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Next generation sequencing of progressive colorectal liver metastases after portal vein embolization

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Abstract

Portal vein embolization (PVE) can be required to stimulate liver regeneration before hepatectomy for colorectal liver metastasis (CRCLM), however PVE may also trigger CRCLM progression in patients initially exhibiting chemotherapy response. Using RNA-seq, we aimed to determine the molecular networks involved in metastatic progression in this context. A prospective study including all CRCLM patients undergoing PVE prior to hepatectomy was conducted. Paired biopsies of metastatic lesions were obtained prior to and after PVE and total RNA was isolated and used to prepare Illumina rRNA-depleted TruSeq stranded cDNA libraries for HiSeq 100 bp paired-end sequencing. Patients were classified with progression of disease (PDPVE) or stable disease (SDPVE) post-PVE using 3D-CT tumor volumetric analysis. Results: Twenty patients were included, 13 (65.0%) in the PDPVE group (median 58.0% (18.6–234.3) increase in tumor volume) and 7 (35.0%) in the SDPVE group exhibiting continuous chemotherapy response (median −14.3% (−40.8 to −2.8) decrease in tumor volume) (p < 0.0001). Our results showed that progressive CRCLM after PVE undergo gene expression changes that indicate activation of core cancer pathways (IL-17 (p = 5.94 × 10−03), PI3K (p = 8.71 × 10−03), IL6 and IGF-1 signaling pathways), consistent with changes driven by cytokines and growth factors. Differential expression analysis in a paired model of progression (EdgeR, DeSeq) identified significantly dysregulated genes in the PDPVE group (FOS, FOSB, RAB20, IRS2). Conclusion: Differentially expressed genes and pathways with known links to cancer and metastasis were identified post-PVE in patients with disease progression. Highlighting these molecular changes is a crucial first step towards development of targeted therapeutic strategies that may mitigate the effects of PVE on tumor growth.

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Abbreviations

CRCLM:

Colorectal cancer liver metastasis

PVE:

Portal vein embolization

RNA:

Ribonucleic acid

FLR:

Future liver remnant

RIN:

RNA intergrity score

CT:

Computed tomography

TLV:

Total liver volume

TV:

Tumor volume

TTV:

Total tumor volume

PDPVE :

Progression of disease post-PVE

SDPVE :

Stable disease post-PVE

RECIST:

Response Evaluation Criteria In Solid Tumors

CR:

Complete response

PR:

Partial response

PD:

Progression of disease

SD:

Stable disease

DEG:

Differentially expressed genes

qRT-PCR:

Quantitative reverse transcription polymerase chain reaction

rRNA:

Ribosomal ribonucleic acid

FDR:

False discovery rate

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Acknowledgements

This study was supported by the Liver Disease Biobank (McGill University Health Center). We would like to thank Dr Bia Dias, as well as the interventional radiology fellows and angiography technicians of the McGill University Health Center Radiology Department. We also would like to thank Genome Quebec for the sequencing and bioinformatics platforms.

Funding

E.S. was supported by a salary grant from FRQS (Fonds de Recherche du Québec en Santé) and by the CIHR (Canadian Institute of Health and Research)/FRSQ training grant in cancer research FRN 53888 of the McGill Integrated Cancer Research Training Program.

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Authors and Affiliations

  1. Department of Surgery, Section of HPB Surgery, McGill University Health Center, Montreal, Canada

    Eve Simoneau, Sarita Negi, Ayat Salman, Anthoula Lazaris, Stephanie Petrillo & Peter Metrakos

  2. Department of Medicine, McGill University, Montreal, Canada

    Jarred Chicoine & Nicole Beauchemin

  3. McGill University Health Center Research Institute, Cancer Research Program, Montreal, Canada

    Anthoula Lazaris & Peter Metrakos

  4. Department of Surgery, King Saud University, Riyadh, Saudi Arabia

    Mazen Hassanain

  5. Department of Oncology, McGill University, Montreal, Canada

    Mazen Hassanain & Nicole Beauchemin

  6. Goodman Cancer Center, Montreal, Canada

    Nicole Beauchemin

  7. Department of Biochemistry, McGill University, Montreal, Canada

    Nicole Beauchemin

  8. Department of Radiology, McGill University Health Center, Montreal, Canada

    David Valenti

  9. Department of Pathology, McGill University Health Center, Montreal, Canada

    Ramila Amre & Peter Metrakos

  10. Department of Surgery, Royal Victoria Hospital, McGill University Health Center, 1001 Decarie Boulevard, Montreal, QC, H4A 3J1, Canada

    Peter Metrakos

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  1. Eve Simoneau
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Correspondence to Peter Metrakos.

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Simoneau, E., Chicoine, J., Negi, S. et al. Next generation sequencing of progressive colorectal liver metastases after portal vein embolization. Clin Exp Metastasis 34, 351–361 (2017). https://doi.org/10.1007/s10585-017-9855-9

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