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Combination of variations in inflammation- and endoplasmic reticulum-associated genes as putative biomarker for bevacizumab response in KRAS wild-type colorectal cancer

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posted on 03.08.2021, 15:15 by Ana Barat, Dominiek Smeets, Bruce Moran, Wu Zhang, Shu Cao, Sudipto DasSudipto Das, Rut Klinger, Johannes Betge, Verena Murphy, Orna Bacon, Elaine W Kay, Nicole C T Van Grieken, Henk M W Verheul, Timo Gaiser, Nadine Schulte, Matthias P Ebert, Bozena Fender, Bryan HennessyBryan Hennessy, Deborah McNamaraDeborah McNamara, Darran O'ConnorDarran O'Connor, William M Gallagher, Chiara Cremolini, Fotios Loupakis, Aparna Parikh, Christoph Mancao, Bauke Ylstra, Diether Lambrechts, Heinz-Josef Lenz, Annette ByrneAnnette Byrne, Jochen PrehnJochen Prehn
Chemotherapy combined with the angiogenesis inhibitor bevacizumab (BVZ) is approved as a first-line treatment in metastatic colorectal cancer (mCRC). Limited clinical benefit underpins the need for improved understanding of resistance mechanisms and the elucidation of novel predictive biomarkers. We assessed germline single-nucleotide polymorphisms (SNPs) in 180 mCRC patients (Angiopredict [APD] cohort) treated with combined BVZ + chemotherapy and investigated previously reported predictive SNPs. We further employed a machine learning approach to identify novel associations. In the APD cohort IL8 rs4073 any A carriers, compared to TT carriers, were associated with worse progression-free survival (PFS) (HR = 1.51, 95% CI:1.03–2.22, p-value = 0.037) and TBK1 rs7486100 TT carriers, compared to any A carriers, were associated with worse PFS in KRAS wild-type (wt) patients (HR = 1.94, 95% CI:1.04–3.61, p-value = 0.037), replicating previous findings. Machine learning identified novel associations in genes encoding the inflammasome protein NLRP1 and the ER protein Sarcalumenin (SRL). A negative association between PFS and carriers of any A at NLRP1 rs12150220 and AA for SRL rs13334970 in APD KRAS wild-type patients (HR = 4.44, 95% CI:1.23–16.13, p-value = 0.005), which validated in two independent clinical cohorts involving BVZ, MAVERICC and TRIBE. Our findings highlight a key role for inflammation and ER signalling underpinning BVZ + chemotherapy responsiveness.

Funding

European Union Seventh Framework Programme FP7 under grant agreement No. 278981 “ANGIOPREDICT”

Science Foundation Ireland (14/IA/2582 and 13/CDA/2183)

History

Comments

The original article is available at https://www.nature.com

Published Citation

Barat A et al. Combination of variations in inflammation- and endoplasmic reticulum-associated genes as putative biomarker for bevacizumab response in KRAS wild-type colorectal cancer. Sci Rep. 2020;10(1):9778.

Publication Date

17 June 2020

PubMed ID

32555399

Department/Unit

  • Beaumont Hospital
  • Centre for Systems Medicine
  • School of Pharmacy and Biomolecular Sciences
  • Physiology and Medical Physics

Research Area

  • Cancer
  • Immunity, Infection and Inflammation

Publisher

Nature Publishing Group

Version

  • Published Version (Version of Record)