Identification and validation of PCSK9 as a prognostic and immune-related influencing factor in tumorigenesis: a pan-cancer analysis

Abstract

IntroductionProprotein convertase subtilisin/kexin-9 (PCSK9) has been primarily studied in the cardiovascular field however, its role in cancer pathophysiology remains incompletely defined. Recently, a pivotal role for PCSK9 in cancer immunotherapy was proposed based on the finding that PCSK9 inhibition was associated with enhancing the antigen presentation efficacy of target programmed cell death-1 (PD-1). Herein, we provide results of a comprehensive pan-cancer analysis of PCSK9 that assessed its prognostic and immunological functions in cancer.MethodsUsing a variety of available online cancer-related databases including TIMER, cBioPortal, and GEPIA, we identified the abnormal expression of PCSK9 and its potential clinical associations in diverse cancer types including liver, brain and lung. We also validated its role in progression-free survival (PFS) and immune infiltration in neuroblastoma.ResultsOverall, the pan-cancer survival analysis revealed an association between dysregulated PCSK9 and poor clinical outcomes in various cancer types. Specifically, PCSK9 was extensively genetically altered across most cancer types and was consistently found in different tumor types and substages when compared with adjacent normal tissues. Thus, aberrant DNA methylation may be responsible for PCSK9 expression in many cancer types. Focusing on liver hepatocellular carcinoma (LIHC), we found that PCSK9 expression correlated with clinicopathological characteristics following stratified prognostic analyses. PCSK9 expression was significantly associated with immune infiltrate since specific markers of CD8+ T cells, macrophage polarization, and exhausted T cells exhibited different PCSK9-related immune infiltration patterns in LIHC and lung squamous cell carcinoma. In addition, PCSK9 was connected with resistance of drugs such as erlotinib and docetaxel. Finally, we validated PCSK9 expression in clinical neuroblastoma samples and concluded that PCSK9 appeared to correlate with a poor PFS and natural killer cell infiltration in neuroblastoma patients.ConclusionPCSK9 could serve as a robust prognostic pan-cancer biomarker given its correlation with immune infiltrates in different cancer types, thus potentially highlighting a new direction for targeted clinical therapy of cancers.

Prognostic Value of PCSK9 Levels in Premenopausal Women at Risk of Breast Cancer—Evidence from a 17-Year Follow-Up Study

“…However, no prognostic conclusions were made [14]. A pan-cancer analysis found that PCSK9 expression was considerably higher in invasive breast carcinoma [24]. A large Mendelian randomization study including results from >400,000 participants showed that LDL-C variants mimicking PCSK9 inhibitors were associated with a lower risk [15].…”

Drug development advances in human genetics‐based targets

“…94 Furthermore, several experiments have demonstrated that PCSK9 is associated with cancers. 95,96 In conclusion, PCSK9 can play pleiotropic roles in various biological pathways, but the most widely studied remains its function in maintaining cholesterol homeostasis. 98 ) and one siRNA (inclisiran 99 ) targeting PCSK9 have been approved and marketed globally (Table 1).…”

“…It has been shown that PCSK9 LOF prevents the development of abdominal aortic aneurysm in preclinical mouse models 94 . Furthermore, several experiments have demonstrated that PCSK9 is associated with cancers 95,96 . In conclusion, PCSK9 can play pleiotropic roles in various biological pathways, but the most widely studied remains its function in maintaining cholesterol homeostasis.…”

Emerging Targets and Therapeutics in Immuno-Oncology: Insights from Landscape Analysis

“…This could also be a result of the program picking up phrases outside of a given context (i.e., biomarker vs target), though manual curation of data by subject matter experts has ensured, where possible, that concepts picked out are pertinent. Among biomarkers, nectin-4, 55 SET domain containing 2 (SETD2), 56 ENO1, 57 TROP2, 58 tumor mutation burden (TMB), 59 PCSK9, 60 and LILRB1 61 appear to be growing at a fast pace, while p62, 62 COX-2, 63 and TDO 64 show unremarkable/ negligible growth (Figure 2). In addition to the trend landscape map, we also determined the year at which a particular concept started to emerge and crafted timelines for the emergence of targets, therapies, and biomarkers in immuno-oncology (Figures 5, S5, and S6).…”

“…This could also be a result of the program picking up phrases outside of a given context (i.e., biomarker vs target), though manual curation of data by subject matter experts has ensured, where possible, that concepts picked out are pertinent. Among biomarkers, nectin-4, 55 SET domain containing 2 (SETD2), 56 ENO1, 57 TROP2, 58 tumor mutation burden (TMB), 59 PCSK9, 60 and LILRB1 61 appear to be growing at a fast pace, while p62, 62 COX-2, 63 and TDO 64 show unremarkable/negligible growth ( Figure 2 ).…”