**1. Introduction**

Sarcomas represent a divergent and heterogeneous group of malignancies comprising more than 70 subtypes, with a common characteristic of being derived from mesenchymal lineages such as bone, muscle, cartilage, and fat [1]. Sarcomas are rare, accounting for less than 1% of adult cancers and approximately 15% of childhood malignancies [2]. They occur in all ages with an extensive intertumoral and intratumoral biological heterogeneity and widely varied clinical prognosis [3]. The primary standard of care approach for treatment of sarcoma patients is consist of surgery, radiation, and chemotherapy-based strategies [4]. Although the cure rate for the patients with localized sarcoma is generally more than 70%, the survival rate of metastatic and relapsed patients is still less than 30% and has not been changed in the last decades [1, 2, 5, 6]. Based on the tissue type of primary manifestation, sarcoma tumors could be categorized into two main groups: soft-tissue sarcomas (STS) and bone sarcomas. STS are more common with the incidence of approximately 13,000 reported cases versus 3000 cases of bone sarcomas each year in the United States [4]. Among STS, liposarcoma, leiomyosarcomas, and undifferentiated pleomorphic sarcomas are the most common types in adults, whereas rhabdomyosarcoma is the most common type

seen in pediatric age [7]. Osteosarcoma has the highest prevalence among bone sarcomas with a bimodal age distribution; an initial peak between the age of 10 to 20 and a second peak in incidence above the age of 60 [8]. Based on genetic criteria sarcomas can also be classified into two main groups: sarcomas with low level of genomic alterations and fairly normal karyotypes, and sarcomas with high level of genomic alterations and complex karyotypes [5]. The sarcomas found in the first group have chromosomal translocations as illustrated in **Table 1**; whereas osteosarcoma, chondrosarcoma, and liposarcoma are more genetically complex and have broader range of dysregulations resulted from copy number variations, mutations, etc. (**Table 1**) [5, 9–11].

It is well established that DNA damage response (DDR) system has a major impact on prognosis and clinical response to treatment in cancer patients [12–14]. Studies have investigated the dysregulation of different DDR pathways in various types of sarcomas and provided possible prognostic and therapeutic potentials among DDR components in order to overcome drug resistance and improve overall survival of these patients. In this chapter, we review some of the most important dysregulated DDR components which are involved in five different pathways (base excision repair (BER), nucleotide excision repair (NER), DNA mismatch repair (MMR), homologous recombination (HR), Nonhomologous end joining (NHEJ), and DNA damage sensors (ATR and CHK1)) in sarcoma, and discuss the therapeutic developments and prognostic potentials in this area (**Figure 1**).


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*DNA Repair Defects in Sarcomas*

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

**2. DNA repair machinery in Sarcoma**

**2.1 Base excision repair (BER) pathway**

*2.1.1 APE1/Ref-1*

**Figure 1.**

Base excision repair (BER) is a repair mechanism responsible for repairing single-strand DNA breaks (SSBs) or different types of damages including oxidization, deamination, and alkylation on a single base that do not induce significant distortion to the DNA helix [15]. Among several proteins that are involved in this pathway, APE1/Ref-1 and Poly (ADP-ribose) polymerase (PARP) are considered as the most important players in cancer progression and drug resistance [16–19].

*Schematic summary of the most important DDR components and their respective inhibitors in sarcomas.*

One of the most important components of BER pathway is APE1/Ref-1 (apurinic/apyrimidinic endonuclease 1/redox factor-1). APE1/Ref-1 is a multifunctional protein involved in response to oxidative stress, cell cycle regulation, transcriptional activation, protein stability, apoptosis, and cell survival [16, 20]. The different functions of this protein can be categorized into two main activities: apurinic/apyrimidinic endonuclease activity and reduction–oxidation (redox) activity. The endonuclease activity allows APE1/Ref-1 protein to function as a DDR component in BER pathway by recognizing and cleavage of the abasic site [21]. The redox activity of APE1/Ref-1 gives it a critical transcriptional regulatory role in which enhances the activity of numerous transcription factors, including STAT3, NF-kB, HIF-1, and AP-1 [21, 22]. APE1/Ref-1 has a crucial role in maintaining cancer cells in a survival state through its DNA repair properties [23, 24]. Also, its redox function increases the activity of signaling pathways that are involved in promoting growth, migration, and survival in tumor cells as well as inflammation and angiogenesis in the tumor microenvironment [23, 25]. The overexpression of APE1/Ref-1 has been reported in many tumor types, and that change is associated with drug resistance, metastasis, cancer aggressiveness, and overall poor prognosis [16]. Several studies have shown that APE1/Ref-1 protein is overexpressed in sarcoma patients and is correlated with metastasis and lower survival rates [26–30].

*References: [9, 12–14].*

#### **Table 1.**

*Most common chromosomal aberrations in sarcomas.*

*DNA - Damages and Repair Mechanisms*

mutations, etc. (**Table 1**) [5, 9–11].

this area (**Figure 1**).

seen in pediatric age [7]. Osteosarcoma has the highest prevalence among bone sarcomas with a bimodal age distribution; an initial peak between the age of 10 to 20 and a second peak in incidence above the age of 60 [8]. Based on genetic criteria sarcomas can also be classified into two main groups: sarcomas with low level of genomic alterations and fairly normal karyotypes, and sarcomas with high level of genomic alterations and complex karyotypes [5]. The sarcomas found in the first group have chromosomal translocations as illustrated in **Table 1**; whereas osteosarcoma, chondrosarcoma, and liposarcoma are more genetically complex and have broader range of dysregulations resulted from copy number variations,

It is well established that DNA damage response (DDR) system has a major

EWSR1-ERG EWSR1-ETV1 EWSR1-E1AF EWSR1-FEV TLS-ERG EWSR1-ZSG

EWSR1-NR4A3 TAF15-NR4A3 TCF12-CHN

PAX7-FOXO1

COL1A-PFGFB FUS-CREB3L1

impact on prognosis and clinical response to treatment in cancer patients [12–14]. Studies have investigated the dysregulation of different DDR pathways in various types of sarcomas and provided possible prognostic and therapeutic potentials among DDR components in order to overcome drug resistance and improve overall survival of these patients. In this chapter, we review some of the most important dysregulated DDR components which are involved in five different pathways (base excision repair (BER), nucleotide excision repair (NER), DNA mismatch repair (MMR), homologous recombination (HR), Nonhomologous end joining (NHEJ), and DNA damage sensors (ATR and CHK1)) in sarcoma, and discuss the therapeutic developments and prognostic potentials in

**Sarcoma type Gene translocation/inversion**

Ewing sarcoma EWSR1-FL1

Synovial sarcoma SSX-SS18 Chondrosarcoma HEY1-NCOA2

Liposarcoma FUS-DDIT3 Rhabdomyosarcoma PAX3-FOXO1

Fibrosarcoma ETV6-NTRK3

*Most common chromosomal aberrations in sarcomas.*

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**Table 1.**

*References: [9, 12–14].*

**Figure 1.** *Schematic summary of the most important DDR components and their respective inhibitors in sarcomas.*
