RNA sequencing distinguishes benign from malignant pancreatic lesions sampled by EUS-guided FNA

Rodriguez, Sarah A.; Impey, Soren; Pelz, Carl; Enestvedt, Brintha K.; Bakis, Gennadiy; Owens, Michael C.; Morgan, Terry K.

doi:10.1016/j.gie.2016.01.042

Cited by 23 publications

(22 citation statements)

References 31 publications

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“…More recently, the transcriptome profile of EUS‐FNA‐derived RNA for PC has been reported . Our study used RNASeq to profile malignant and benign samples in order to generate a diagnostic gene signature, intended for lesions that cannot be diagnosed with cytology alone.…”

Section: Discussionmentioning

confidence: 99%

Endoscopic ultrasound-guided fine-needle aspirate-derived preclinical pancreatic cancer models reveal panitumumab sensitivity inKRASwild-type tumors

et al. 2017

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Pancreatic cancer (PC) is largely refractory to existing therapies used in unselected patient trials, thus emphasizing the pressing need for new approaches for patient selection in personalized medicine. KRAS mutations occur in 90% of PC patients and confer resistance to epidermal growth factor receptor (EGFR) inhibitors (e.g., panitumumab), suggesting that KRAS wild-type PC patients may benefit from targeted panitumumab therapy. Here, we use tumor tissue procured by endoscopic ultrasound-guided fine-needle aspirate (EUS-FNA) to compare the in vivo sensitivity in patient-derived xenografts (PDXs) of KRAS wild-type and mutant PC tumors to panitumumab, and to profile the molecular signature of these tumors in patients with metastatic or localized disease. Specifically, RNASeq of EUS-FNA-derived tumor RNA from localized (n = 20) and metastatic (n = 20) PC cases revealed a comparable transcriptome profile. Screening the KRAS mutation status of tumor genomic DNA obtained from EUS-FNAs stratified PC patients into either KRAS wild-type or mutant cohorts, and the engraftment of representative KRAS wild-type and mutant EUS-FNA tumor samples into NOD/SCID mice revealed that the growth of KRAS wild-type, but not mutant, PDXs was selectively suppressed with panitumumab. Furthermore, in silico transcriptome interrogation of The Cancer Genome Atlas (TCGA)-derived KRAS wild-type (n = 38) and mutant (n = 132) PC tumors revealed 391 differentially expressed genes. Taken together, our study validates EUS-FNA for the application of a novel translational pipeline comprising KRAS mutation screening and PDXs, applicable to all PC patients, to evaluate personalized anti-EGFR therapy in patients with KRAS wild-type tumors.

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Section: Discussionmentioning

confidence: 99%

Endoscopic ultrasound-guided fine-needle aspirate-derived preclinical pancreatic cancer models reveal panitumumab sensitivity inKRASwild-type tumors

et al. 2017

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“…In addition, there was inadequate RNA in 9 of the 48 enrolled subjects, limiting this adjunct in a similar way to cytopathology. 13 MicroRNA signatures also hold promise to improve the diagnostic accuracy of EUS-guided FNA, with specificity of 85% to 95% at the cost of sensitivity of 81% to 83%. 22,23 Combination fluorescence in situ hybridization and K-ras analysis hold promise with higher sensitivity (87.9%) and specificity (93.8%), but are not readily available at many centers and need further validation.…”

Section: Discussionmentioning

confidence: 99%

“…[6][7][8][9][10] Elastography, fluorescence in situ hybridization, K-RAS analysis, microRNAs, immunostaining, and RNA-sequencing analysis have all been proposed as supplementary tests to cytopathology, but none have gained widespread use. [11][12][13][14] Here, we explore the inflammatory milieu of the PDAC microenvironment as a potential diagnostic supplement to cytopathology. Desmoplastic stroma represents as much as 80% of the overall PDAC tumor volume.…”

mentioning

confidence: 99%

Protein Signatures and Tissue Diagnosis of Pancreatic Cancer

Underwood

Gerber

Nguyen

et al. 2020

Journal of the American College of Surgeons

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BACKGROUND: Endoscopic ultrasound-guided fine-needle aspiration fails to diagnose up to 25% of patients with pancreatic ductal adenocarcinoma (PDAC). Proteomics can help to overcome this clinical dilemma. We hypothesized that soluble protein signatures can differentiate PDAC from benign tissues. STUDY DESIGN: Tissues were obtained from resected surgical specimens, lysed, and homogenates collected for analysis with a 41-protein multiplex assay. Analyte concentrations were normalized to total protein. Statistical analysis was performed to evaluate for differences in PDAC vs benign tissue. RESULTS: Tissues were obtained from 159 patients, 82 patients with PDAC naïve to therapy and 77 with benign pancreatic pathology. Fourteen analytes had a receiver operating characteristic curve area of >0.75 for predicting PDAC vs benign tissue. A recursive partitioning model using only 2 analytes, interleukin 1 receptor antagonist and transforming growth factor-a, provided an accuracy, sensitivity, and specificity of 91.2%, 90.2%, and 92.2%, respectively. A penalized logistic regression model found 12 analytes that provide diagnostic value to a protein signature. The mean area under the receiver operating characteristic after 50 tenfold cross-validations was 0.951. Accuracy, sensitivity, and specificity of this model were 91.2%, 87.8%, and 94.8%, respectively. Applying the scenario of 80% disease prevalence in patients undergoing endoscopic ultrasound with fine-needle aspiration for a pancreatic head mass, positive predictive value is 98.5% (95% CI 93.0% to 99.7%) and negative predictive value is 66.0% (95% CI 54.9% to 75.6%). CONCLUSIONS: Protein signatures from pancreatic specimens can differentiate PDAC from benign tissue. Additional work to validate these findings in a unique sample set is warranted.

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“…For EUS-FNB specimen prepared by formalin-fixed, paraffinembedded, a 95% success rate for NGS is expected when samples have a tissue volume of 1.2 cm 2 and at least 5 ng/mL of analyzable DNA. 49 Although much of the initial work on EUS-TA has focused on NGS and is the focus of this paper, numerous additional methods, such as RNA and microRNA sequencing, [59][60][61][62] use of fluorescence in situ hybridization, 63,64 identification of protein and immune markers, the creation of tumor organoids, [65][66][67][68] and low cost whole-exome sequencing are emerging. Of these methods, the ability to create organoids, which are in vitro 3-dimensional tissue models, is particularly promising.…”

Section: Role Of Endoscopic Ultrasound In Personalized Medicinementioning

confidence: 99%

“…In addition to NGS, RNA and microRNA analyses of specimen obtained by EUS-FNA have also been performed. RNA sequencing has been shown to potentially aid in distinguishing adenocarcinoma from benign pancreatic masses 59 and in determining response to chemotherapy. 62 Similarly, microRNA analyses may aid in not only in achieving a diagnosis, but also in predicting prognosis and identifying tumor susceptibility to chemotherapeutic agents in pancreatic ductal adenocarcinomas.…”

Section: Solid and Cystic Pancreatic Lesionsmentioning

confidence: 99%

AGA White Paper: Optimizing Endoscopic Ultrasound–Guided Tissue Acquisition and Future Directions

Wani

Muthusamy

McGrath

et al. 2018

Clinical Gastroenterology and Hepatology

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RNA sequencing distinguishes benign from malignant pancreatic lesions sampled by EUS-guided FNA

Cited by 23 publications

References 31 publications

Endoscopic ultrasound-guided fine-needle aspirate-derived preclinical pancreatic cancer models reveal panitumumab sensitivity inKRASwild-type tumors

Endoscopic ultrasound-guided fine-needle aspirate-derived preclinical pancreatic cancer models reveal panitumumab sensitivity inKRASwild-type tumors

Protein Signatures and Tissue Diagnosis of Pancreatic Cancer

AGA White Paper: Optimizing Endoscopic Ultrasound–Guided Tissue Acquisition and Future Directions

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