Recently several supervised learning methods such as

Recently, several supervised learning methods, such as decision trees, have been applied to the analysis of cDNA microarrays to refine prognosis in nasopharyngeal carcinoma, breast cancer and non–small-cell lung cancer.(Chen et al., 2007) State-of-the-art classification algorithms such as support vector machines (SVMs) can be used to select a small subset of highly discriminating markers and patients or disease attributes to build reliable cancer classifiers.(Wang et al., 2011). In this study, we analyzed PAK6 herpes simplex virus in GC specimens by immunohistochemical (IHC) analysis and assessed its relationship with disease-free survival (DFS), overall survival (OS) and chemosensitivity. We further assessed the predictive value of COX2, p21, Ki-67, TS and ERCC1 and then constructed a SVM classifier – chemotherapy score (CS-SVM) – integrating PAK6, Ki-67, TS, ERCC1, COX2, and p21, that could effectively identify a small subset of GC patients that would highly benefit from 5-FU/oxaliplatin chemotherapy.
Materials and Methods
Results
Discussion To our knowledge, this is the first study to identify the potential prognostic and predictive value of PAK6 in GC. Increased PAK6 expression indicated a more aggressive phenotype and chemoresistance to 5-FU/oxaliplatin chemotherapy. We further assessed the predictive value of PAK6, COX2, p21, Ki-67, TS, and ERCC1 in stage II and III GC and then constructed a SVM classifier integrating PAK6, Ki-67, TS, COX2, ERCC1, and p21. The classifier effectively helped to identify a subgroup of stage II and III patients who would highly benefit from 5-FU/oxaliplatin chemotherapy, thus leading to a more personalized therapy. Overexpression of PAK6 has previously been reported in primary and metastatic pancreatic cancer and has been shown to be further increased in recurrence tumors after androgen deprivation therapy.(Kaur et al., 2008) In addition, PAK6 expression has been found to be increased in PCa, CRC and HCC (Chen et al., 2014, 2015) but decreased in ccRCC (Liu et al., 2014). PAK6 expression was also regarded as a potentially predictor for the differentiation of human uterine cervical adenocarcinoma from squamous cell carcinoma (Lee et al., 2010). Furthermore, PAK6 decreased 5-FU drug susceptibility in colon cancer cells and was an independent prognostic factor for adjuvant 5-FU-based chemotherapy in patients with stage II and III colon cancer (Chen et al., 2015). High PAK6 expression in PCa may reduce chemosensitivty and decrease survival (Wen et al., 2009; Zhang et al., 2010). In the present study, we initially measured PAK6 expression by IHC in FFPE GC specimens and found that PAK6 had higher expression in GC tissues than in the surrounding nontumor mucosa. PAK6 expression was associated with poor prognosis of GC patients with chemotherapy, but was not significantly associated with prognosis in the no chemotherapy patients. Furthermore, high PAK6 expression increased chemoresistance in 5-FU/oxaliplatin chemotherapy patients. Microsatellite instability (MSI) is a tumor phenotype linked to somatic or germline (Lynch syndrome) inactivating alterations of DNA mismatch repair genes. Results from a large cohort showed that MSI-H tumors were associated with a good prognosis in Stage II and III gastric cancer when patients were treated by surgery alone, and the benefits of MSI-H status were attenuated by chemotherapy (Kim et al., 2015). In the Medical Research Council Adjuvant Gastric Infusional Chemotherapy (MAGIC) trial, mismatch repair (MMR) deficiency and high MSI were associated with a positive prognostic effect in patients treated with surgery alone and a differentially negative prognostic effect in patients treated with chemotherapy (Smyth et al., 2017). According to a phase II study, MMR deficiency renders different solid tumors highly sensitive to immune checkpoint blockade with the PD-1 inhibitor pembrolizumab, and these tumors contain prominent immune infiltrates (Le et al., 2015; Lee et al., 2016). However, there were not studies about the relationship of PAK6 with MSI expression or immunotherapy. In the future, we will study the association of PAK6 with MSI expression and immunotherapy.