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

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.