Abstract
Pancreatic adenocarcinoma (PAAD) is one of the deadliest malignancies and mortality for PAAD have remained increasing under the conditions of substantial improvements in mortality for other major cancers. Although multiple of studies exists on PAAD, few studies have dissected the oncogenic mechanisms of PAAD based on genomic variation. In this study, we integrated somatic mutation data and gene expression profiles obtained by high-throughput sequencing to characterize the pathogenesis of PAAD. The mutation profile containing 182 samples with 25,470 somatic mutations was obtained from The Cancer Genome Atlas (TCGA). The mutation landscape was generated and somatic mutations in PAAD were found to have preference for mutation location. The combination of mutation matrix and gene expression profiles identified 31 driver genes that were closely associated with tumor cell invasion and apoptosis. Co-expression networks were constructed based on 461 genes significantly associated with driver genes and the hub gene FAM133A in the network was identified to be associated with tumor metastasis. Further, the cascade relationship of somatic mutation-Long non-coding RNA (lncRNA)-microRNA (miRNA) was constructed to reveal a new mechanism for the involvement of mutations in post-transcriptional regulation. We have also identified prognostic markers that are significantly associated with overall survival (OS) of PAAD patients and constructed a risk score model to identify patients’ survival risk. In summary, our study revealed the pathogenic mechanisms and prognostic markers of PAAD providing theoretical support for the development of precision medicine.
Highlights
Pancreatic adenocarcinoma (PAAD) remains one of the deadliest cancer types and has become the leading cause of cancer-related mortality in the United States (Rahib et al, 2014; Ilic and Ilic, 2016)
We found that somatic mutations were significantly enriched on chromosomes 17 and 19 (Figure 1A), suggesting the preference of PAAD somatic mutation in the mutation position
As a mutated gene commonly occurring in PAAD patients, TTN has multiple non-sense mutation hot spots (Figure 1D), which will have a significant impact on the function and structure of its encoded protein
Summary
Pancreatic adenocarcinoma (PAAD) remains one of the deadliest cancer types and has become the leading cause of cancer-related mortality in the United States (Rahib et al, 2014; Ilic and Ilic, 2016). The incidence and mortality rates of PAAD vary widely worldwide and are highest in developed countries (McGuigan et al, 2018). Several of treatments exist that can improve the prognosis of PAAD patients. Nab-paclitaxel plus gemcitabine (Von Hoff et al, 2013) and FOLFIRINOX vs gemcitabine (Conroy et al, 2011). These treatments have improved the survival of some patients, the 5-year survival rate of PAAD still remains severe at 8% (Siegel et al, 2017). It is necessary to deeply discover the carcinogenic mechanism and possible therapeutic targets of PAAD
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