Stage Dependence, Cell-Origin Independence, and Prognostic Capacity of Serum Glycan Fucosylation, β1–4 Branching, β1–6 Branching, and α2–6 Sialylation in Cancer

Glycans represent a promising but
only marginally accessed source
of cancer markers. We previously reported the development of a molecularly
bottom-up approach to plasma and serum (P/S) glycomics based on glycan
linkage analysis that captures features such as α2–6
sialylation, β1–6 branching, and core fucosylation as
single analytical signals. Based on the behavior of P/S glycans established
to date, we hypothesized that the alteration of P/S glycans observed
in cancer would be independent of the tissue in which the tumor originated
yet exhibit stage dependence that varied little between cancers classified
on the basis of tumor origin. Herein, the diagnostic utility of this
bottom-up approach as applied to lung cancer patients (n = 127 stage I; n = 20 stage II; n = 81 stage III; and n = 90 stage IV) as well as
prostate (n = 40 stage II), serous ovarian (n = 59 stage III), and pancreatic cancer patients (n = 15 rapid autopsy) compared to certifiably healthy individuals
(n = 30), nominally healthy individuals (n = 166), and risk-matched controls (n =
300) is reported. Diagnostic performance in lung cancer was stage-dependent,
with markers for terminal (total) fucosylation, α2–6
sialylation, β1–4 branching, β1–6 branching,
and outer-arm fucosylation most able to differentiate cases from controls.
These markers behaved in a similar stage-dependent manner in other
types of cancer as well. Notable differences between certifiably healthy
individuals and case-matched controls were observed. These markers
were not significantly elevated in liver fibrosis. Using a Cox proportional
hazards regression model, the marker for α2–6 sialylation
was found to predict both progression and survival in lung cancer
patients after adjusting for age, gender, smoking status, and stage.
The potential mechanistic role of aberrant P/S glycans in cancer progression
is discussed.