Use of leucine-rich and immunoglobulin-like domains germ-line polymorphisms to predict clinical outcome in metastatic colorectal cancer.

Abstract

e14052 Background: Leucine-rich and immunoglobulin-like domains (LRIG) 1, 2, and 3 are integral membrane proteins recently discovered as regulators of the epidermal growth factor signalling. LRIG1 negatively regulates growth factor signaling and increasing evidence indicates that LRIG1 is a tumor suppressor in certain cancer types. Lrig1 is expressed at low levels in several cancer types but is overexpressed in some colorectal tumors.We postulate that polymorphisms located in the LRIG1 gene could influence the EGFR signalling pathway and be related with the clinical outcome in metastatic colorectal cancer (mCRC). Methods: This study included 318 patients with mCRC treated between 1992 and 2003 at the University of Southern California/Norris Comprehensive Cancer Center or Los Angeles County/University of Southern California Medical Center. Common and putatively functional polymorphisms in the LRIG genes were selected using public literature resources and databases (NCBI, PubMed, db SNP, Ensembl and GeneCards). Whole blood samples were analyzed for germline polymorphisms by direct DNA-sequencing. Overall survival (OS) was evaluated according to each genotype. Furthermore, polymorphisms with suggestive statistical significance were replicated in an independent validation cohort of 126 Spanish mCRC. Results: In a preliminary analysis, two non-synonymous (c3158A>C and c1843A>G) and two synonymous (c2221T>C and c1317C>T) polymorphisms in the LRIG1 gene were selected. There were significant interactions between LRIG1 c1317C>T polymorphisms and clinical outcome. OS was lower for patients harboring T/T genotype (median=11.9 months, 95% C.I (3.5-16 months) than for patients with the C/C or C/T genotypes (median=14.5 months; 95% C.I (12.2-18.3 months); p= 0.04, log-rank test) and the association was also significant in the validation cohort (p=0.01). Conclusions: In this study, we identified common germline variants in LRIG1 gene predicting clinical outcome in patients with mCRC. Although, no functionality has been documented for these SNPs to date, our clinical data suggest that these polymorphisms may affect the mRNA stability and/or translation efficiency of the gene.