Analysis of immune-related genes (IRGs) and their potential role in sexual dimorphism in patients (pts) with metastatic colorectal cancer (mCRC).
Authors: Mittal Pooja , Yang Yan , Soni Shivani , Battaglin Francesca , Millstein Joshua , Stintzing Sebastian , Parikh Aparna Raj , Lo Jae Ho , Torres-Gonzalez Lesly , Algaze Sandra , Jayachandran Priya , Ashouri Karam , Wong Alexandra , Zhang Wu , Venook Alan P. , Mancao Christoph , Cremolini Chiara , Heinemann Volker , Singh Indrakant Kumar , Lenz Heinz-Josef 
Published: January 2024

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Background: Sex-based disparities have been reported for mCRC both in incidence, males having higher incidence than females, and in outcome, younger females having better outcome than males of same age or older females. Tumor immune microenvironment is hypothesized to have role in this sexual dimorphic pattern. Herein, we explored the role of gene expression (exp) and genetic variation of IRGs on progression-free (PFS) and overall survival (OS) in mCRC pts. Methods: 21 IRGs with potential roles in CRC were identified from literature review. The association of tumor gene exp with PFS and OS was evaluated in pts with mCRC (433 pts, RNA seq) from CALGB/SWOG 80405. Subgroup analyses were based on treatment (bevacizumab [bev] (N = 226) / cetuximab [cet] (N = 207)) and sex (male (N = 271) / female (N = 162)). Further, the impact on outcome of 5 selected germline single nucleotide polymorphisms (SNPs) in 3 significant IRGs, SCG2 (rs600257, rs9283537), CRIP2 rs66717274, and AXIN2 (rs7591, rs2240308), was evaluated in genotyped (OncoArray, Illumina) samples of 451 pts from 2 clinical trials: FIRE-3 (FOLFIRI-bev, N = 107; FOLFIRI-cet, N = 129) and TRIBE (FOLFIRI-bev, N = 215). Unadjusted associations were evaluated using log-rank (lr) tests; covariate-adjusted analyses were performed using Cox models for hazard ratio (HR) estimation and likelihood ratio testing. Results: Of 21 analyzed IRGs, SCG2, CRIP2 and AXIN2 significantly associated with PFS and OS in mCRC pts in CALGB/SWOG 80405 divided into tertiles of high, medium and low exp. Among pts receiving cet treatment, SCG2high (PFS: median 9.0 vs 13.0 months (mo), lrP = 0.015; OS: 20.4 vs 37.4 mo, lrP = 2.9e-05) and CRIP2high (PFS: 9.2 vs 14.2 mo, lrP = 0.00076; OS: 20.9 vs 36.3 mo, lrP = 8.3e-05) were significantly associated with shorter PFS and OS, whereas AXIN2high (PFS: 14.1 vs 7.3 mo, lrP = 2.4e-06; OS: 37.1 vs 15.6 mo, lrP = 4.9e-05) correlated with longer PFS and OS. Sex-based differences were observed, SCG2high exp associated with shorter PFS (10.0 vs 13.1 mo, lrP = 0.0054) and OS (22.3 vs 36.0 mo, lrP = 7.7e-05), and similarly CRIP2high associated with shorter PFS (9.8 vs 14.2 mo, lrP = 0.012) and OS (23.6 vs 35.8 mo, lrP = 4e-04), in males but not in females. In univariate SNP analysis, SCG2 rs9283537 any A allele showed shorter PFS (HR = 0.62, 95% Confidence interval [CI] = 0.40-0.98, P = 0.039) in females but longer PFS (HR = 2.37, 95% CI = 1.07-5.22, P = 0.028) in males compared to G/G carriers in the FIRE-3 cet cohort and interaction analysis showed significant p-values for PFS and OS (P<0.005). Conclusions: Our results highlight important role for SCG2, CRIP2, and AXIN2 as prognostic and predictive biomarkers for first-line treatment in mCRC, with potential targeted agent- and pt’s sex-based differences. These biomarkers with further validation may contribute to personalized treatment strategies for mCRC pts.