Sex-Associated Gene Expression Alterations Correlate With Esophageal Cancer Survival

Esophageal cancer (EC) is a significant cause of cancer death with 5-year survival of 10%-15% and males more frequently affected. Genetic evaluation for loci highlighting risk has been performed, but survival data are limited. The Cancer Genome Atlas (TCGA) data sets allow for potential prognostic marker assessment in large patient cohorts. The study aimed to use the TCGA EC data set to assess whether survival varies by sex and explore genetic alterations that may explain variation observed.

TCGA clinical/RNA-seq data sets (n = 185, 158 males/27 females) were downloaded from the cancer genome browser. Data analysis/figure preparation was performed in R and GraphPad Prism 7. Survival analysis was performed using the survival package. Text mining of PubMed was performed using the tm, RISmed, and wordcloud packages. Pathway analysis was performed using the Reactome database.

In EC, male sex/high tumor grade reduced overall survival (hazard ratio = 2.27 [0.99-5.24] for M vs F and 2.49 [0.89-6.92] for low vs high grade, respectively) and recurrence-free survival (hazard ratio = 4.09 [0.98-17.03] for M vs F and 3.36 [0.81-14.01] for low vs high grade, respectively). To investigate the genetic basis for sex-based survival differences in EC, corresponding gene expression data were analyzed. Sixty-nine genes were dysregulated at the P < 0.01 level by the Wilcox test, 33% were X-chromosome genes, and 7% were Y-chromosome genes.

Female sex potentially confers an EC survival advantage. Importantly, we demonstrate a genetic/epigenetic basis for these survival differences that are independent of lifestyle-associated risk factors overrepresented in males. Further research may lead to novel concepts in treating/measuring EC aggressiveness by sex.