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cfDNA analysis reveals relation of POLR1D amplification to bevacizumab resistance in colorectal cancer patients

Bevacizumab is an approved anti-angiogenic drug for patients with metastasized colorectal cancer (mCRC) targeting VEGF. The survival benefit of anti-VEGF therapy in mCRC patients is limited to a few months and acquired resistance mechanisms are greatly unknown. Using plasma DNA, we studied the evolution of tumor genomes in a cohort of patients with mCRC (n=150) and observed a recurrent focal amplification (8.7% of cases) on chromosome 13q12.2. Analysis of TCGA data (n=619) suggested an association with later stages, which we confirmed by longitudinal plasma analyses. We defined the minimally amplified region and studied the mechanistic consequences of copy number gain of the involved genes. The amplification of one gene, POLR1D, impacted cell proliferation, resulting in upregulation of VEGFA, an important regulator of angiogenesis which has been implicated in the resistance to bevacizumab. In several patients, we observed the emergence of this 13q12.2 amplicon under bevacizumab treatment, which was invariably associated with evolution of therapy resistance. Hence, we describe a novel resistance mechanism against a widely applied treatment in mCRC patients which will impact clinical management .

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CTC - Plasma-DNA - MONDO:0005575

European Genome-Phenome Archivec/o European Bioinformatics InstituteWellcome Trust Genome CampusHinxtonCambridgeCB10 1SDUnited KingdomTo whom it may concern,This document refers to the study EGAS00001000337 which has been submitted to the European Genome Archive (EGA) for the restricted access by legitimate academic institutions that have agreed to comply with the terms of a Data Access Agreement drafted by Ellen Heitzer.There are a number of steps that a researcher must take to obtain access to this data and the process is overseen by Ellen HeitzerEllen Heitzer is a Postdoctoral Fellow and is authorized to approve researchers to have encrypted access to the data submitted to the EGA. Please be advised that Ellen Heitzer (ellen.heitzer@medunigraz.at) is authorized to upload data to the EGA for archiving and distribution as part of your submission process, which will enable approved researchers to have encrypted access to the data. We can confirm that this submission is consistent with the informed consent of the participants of the study or has been granted ethical approval and is in accordance with the applicable laws and regulations.Sincerely,Michael R. SpeicherPrinciple Investigator

Studies are experimental investigations of a particular phenomenon, e.g., case-control studies on a particular trait or cancer research projects reporting matching cancer normal genomes from patients.

Study ID Study Title Study Type
EGAS00001003791 Other

This table displays only public information pertaining to the files in the dataset. If you wish to access this dataset, please submit a request. If you already have access to these data files, please consult the download documentation.

ID File Type Size Located in
EGAF00003127395 fastq.gz 409.7 MB
EGAF00003127396 fastq.gz 500.1 MB
EGAF00003127397 fastq.gz 360.4 MB
EGAF00003127398 fastq.gz 461.3 MB
EGAF00003127399 fastq.gz 400.3 MB
EGAF00003127400 fastq.gz 177.8 MB
EGAF00003127401 fastq.gz 239.0 MB
EGAF00003127402 fastq.gz 156.2 MB
EGAF00003127403 fastq.gz 175.6 MB
EGAF00003127404 fastq.gz 331.8 MB
EGAF00003127405 fastq.gz 559.2 MB
EGAF00003127406 fastq.gz 437.9 MB
EGAF00003127407 fastq.gz 971.7 MB
EGAF00003127408 fastq.gz 278.7 MB
EGAF00003127409 fastq.gz 287.8 MB
EGAF00003127410 fastq.gz 428.4 MB
EGAF00003127411 fastq.gz 513.3 MB
EGAF00003127412 fastq.gz 1.3 GB
EGAF00003127413 fastq.gz 381.2 MB
EGAF00003127414 fastq.gz 469.9 MB
EGAF00003127415 fastq.gz 332.5 MB
EGAF00003127416 fastq.gz 362.2 MB
EGAF00003127417 fastq.gz 346.0 MB
EGAF00003127418 fastq.gz 426.9 MB
EGAF00003127419 fastq.gz 2.6 GB
EGAF00003127420 fastq.gz 500.5 MB
EGAF00003127421 fastq.gz 296.3 MB
EGAF00003127422 fastq.gz 545.7 MB
EGAF00003127423 fastq.gz 428.9 MB
EGAF00003127424 fastq.gz 319.9 MB
EGAF00003127425 fastq.gz 635.0 MB
EGAF00003127426 fastq.gz 385.5 MB
EGAF00003127427 fastq.gz 546.4 MB
EGAF00003127428 fastq.gz 318.3 MB
EGAF00003127429 fastq.gz 379.4 MB
EGAF00003127430 fastq.gz 448.0 MB
EGAF00003127431 fastq.gz 397.4 MB
EGAF00003127432 fastq.gz 313.5 MB
38 Files (18.4 GB)