Combination of variations in inflammation- and endoplasmic reticulum-associated genes as putative biomarker for bevacizumab response in KRAS wild-type colorectal cancer
journal contributionposted 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.
European Union Seventh Framework Programme FP7 under grant agreement No. 278981 “ANGIOPREDICT”
Science Foundation Ireland (14/IA/2582 and 13/CDA/2183)
CommentsThe original article is available at https://www.nature.com
Published CitationBarat 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 Date17 June 2020
- Beaumont Hospital
- Centre for Systems Medicine
- School of Pharmacy and Biomolecular Sciences
- Physiology and Medical Physics
- Immunity, Infection and Inflammation
PublisherNature Publishing Group
- Published Version (Version of Record)
Endoplasmic ReticulumColorectal NeoplasmsInflammationAngiogenesis InhibitorsAdaptor Proteins, Signal TransducingMembrane ProteinsCombined Modality TherapyCohort StudiesSignal TransductionPolymorphism, Single NucleotideProto-Oncogene Proteins p21(ras)Apoptosis Regulatory ProteinsGenetic Association StudiesMachine LearningBiomarkers, TumorBevacizumabProgression-Free SurvivalOutcome and Process Assessment, Health Care