Proto-oncogene HRAS transcript level and overall survival in stage II and III colorectal cancer.

231 Background: Mutational landscape is prognostic in colorectal cancer (CRC). Driver mutations in the RAS proto-oncogenes such as KRAS and NRAS portend poor survival outcomes, whereas HRAS mutations are extremely rare and their prognostic value remains uncertain. The prognostic implication of RAS gene activity at the transcript level is also obscure. Here, we retrospectively review stage II and III CRC tumor RNA-Seq data and demonstrate that high transcript levels of HRAS are associated with superior overall survival (OS). Methods: Tumor RNA-Seq of 734 stage II and III CRC cases and their associated clinical data were retrieved from the ORIEN AVATAR database (Aster Insights). Transcript level was determined by batch-corrected TPM (transcripts per million) of each gene, and cohort median was used as a reference to determine “high” versus “low” in subgroup analyses. The p-value and hazard ratio (HR) derived from Kaplan-Meier survival analysis are log-rank. Results: The 4-year HR for death in patients with “very high” HRAS transcript level (top 5%) was 0.15 (95% CI 0.07-0.34, p=0.03) compared to the rest, and this superior OS was independent from TNM stage or peri-operative 5-FU treatment history. In subgroup analyses, “high” HRAS expression was associated with superior OS only in patients with concomitant “low” KRAS expression in the absence of pathologic KRAS mutations in codons 12, 13 and 61 – the 5-year HR in “low” KRAS group was 0.42 (95% CI 0.18-0.96, p=0.03) compared to “high” KRAS group. NRAS transcript level did not influence OS. When further sub-grouped based on primary disease location, this superior OS was present only in the right-sided primary disease group with 5-year HR of “low” KRAS group at 0.17 (95% CI 0.03-0.99, p=0.06) compared “high” KRAS group. Conclusions: Contrary to the notion that RAS family genes are proto-oncogenic, we demonstrate that high HRAS transcript levels are associated with superior OS in stage II and III CRC. The high HRAS-associated OS benefit was most pronounced in patients with right-sided primary expressing low KRAS transcript levels in the absence of pathologic KRAS mutations. We speculate that when expressed at high levels, HRAS may counteract proto-oncogene KRAS but not oncogene KRAS at the transcript level. The potential of HRAS as a prognostic biomarker should be explored further.