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

• Published in: Scientific reports 2020-06, Vol.10 (1), p.9778-9778, Article 9778
• Main Authors: Barat, Ana, Smeets, Dominiek, Moran, Bruce, Zhang, Wu, Cao, Shu, Das, Sudipto, Klinger, Rut, Betge, Johannes, Murphy, Verena, Bacon, Orna, Kay, Elaine W., Van Grieken, Nicole C. T., Verheul, Henk M. W., Gaiser, Timo, Schulte, Nadine, Ebert, Matthias P., Fender, Bozena, Hennessy, Bryan T., McNamara, Deborah A., O’Connor, Darran, Gallagher, William M., Cremolini, Chiara, Loupakis, Fotios, Parikh, Aparna, Mancao, Christoph, Ylstra, Bauke, Lambrechts, Diether, Lenz, Heinz-Josef, Byrne, Annette T., Prehn, Jochen H. M.
• Format: Article
• Language: English
• Subjects: 45/23; 631/67/2324; 692/4028/67/1504/1885; Adaptor Proteins, Signal Transducing - genetics; Aged; Angiogenesis inhibitors; Angiogenesis Inhibitors - therapeutic use; Apoptosis Regulatory Proteins - genetics; Bevacizumab; Bevacizumab - therapeutic use; Biomarkers; Biomarkers, Tumor - genetics; Chemotherapy; Cohort Studies; Colorectal cancer; Colorectal carcinoma; Colorectal Neoplasms - drug therapy; Colorectal Neoplasms - genetics; Colorectal Neoplasms - therapy; Combined Modality Therapy; Endoplasmic reticulum; Endoplasmic Reticulum - genetics; Endoplasmic Reticulum - metabolism; Female; Genetic Association Studies; Humanities and Social Sciences; Humans; Immunotherapy; Inflammasomes; Inflammation - genetics; Interleukin 8; K-Ras protein; Learning algorithms; Machine Learning; Male; Membrane Proteins - genetics; Metastases; Middle Aged; Monoclonal antibodies; multidisciplinary; Outcome and Process Assessment, Health Care - methods; Patients; Polymorphism, Single Nucleotide; Progression-Free Survival; Proto-Oncogene Proteins p21(ras) - genetics; Science; Science (multidisciplinary); Signal Transduction; Single-nucleotide polymorphism; Targeted cancer therapy
• ISSN: 2045-2322; 2045-2322
• DOI: 10.1038/s41598-020-65869-2

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.