Random survival forests identify pathways with polymorphisms predictive of survival in KRAS mutant and KRAS wild-type metastatic colorectal cancer patients

Naseem, Madiha; Cao, Shu; Yang, Dongyun; Millstein, Joshua; Puccini, Alberto; Loupakis, Fotios; Stintzing, Sebastian; Cremolini, Chiara; Tokunaga, Ryuma; Battaglin, Francesca; Soni, Shivani; Berger, Martin D.; Barzi, Afsaneh; Zhang, Wu; Falcone, Alfredo; Heinemann, Volker und Lenz, Heinz-Josef (2021): Random survival forests identify pathways with polymorphisms predictive of survival in KRAS mutant and KRAS wild-type metastatic colorectal cancer patients. In: Scientific Reports, Bd. 11, Nr. 1, 12191

Abstract

KRAS status serves as a predictive biomarker of response to treatment in metastatic colorectal cancer (mCRC). We hypothesize that complex interactions between multiple pathways contribute to prognostic differences between KRAS wild-type and KRAS mutant patients with mCRC, and aim to identify polymorphisms predictive of clinical outcomes in this subpopulation. Most pathway association studies are limited in assessing gene-gene interactions and are restricted to an individual pathway. In this study, we use a random survival forests (RSF) method for identifying predictive markers of overall survival (OS) and progression-free survival (PFS) in mCRC patients treated with FOLFIRI/bevacizumab. A total of 486 mCRC patients treated with FOLFIRI/bevacizumab from two randomized phase III trials, TRIBE and FIRE-3, were included in the current study. Two RSF approaches were used, namely variable importance and minimal depth. We discovered that Wnt/beta -catenin and tumor associated macrophage pathway SNPs are strong predictors of OS and PFS in mCRC patients treated with FOLFIRI/bevacizumab independent of KRAS status, whereas a SNP in the sex-differentiation pathway gene, DMRT1, is strongly predictive of OS and PFS in KRAS mutant mCRC patients. Our results highlight RSF as a useful method for identifying predictive SNPs in multiple pathways.

• Dokumententyp: Zeitschriftenartikel
• Fakultät: Medizin
• Themengebiete: 600 Technik, Medizin, angewandte Wissenschaften > 610 Medizin und Gesundheit
• ISSN: 2045-2322
• Sprache: Englisch