Analysis of Gene Expression Profiles of Soft Tissue Sarcoma Using a Combination of Knowledge-Based Filtering with Integration of Multiple Statistics

Abstract

The diagnosis and treatment of soft tissue sarcomas (STS) have been difficult. Of the diverse histological subtypes, undifferentiated pleomorphic sarcoma (UPS) is particularly difficult to diagnose accurately, and its classification per se is still controversial. Recent advances in genomic technologies provide an excellent way to address such problems. However, it is often difficult, if not impossible, to identify definitive disease-associated genes using genome-wide analysis alone, primarily because of multiple testing problems. In the present study, we analyzed microarray data from 88 STS patients using a combination method that used knowledge-based filtering and a simulation based on the integration of multiple statistics to reduce multiple testing problems. We identified 25 genes, including hypoxia-related genes (e.g., MIF, SCD1, P4HA1, ENO1, and STAT1) and cell cycle- and DNA repair-related genes (e.g., TACC3, PRDX1, PRKDC, and H2AFY). These genes showed significant differential expression among histological subtypes, including UPS, and showed associations with overall survival. STAT1 showed a strong association with overall survival in UPS patients (logrank p = 1.84×10−6 and adjusted p value 2.99×10−3 after the permutation test). According to the literature, the 25 genes selected are useful not only as markers of differential diagnosis but also as prognostic/predictive markers and/or therapeutic targets for STS. Our combination method can identify genes that are potential prognostic/predictive factors and/or therapeutic targets in STS and possibly in other cancers. These disease-associated genes deserve further preclinical and clinical validation.

Prognostic value of hypoxia-inducible factor-1 alpha and prolyl 4-hydroxylase beta polypeptide overexpression in gastric cancer

“…Moreover, P4HA1[ 33 ] and P4HA2[ 34 ] are also treated as a hypoxia-associated gene in head and neck squamous cell carcinoma (HNSCC), and its signature is a prognostic tool in treatment of HNSCC patients. The interaction between P4HA1/2 has also been reported in chondrosarcoma cells[ 35 ] and soft tissue sarcomas[ 36 ], but whether P4HA1/2 is directly regulated by HIF-1 has not been reported.…”

STAT1 as a potential prognosis marker for poor outcomes of early stage colorectal cancer with microsatellite instability

“…The prognostic potential of STAT1 for cancers as reported up to date has been variable and sometimes even controversial. Correlation of STAT1 expression with better prognosis has been reported for several cancers, including colorectal cancer [26][27][28][29], esophageal cancer [30], pancreatic cancer [31], hepatocellular carcinoma [32], soft tissue sarcoma [33], and metastatic melanomas [34]. In breast cancer, correlations with good and poor prognosis have been reported for STAT1 expression [35][36][37], and high protein expression of STAT1 together with high levels of CD74 defined a subtype of triple negative breast cancer with increased invasiveness and metastatic potential [38].…”

Peroxiredoxin 1 – an antioxidant enzyme in cancer

“…The identification of PRDX1 as a potential oncogene was reported in the cases of lung adenocarcinomas [41,42], colorectal cancer [43] and soft tissue sarcomas [44]. 1q is amplified in approximately 35.5% of lung cancer [45], and the PRDX1 expression is significantly elevated in lung cancer patients as compared with patients with benign lung disease [46].…”