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Emerging transcriptional landscape and putative therapeutic targets in young patients with metastatic colorectal cancer (CRC).
Background: Patients younger than 50 yrs of age comprise roughly 10% of the total incidence of CRC, but the incidence in the younger population is increasing. Recent data suggest that younger patients are at higher risk of progression of disease and death from CRC. The purpose of this pilot study was to investigate genomic differences between younger and older CRC tumors to generate hypotheses regarding potential differences in tumor biology that may explain worse outcome in young patients. Methods: To determine genomic differences in tumors from younger and older patients with CRC, a cohort of metastatic microsatellite stable CRC tumors was selected using tumors from 9 younger patients (< 35 yrs) and 7 older patients (> 70 yrs). Total RNA was extracted from tumor tissues and sequenced with Illumina HiSeq 2000. On average, 45 million reads were obtained from individual tumor samples. Sequencing reads were mapped to the reference genome using Bowtie; exon junctions were mapped using TopHat and transcript assembly was performed using Cufflinks. Results: The median ages for the younger and older cohorts were 31 and 73, respectively. From the RNA-seq analysis, gene expression profiles from younger patients were enriched for pathways involved in cell proliferation. Specifically ERBB2, NOTCH3, CAV1 were upregulated in multiple pathways in young patients (p < 0.00001). The expression pattern was noted to be different in older patients with enrichment for CDX2, HMGB3, and EPHB2 within pathways involved in regulation of cell differentiation (p = 0.07). In total 77 genes were noted to be enriched in younger patients compared with older patients and 23 genes were enriched in older patients compared with young patients (FDR < 0.05). These data, although preliminary, may provide support to explore ERBB2, NOTCH, and downstream signaling pathways as therapeutic targets for younger patients. Conclusions: In this pilot study, patients < 35 yrs with metastatic CRC exhibited gene sets enriched for several cellular proliferation pathways, including significant upregulation of ERRB2, NOTCH3, and CAV1. These results are hypothesis generating and are being investigated further in a larger validation cohort.