*2.2.1 ERCC1*

ERCC1 is the key component of NER pathway that has been investigated in a large number of studies due to its prognostic properties in cancer treatment [61–63]. The association between the expression of ERCC1 and response to trabectedin in STS was investigated in a recent translational study designed by Moura et al. [64]. Expression levels were evaluated using qRT-PCR in 66 patients with advanced STS who were treated with trabectedin. The results showed that the expression level of ERCC1 is correlated with patients' progression-free survival [PFS (the length of time during and after treatment that the disease does not get worse)] and overall survival. Patients who had higher expression levels of ERCC1 showed better responses to the trabectedin and had longer PFS rates [64]. Similarly, ERCC1 expression has reported to be associated with treatment response in other sarcomas such as osteosarcoma and leiomyosarcoma, highlighting the importance of this key NER protein as a predictable biomarker in sarcoma [65, 66]. Polymorphism of NER genes and the relation of different alleles with the treatment response has also been investigated in osteosarcoma, indicating the association of some polymorphisms with a higher risk of osteosarcoma development [67]. A study conducted by Obiedat et al., investigated the relationship between polymorphisms of ERCC1 and ERCC2 and response to cisplatin-based chemotherapy and clinical outcomes in osteosarcoma patients [68]. They analyzed the association between ERCC1


**149**

*DNA Repair Defects in Sarcomas*

*DOI: http://dx.doi.org/10.5772/intechopen.94881*

(C118T (rs11615) and C8092A (rs3212986)) and ERCC2 (A751C (rs171140) and G312A (rs1799793)) polymorphisms and clinical parameters including event-free survival (EFS) (the length of time after treatment that a patient lives without any complications or event that the treatment intended to prevent or delay) rates in 44 patients with osteosarcoma who were treated with cisplatin-based neoadjuvant chemotherapy [68]. The findings illustrated that there is a significant positive correlation between ERCC1 C8092 A genotypes and median EFS rate. In other words, the patients who carried allele C (CC & CA) had longer EFS rates than patients with AA genotype, highlighting the importance of ERCC1 polymorphism in osteosarcoma [68]. Taken together, these studies suggested that ERCC1 could be considered as a reliable predictive factor of the effectiveness of some DNA-damaging chemotherapeutic drugs in sarcoma patients, and different polymorphisms could be used as

MMR pathway is responsible for repairing base mismatches, insertions and deletions arise from DNA replication, genomic recombination, and other error-prone DNA repair systems [69]. MSH2-MSH6 (MutSα) complex plays an important role in this pathway by recognizing the mismatched bases and starting the MMR process [69]. Different polymorphisms and expression levels of MMR components have shown to be associated with prognosis and survival in cancer patients [70–72]. A study conducted by Li et al., emphasized the importance of MMR pathway in Ewing sarcoma and showed that the expression levels of MSH2 and MSH6 is correlated with an increased chance of metastasis and poor prognosis in these patients [73]. They used the GEO database to investigate the correlation of the key dysregulated genes and pathways with prognosis information and metastasis status of the Ewing sarcoma patients [73]. The findings highlighted the MMR pathway as the most significantly enriched KEGG pathway in EWS patients [73]. The expression levels of key MMR components including MSH2 and MSH6 are found to be significantly associated with metastasis, shorter EFS, and overall poor prognosis in Ewing sarcoma patients [73]. Several studies have investigated the role of MMR pathway in osteosarcoma. Liu et al., investigated the growth-suppressive effects of MSH6 gene silencing in combination with cisplatin in osteosarcoma [74]. Microarray-based gene expression analysis of samples obtained from 67 osteosarcoma patients along with 24 normal patients demonstrated that MSH6 is significantly up-regulated in osteosarcoma patients [74]. Then, they evaluated cell proliferation, cell cycle distribution, gene and protein expression, and apoptosis of osteosarcoma cell line MG63 after co-treatment with cisplatin and siRNA targeting MSH6 [74]. The data showed that silencing MSH6 in combination with cisplatin reduced expression levels c-Myc, cyclin D1, Bcl-2, Stathmin, and PCNA and increased BAX expression in osteosarcoma cells [74]. This combination treatment also induced significant anti-proliferative effects, indicating that MSH6 could be considered as a potential therapeutic target for treatment of osteosarcoma patients [74]. In another study, proteomic analysis for identification of proteins that are differentially expressed between osteosarcoma and normal osteoblastic cells revealed that chromosome segregation 1-like (CSE1L) protein is significantly associated with the growth of osteosarcoma cells [75].

Co-immunoprecipitation and RNA-seq analysis in this study showed that CSE1L acts as a positive regulator of MSH6 in osteosarcoma cells [75]. In addition, they knocked down CSE1L protein in osteosarcoma cells and found significant growth suppression [75]. Furthermore, to investigate the role of MSH6, they overexpressed MSH6 in

prognostic biomarkers for designing the best treatment strategy.

**2.3 DNA mismatch repair (MMR) pathway**

*2.3.1 MSH2-MSH6 (MutS*α*)*
