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Evidence for the importance of personalized molecular profiling in pancreatic cancer.

ABSTRACT: OBJECTIVES: There is a growing body of evidence that targeted gene therapy holds great promise for the future treatment of cancer. A crucial step in this therapy is the accurate identification of appropriate candidate genes/pathways for targeted treatment. One approach is to identify variant genes/pathways that are significantly enriched in groups of afflicted individuals relative to control subjects. However, if there are multiple molecular pathways to the same cancer, the molecular determinants of the disease may be heterogeneous among individuals and possibly go undetected by group analyses. METHODS: In an effort to explore this question in pancreatic cancer, we compared the most significantly differentially expressed genes/pathways between cancer and control patient samples as determined by group versus personalized analyses. RESULTS: We found little to no overlap between genes/pathways identified by gene expression profiling using group analyses relative to those identified by personalized analyses. CONCLUSIONS: Our results indicate that personalized and not group molecular profiling is the most appropriate approach for the identification of putative candidates for targeted gene therapy of pancreatic and perhaps other cancers with heterogeneous molecular etiology.

SUBMITTER: Lili LN

PROVIDER: S-EPMC4206352 | biostudies-literature | 2014 Mar

REPOSITORIES: biostudies-literature

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Evidence for the importance of personalized molecular profiling in pancreatic cancer.

Lili Loukia N LN Matyunina Lilya V LV Walker L DeEtte LD Daneker George W GW McDonald John F JF

Pancreas 20140301 2

<h4>Objectives</h4>There is a growing body of evidence that targeted gene therapy holds great promise for the future treatment of cancer. A crucial step in this therapy is the accurate identification of appropriate candidate genes/pathways for targeted treatment. One approach is to identify variant genes/pathways that are significantly enriched in groups of afflicted individuals relative to control subjects. However, if there are multiple molecular pathways to the same cancer, the molecular dete ...[more]

PMID: 24518497

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Project description:BackgroundPancreatic ductal adenocarcinoma (PDAC) has the worst prognosis among common cancers. The genomic landscape of PDAC is defined by four mutational pathways: kirsten rat sarcoma virus (KRAS), cellular tumor antigen p53 (TP53), cyclin dependent kinase inhibitor 2A (CDKN2A), and SMAD family member 4 (SMAD4). However, there is a paucity of data on the molecular features associated with clinical outcomes after surgery or chemotherapy.MethodsWe performed comprehensive molecular characterization of tumor specimens from 83 patients with PDAC who received surgery, using whole-exome sequencing and ribonucleic acid sequencing on tumor and matched normal tissues derived from patients. We also systematically performed integrative analysis, combining genomic, transcriptomic, and clinical features to identify biomarkers and possible therapeutic targets.ResultsKRAS (75%), TP53 (67%), CDKN2A (12%), SMAD4 (20%), and ring finger protein 43 (RNF43) (13%) were identified as significantly mutated genes. The tumor-specific transcriptome was classified into two clusters (tumor S1 and tumor S2), which resembled the Moffitt tumor classification. Tumor S1 displayed two distinct subclusters (S1-1 and S1-2). The transcriptome of tumor S1-1 overlapped with the exocrine-like (Collisson)/ADEX (Bailey) subtype, while tumor S1-2 mostly consisted of the classical (Collisson)/progenitor (Bailey) subtype. In the analysis of combinatorial gene alterations, concomitant mutations of KRAS with low-density lipoprotein receptor related protein 1B (LRP1B) were associated with significantly worse disease-free survival after surgery (p = 0.034). One patient (1.2%) was an ultrahypermutant with microsatellite instability. We also identified high protein kinase C lota (PRKCI) expression as an overlapping, poor prognostic marker between our dataset and the TCGA dataset.ConclusionWe identified potential prognostic biomarkers and therapeutic targets of patients with PDAC. Understanding these molecular aberrations that determine patient outcomes after surgery and chemotherapy has the potential to improve the treatment outcomes of PDAC patients.

Project description:Purpose: Pediatric cancers are often difficult to classify and can be complex to treat. To ensure precise diagnostics and identify relevant treatment targets, we implemented comprehensive molecular profiling of consecutive pediatric patients with cancer relapse. We evaluated the clinical impact of extensive molecular profiling by assessing the frequency of identified biological onco-drivers, altered diagnosis, and/or identification of new relevant targeted therapies. Patients and Methods: Forty-six tumor samples (44 fresh-frozen; two formalin-fixed paraffin embedded), two bone marrow aspirates, three cerebrospinal fluid samples, and one archived DNA were obtained from 48 children (0-17 years; median 9.5) with relapsed or refractory cancer, where the disease was rapidly progressing in spite of their current treatment or they had exhausted all treatment options. The samples were analyzed by whole-exome sequencing (WES), RNA sequencing (RNAseq), transcriptome arrays, and SNP arrays. Final reports were available within 3-4 weeks after patient inclusion and included mutation status, a description of copy number alterations, differentially expressed genes, and gene fusions, as well as suggestions for targeted treatment. Results: Of the 48 patients, 33 had actionable findings. The most efficient method for the identification of actionable findings was WES (39%), followed by SNP array (37%). Of note, gene fusions were identified by RNAseq in 21% of the samples. Eleven findings led to clinical intervention, i.e., oncogenetic counseling, targeted treatment, and treatment based on changed diagnosis. Four patients received compassionate use targeted therapy. Six patients experienced direct benefits in the form of stable disease or response. Conclusion: The application of comprehensive genetic diagnostics in children with recurrent cancers allowed for discovery and implementation of effective targeted therapies and hereby improvement of outcome in some patients.

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Evidence for the importance of personalized molecular profiling in pancreatic cancer.

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Evidence for the importance of personalized molecular profiling in pancreatic cancer.

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