Identification of Multisialylated LacdiNAc Structures as Highly Prostate Cancer Specific Glycan Signatures on PSA

Abstract

Serum prostate-specific antigen (PSA) test is the current gold standard for screening and diagnosis of prostate cancer (PCa), while overdiagnosis and overtreatment are social problems. In order to improve the specificity and exclude a false positive diagnosis in PSA test, PCa-specific glycosylation subtypes of PSA were explored using in-depth quantitative profiling of PSA glycoforms based on mass spectrometric oxonium ion monitoring technology. As a result of analysis using sera from 15 PCa or 15 benign prostate hyperplasia (BPH) patients whose PSA levels were in the "gray zone" (4.0−10.0 ng/mL), 52 glycan structures on PSA were quantitatively observed. We found that abundance of multisialylated LacdiNAc (GalNAcβ1−4GlcNAc) structures were significantly upregulated in the PCa group compared to the BPH group. A couple of those glycoforms were then extracted and subjected to establish a novel PCa-specific diagnosis model (PSA G-index). When the diagnostic power was assessed using an independent validation sample set (15 PCa and 15 BPH patients in the PSA gray zone), an AUC of PSA G-index was 1.00, while that of total PSA or PSA f/T ratio was 0.50 or 0.60, respectively. Moreover, both PSA glycoforms showed significant correlation with Gleason scores. Lectin histochemical staining analysis also showed that PCa cells overexpressed glycoproteins containing LacdiNAc and sialic acids moieties. Thus, PSA G-index could serve as not only an effective secondary screening method to exclude false positive diagnosis in PSA screening, but also a potential grading biomarker for PCa.

Study of glycosylation of prostate-specific antigen secreted by cancer tissue-originated spheroids reveals new candidates for prostate cancer detection

“…We previously identified PSA with tri-antennary glycan in prostate cancer serum by MALDI-MS 38 . Haga et al 39 analysed glycan structures of PSA using LC-MS/MS and their data showed that multi-antennary glycans are present in greater amounts in the sera of prostate cancer patients compared with BPH patients.…”

“…Many studies have been done which focus glycans as biomarkers in prostate cancer 3 , especially N-glycan alterations of PSA [9][10][11][12]39,43,44 . Previous studies have revealed that not all patients can be detected by measuring the increase focusing only on a specific glycan structure such as α2,3-sialyl or LacdiNAc residues [9][10][11][12]43,44 .…”

Laser cleavable probes for in situ multiplexed glycan detection by single cell mass spectrometry

“…The aberrant expression of glycans is oen associated with various human diseases, such as prostate cancer and colorectal cancer. [5][6][7][8][9] Therefore, the analysis of glycans can offer insight into glycosylation functions and contribute to diagnosis and targeted therapy.…”

Strategies for the Development of Metallic‐Nanoparticle‐Based Label‐Free Biosensors and Their Biomedical Applications

“…Prostate cancer is the leading cancer in males from which the mortality rate is increasing . Early diagnosis of this disease is needed for therapy.…”

“…Prostate cancer is the leadingc ancer in males from which the mortality rate is increasing. [120] Early diagnosis of this disease is neededf or therapy. Prostate cancera ntigen 3( PCA3) is expressed rapidly in prostate tissue during this disease.…”