Focal adhesion kinase (FAK) is a cytoplasmic
tyrosine kinase that mediates multiple cellular functions such as survival, invasion, and migration. FAK has been found to be over-expressed in various human
cancers, including
melanoma. FAK molecule has several
tyrosine,
serine, and
threonine phosphorylation sites which have an important regulatory role.
Tyrosine phosphorylation of FAK has been extensively studied, however little is known about the role of
serine phosphorylation. We sought to examine the frequency and extent of serine-910 phosphorylated FAK (P-FAKSer910) expression in a spectrum of melanocytic proliferations as well as it's correlation with other histopathologic predictors and its effect on patient's survival. Clinicopathologic features and immunohistochemical expression of P-FAKSer910 were evaluated in 147 melanocytic proliferations: 73 primary
melanoma (PM), 19 metastatic
melanoma (MetM), 2
melanoma in situ, and 53
melanocytic nevi (MN). Higher cytoplasmic intensity predicted better overall survival (OS) in PM (χ=5.69; P=0.034) and was associated with 48% decrease in death risk (HR, 0.52; 95% CI, 0.28-0.95; P=0.036). In contrast, increased nuclear intensity was significantly associated with better disease-free survival (DFS) when stratified by
tumor stage Log-rank test, trend of survival (χ=5.83, P=0.015) and independently on multivariate analysis when subcategorized into 3-tier categories (HR, 0.43; 95% CI, 0.18-0.98; P=0.045). Also, Clark's level and tumor-infiltrating lymphocytes (TILS) were independent predictors of DFS. Cytoplasmic intensity correlated inversely with American Joint Commission on
Cancer stage in primary
melanoma cases as well with vascularity in both primary and metastatic
melanoma. Nuclear intensity independently correlated negatively with angioinvasion and TILS when subcategorized to 3 tier system. We found American Joint Commission on
Cancer tumor stage, Clark's level, depth, ulceration, TILS, mitosis, angioinvasion, and
tumor vascularity predictors of both DFS and OS. There was no significant difference in cytoplasmic or nuclear expression among the major categories of melanocytic proliferation. In this pilot immunohistochemistry-based study, we found P-FAKSer910 expression in
melanoma by cytoplasmic intensity to correlate with better OS while nuclear intensity correlated with better DFS.