Copy number gains at chr3p25 and chr11p11 are associated with lymph node involvement and survival in muscle-invasive bladder tumors

Abstract

Patients with muscle-invasive bladder cancer (MIBC) have poorer prognoses if cancer has metastasized to the lymph nodes. Genomic markers of lymph node involvement (LNI) would be useful for treatment planning, especially if measured at the biopsy stage, but large-scale studies of tumor tissue at any stage are needed to discover robust markers of LNI. We performed a genome-wide query of copy number alterations (CNA) in 237 MIBC surgical tumor specimens from patients in The Cancer Genome Atlas who had radical cystectomy and lymphadenectomy without neoadjuvant treatment. Pathology reports were independently reviewed to confirm LNI, and copy number data was analyzed to confirm gene-level gains and losses while adjusting for tumor purity and ploidy. Using logistic regression and elastic net models, we identified the CNA most significantly associated with LNI. Multivariable logistic regression was used to describe these CNA associations while adjusting for clinical variables. Kaplan-Meier and Cox regression were used to describe their association with overall survival. Gains in 26 genes were identified as having strong associations with LNI. After adjusting for age, gender, race, pathological tumor stage, histology, and number of nodes examined, gains in 22 genes on chr3p25 or chr11p11 remained significantly associated with LNI (p<0.01) and improved model discrimination over clinical variables alone (p = 0.04). They were also associated with shorter overall survival (adjusted p = 0.02). These results suggest that a simple genomic test for gains in chr3p25 and chr11p11 could inform adjuvant treatment or clinical trial decisions if validated in external cohorts. Additional studies will also be needed to determine if these CNA are detectible in biopsy tissue and can inform clinical decisions at the preoperative stage.