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Understanding the Implications of Mutational Status in Intrahepatic Cholangiocarcinoma

Angelica Welch
Published: Tuesday, Jan 09, 2018

Jesper B. Andersen, MSc, PhD
Jesper B. Andersen, MSc, PhD
There continues to be a dramatic increase in both incidence and mortality rate of cholangiocarcinoma worldwide, according to Jesper B. Andersen, MSc, PhD.

In a study recently published in Hepatology from the Andersen Group at Biotech Research and Innovation Center, it was shown that using a single-gene dissection approach in patients with intrahepatic cholangiocarcinoma can characterize divergent cancer programs and drug vulnerabilities. Through this, therapeutic sensitives for this patient population can be identified, aiding in the process of targeted genotyping.

This study evaluates the genomic, epigenetic, and pharmacologic landscapes of intrahepatic cholangiocarcinoma, which is both molecularly heterogeneous and resistant to chemotherapy.

"There is a clinical need to highlight these patients,” said Andersen in an interview with OncLive. “This is not only a question of highlighting our study. This disease is a rare malignancy that has progressed since the 1980s. Whereas the therapeutic options have improved for many other diseases, the clinical opportunities for most patients diagnosed with cholangiocarcinoma are limited—this is a dismal disease.”

The appropriate stratification of patients with intrahepatic cholangiocarcinoma comes with implications for the development of precision medicine in this disease, Andersen adds. This could be groundbreaking, as there are no approved therapies for this patient population, and only 10% to 30% of patients are eligible for curative surgery.

During an interview with OncLive, Andersen, who is an associate professor and leader of the Andersen Group at Biotech Research and Innovation Centre, Department of Health and Medical Sciences at the University of Copenhagen, discussed the findings of this study and the implications it could have on the future treatment of patients with cholangiocarcinoma.

OncLive: Can you please provide an overview of this study?

Andersen: The study is focused on tumors that arise in the bile duct epithelium within the liver, meaning they are anatomically classified as intrahepatic cholangiocarcinomas. That was a deliberate strict inclusion of patients into this study to introduce minimal genomic heterogeneity, because cholangiocarcinoma is a tumor type that exists both in the liver and right outside the liver (extrahepatic). We used a total cohort size of 496 intrahepatic tumors, and analyzed these by whole-exome sequencing, targeted-exome sequencing, transcriptomics, structural variances, and DNA methylation.

We have defined a novel strategy that stratified the patient based on the recurrent genetic alterations that occur and give rise to unique or distinct regulatory networks between groups. We did that by stratifying the patient based on 3 driver-gene groupings—IDH1/2, KRAS, and TP53—that led to the discovery of a fourth group that we termed “undetermined.” This means we did not know the cause of the underlying driver of this disease subgroup. As such, the undetermined group is wild-type for the 3 driver genes. Those could be distinctly classified based on distinct mutational signatures, structural alterations and DNA-methylation profiles.

This classification scheme led to a stratification of unique pathway enrichment for each of these 4 patient groups who were associated with pharmacogenomic and -epigenetic signatures, clinical significance, and specific therapeutic response when we tested patient-matched cell lines in a large-scale drug screening of 525 different drugs that are late-stage or FDA approved.

The undetermined group became quite interesting in the sense that we didn't know what was causing that group. There, we found an enrichment of FGFR2 gene fusions and amplification in the chromosomal focal region of the gene (METTL13). This gene is a putative novel methyltransferase with very little information in the literature (metyltransferase-like 13). We are continuing to identify the role of METTL13 in general and its oncogenic potential in patients with intrahepatic cholangiocarcinoma.  

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Oncology Briefings™: Individualizing Treatment After Second-Line Therapy for Patients With mCRCAug 29, 20191.0
Community Practice Connections™: Navigating New Sequencing Challenges for the Treatment of Hepatocellular CarcinomaAug 30, 20191.5
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