Dataset Information

Clinical Practice of Targeted Capture Sequencing to Identify Actionable Alterations in Cholangiocarcinoma.

ABSTRACT: The early diagnosis and treatment of cholangiocarcinoma (CCA) remain a challenge worldwide. Genetic testing promises to solve these problems. Due to the different mutation landscapes across populations and the paucity of sequencing data of Chinese patients with CCA, the existing mutation landscape is insufficient to reflect the mutation characteristics of Chinese patients. Thus, we retrospectively analyzed 72 Chinese patients with CCA who had received genetic testing of targeted capture sequencing. A total of 2152 somatic mutations were detected in 56 (77.78%) patients, of which, the frequently mutated driver genes were TP53 (27.78%), KMT2D (23.81%), KMT2C (20.63%), BCOR (18.06%), APC (15.28%), BAP1 (13.89%), ARID1A (12.50%), NF1 (12.50%), PIK3CA (12.50%), KRAS (11.11%), and LRP1B (11.11%). Most mutations were enriched in NRF2, TP53, and TGF-Beta oncogenic signaling pathways and cadherin repeat domains which were associated with intercellular adhesion. Based on cancer-related public databases and multiple protein function prediction algorithms, we identified 118 novel pathogenic or likely pathogenic somatic mutations and 77 actionable alterations. Molecular analysis of tumors from a precision oncology perspective can provide potential targets for early diagnosis and treatment of CCA and assist physicians in clinical decision making.

SUBMITTER: Ma K

PROVIDER: S-EPMC9600135 | biostudies-literature | 2022 Oct

REPOSITORIES: biostudies-literature

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Clinical Practice of Targeted Capture Sequencing to Identify Actionable Alterations in Cholangiocarcinoma.

Ma Kai K Wang Youpeng Y Zhang Yuanzheng Y Sun Hongfa H Zhang Xuhui X Sun Chuandong C Zhang Bingyuan B Zhang Ying Y Cheng Haoyue H Liu Ao A Wang Mengyao M Han Bing B

Cancers 20221016 20

The early diagnosis and treatment of cholangiocarcinoma (CCA) remain a challenge worldwide. Genetic testing promises to solve these problems. Due to the different mutation landscapes across populations and the paucity of sequencing data of Chinese patients with CCA, the existing mutation landscape is insufficient to reflect the mutation characteristics of Chinese patients. Thus, we retrospectively analyzed 72 Chinese patients with CCA who had received genetic testing of targeted capture sequenci ...[more]

PMID: 36291846

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Project description:BackgroundMolecular characterization has the potential to advance the management of pediatric cancer and high-risk hematologic disease. The clinical integration of genome sequencing into standard clinical practice has been limited and the potential utility of genome sequencing to identify clinically impactful information beyond targetable alterations has been underestimated.MethodsThe Precision in Pediatric Sequencing (PIPseq) Program at Columbia University Medical Center instituted prospective clinical next generation sequencing (NGS) for pediatric cancer and hematologic disorders at risk for treatment failure. We performed cancer whole exome sequencing (WES) of patient-matched tumor-normal samples and RNA sequencing (RNA-seq) of tumor to identify sequence variants, fusion transcripts, relative gene expression, and copy number variation (CNV). A directed cancer gene panel assay was used when sample adequacy was a concern. Constitutional WES of patients and parents was performed when a constitutionally encoded disease was suspected. Results were initially reviewed by a molecular pathologist and subsequently by a multi-disciplinary molecular tumor board. Clinical reports were issued to the ordering physician and posted to the patient's electronic medical record.ResultsNGS was performed on tumor and/or normal tissue from 101 high-risk pediatric patients. Potentially actionable alterations were identified in 38% of patients, of which only 16% subsequently received matched therapy. In an additional 38% of patients, the genomic data provided clinically relevant information of diagnostic, prognostic, or pharmacogenomic significance. RNA-seq was clinically impactful in 37/65 patients (57%) providing diagnostic and/or prognostic information for 17 patients (26%) and identified therapeutic targets in 15 patients (23%). Known or likely pathogenic germline alterations were discovered in 18/90 patients (20%) with 14% having germline alternations in cancer predisposition genes. American College of Medical Genetics (ACMG) secondary findings were identified in six patients.ConclusionsOur results demonstrate the feasibility of incorporating clinical NGS into pediatric hematology-oncology practice. Beyond the identification of actionable alterations, the ability to avoid ineffective/inappropriate therapies, make a definitive diagnosis, and identify pharmacogenomic modifiers is clinically impactful. Taking a more inclusive view of potential clinical utility, 66% of cases tested through our program had clinically impactful findings and samples interrogated with both WES and RNA-seq resulted in data that impacted clinical decisions in 75% of cases.

Dataset Information

Clinical Practice of Targeted Capture Sequencing to Identify Actionable Alterations in Cholangiocarcinoma.

Publications

Clinical Practice of Targeted Capture Sequencing to Identify Actionable Alterations in Cholangiocarcinoma.

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