estimates, Student's t‐test, the Kruskal–Wallis H test, and the chi‐square test, receiver operating characteristic curve, and decision curve analysis.

     Results

    A log‐rank test showed that the survival duration in the CD8‐high group (25.51 months) was significantly longer than that in the CD8‐low group (22.92 months). The mixed model included all MRI characteristics and 13 selected radiomics features, and the area under the curve (AUC) was 0.89 (95% confidence interval [CI], 0.77–0.92) and 0.69 (95% CI, 0.53–0.82) in the training and validation cohorts. The radiomics model included 13 radiomics features, which showed good discrimination in the training cohort (AUC, 0.85; 95% CI, 0.77–0.92) and the validation cohort (AUC, 0.76; 95% CI, 0.61–0.87).

     Data Conclusions

    This study developed a noncontrast MRI‐based radiomics model that can preoperatively determine CD8+T‐cell expression in patients with PDAC and potentially immunotherapy planning.

     Evidence Level

    5

     Technical Efficacy

    Stage 2

     
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    Abstract

    Although the overall five-year survival of patients with pancreatic ductal adenocarcinoma (PDAC) is dismal, there are survival differences between cases with clinically and pathologically indistinguishable characteristics, suggesting that there are uncharacterized properties that drive tumor progression. Recent mRNA sequencing studies reported gene-expression signatures that define PDAC molecular subtypes that correlate with differences in survival. We previously identified Keratin 17 (K17) as a negative prognostic biomarker in other cancer types. Here, we set out to determine if K17 is as accurate as molecular subtyping of PDAC to identify patients with the shortest survival. K17 mRNA was analyzed in two independent PDAC cohorts for discovery (n = 124) and validation (n = 145). Immunohistochemical localization and scoring of K17 immunohistochemistry (IHC) was performed in a third independent cohort (n = 74). Kaplan-Meier and Cox proportional-hazard regression models were analyzed to determine cancer specific survival differences in low vs. high mRNA K17 expressing cases. We established that K17 expression in PDACs defines the most aggressive form of the disease. By using Cox proportional hazard ratio, we found that increased expression of K17 at the IHC level is also associated with decreased survival of PDAC patients. Additionally, within PDACs of advanced stage and negative surgical margins, K17 at both mRNA and IHC level is sufficient to identify the subgroup with the shortest survival. These results identify K17 as a novel negative prognostic biomarker that could inform patient management decisions.

     
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    Although pancreatic ductal adenocarcinoma (PDAC) has one of the lowest 5‐year survival rates of all cancers, differences in survival exist between patients with clinically identical characteristics. The authors previously demonstrated that keratin 17 (K17) expression in PDAC, measured by RNA sequencing or immunohistochemistry (IHC), is an independent negative prognostic biomarker. Only 20% of cases are candidates for surgical resection, but most patients are diagnosed by needle aspiration biopsy (NAB). The aims of this study were to determine whether there was a correlation in K17 scores detected in matched NABs and surgical resection tissue sections and whether K17 IHC in NAB cell block specimens could be used as a negative prognostic biomarker in PDAC.

     Methods

    K17 IHC was performed for a cohort of 70 patients who had matched NAB cell block and surgical resection samples to analyze the correlation of K17 expression levels. K17 IHC was also performed in cell blocks from discovery and validation cohorts. Kaplan‐Meier and Cox proportional hazards regression models were analyzed to determine survival differences in cases with different levels of K17 IHC expression.

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    K17 IHC expression correlated in matched NABs and resection tissues. NAB samples were classified as high for K17 when ≥80% of tumor cells showed strong (2+) staining. High‐K17 cases, including stage‐matched cases, had shorter survival.

     Conclusions

    K17 has been identified as a robust and independent prognostic biomarker that stratifies clinical outcomes for cases that are diagnosed by NAB. Testing for K17 also has the potential to inform clinical decisions for optimization of chemotherapeutic interventions.

     
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    Background

    Colorectal cancer is one of the highly malignant cancers with a poor prognosis. The exact mechanism of colorectal cancer progression is not completely known. Recently, microRNAs (miRNAs, miRs) were suggested to participate in the regulation of multiple cancer development, including colorectal cancer.

     Methods

    MiR‐4319 expression in colorectal cancer patient samples was detected by real‐time polymerase chain reaction. MiR‐4319 was knocked down in the colorectal cancer cells by siRNA transfection to study the role of miR‐4319 in the cell cycle and proliferation of colorectal cancer cells.

     Results

    MiR‐4319 expression was found to be inverse correlated with survival in colorectal cancer patients. Overexpression of miR‐4319 markedly reduced the proliferation of colorectal cancer cells and altered cell cycle distribution. A further experiment showed that ABTB1 is the target gene of miR‐4319. MiR‐4319 was regulated by PLZF.

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