DNA and RNA sequencing analysis revealed alterations of ANK3, PKHD1 and olfactory transduction as potential biomarker of three-year survival in gastric cancer.

Abstract

4034 Background: Gastric cancer is the third leading cause of cancer related death worldwide. Although targeted and immune therapy have brought new benefit for patients, it still faces challenges of limited effective group and survival. Here we investigate the association of overall survival with DNA and RNA alterations to explore potential biomarkers of prognosis in gastric cancer. Methods: Whole-exome sequencing, RNA sequencing and clinical data of 442 patients with stomach cancer were downloaded from TCGA. Clinical factors and mutational landscape (insertion/ deletion/ single nucleotide variant) were compared between group of OS3+ (overall survival > 3 years) and OS3- (OS < 3 years). Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses were performed based on differentially expressed RNAs between the two groups. Results: 415 of 442 patients with stage information were included. The corresponding rates of OS3+ for patients in stage of I/II/III/IV was 15.5% (9/58), 10.8% (9/58), 10.9% (9/58), 13.6% (9/58), respectively. When comparing the 49 patients with OS3+ to others with OS3-, no difference of stage or sex distribution was discovered, except that OS3+ group had lower median age at diagnosis than OS3- group (63 vs. 71 years, P = 0.029). Tumor mutation burden was comparable between groups. Mutational landscape showed that the two groups shared 70% of top 20 mutations. Among the 20 hot genes, mutations of ANK3(P = 0.006), PKHD1(P = 0.008) were more frequent in OS3+ group, Studies in breast and prostate cancer inferred that, ANK3 was involved in activity of androgen receptor signaling and cyclins, increased expression of ANK3 in cancer was probably associated with better survival. PKHD1 was involved in calcium ion binding and actin binding and was identified as a protective factor for colorectal cancer. OS3- group tend to have higher mutation frequency of HMCN1(P = 0.062). Previous reports showed that mutation of HMCN1 was enriched in peritoneal metastasis of gastric cancer, it might contribute to progression in gastric cancer. Enrichment analysis revealed difference between the two groups in olfactory transduction ( P < 0.01, KEGG analysis), neuroactive ligand-receptor interaction ( P < 0.05, KEGG analysis) and detection of chemical stimulus in sensory perception of smell ( P < 0.01, GO analysis). Numbers of discussions have inferred that genes involved in olfactory transduction may also participate in tumor cell proliferation, migration, and invasion. Conclusions: Patients with OS3+ was enriched with mutations of ANK3 and PKHD1 and present significant functional difference in olfactory transduction. These are potential biomarkers of better survival in gastric cancer. Further studies are needed to figure out their roles in tumor activity and provide insight for novel antitumor treatment development.