Potential role of Fanconi anemia pathway in the pathogenesis of endometrial cancer (Review).

FANCE encodes a 58 kDa nuclear protein and its products are components of the FA core complex. The integrity of this complex is essential for DNA damage repair and genomic stability ( 22 , 23 ). Using CBioportal data analysis, Salomão et al ( 21 ) found that the FANCE mutation rate in EC was 4.54%. Lynch syndrome (LS) is a common hereditary cancer that is associated with EC. de Angelis de Carvalho et al ( 24 ) incidentally identified a variant of the FANCE gene (c.929dupC; p.Val311Serfs*2-LP) during germline polygenic testing in 14 patients. Zheng et al ( 25 ) found that FANCE expression was markedly lower in EAC than in normal endometrium and that reduced expression was associated with older age and higher tumor grade. By constructing FANCE- overexpressing EC cells, we found that FANCE overexpression promoted the repair of ICL and double-strand breaks (DSBs) in EC. However, in contrast to the findings of Zheng et al ( 25 ), Zhou et al ( 26 ) analyzed the FANCE gene in 33 types of cancer, including EC and found that high FANCE expression was markedly positively associated with MSI, particularly in EC. This contradiction may be due to interference from different subtypes of EC (EAC compared with mixed subtypes) and the possible biphasic function of FANCE in EC. In the early stages, it repairs DNA damage and acts as a tumor suppressor, whereas in the late stages, its continued high expression causes erroneous repair, leading to MSI and acting as a tumor promoter. Zheng et al ( 25 ) found that FANCE is involved in cell cycle regulation. Overexpression of FANCE leads to S phase delay and G 2 /M phase arrest in EC cells, thereby inhibiting the growth of EC tumors in nude mice, whereas low expression induces genomic instability and promotes EC development. Furthermore, Lin et al ( 27 ) found that FANCE may participate in regulating squamous cell carcinoma cell cycle through the Wnt/β-catenin signaling pathway, but whether this mechanism applies to EC needs to be further verified in EC models. In summary, abnormal expression or mutation of FANCE may lead to EC by affecting DNA damage repair, cell cycle, microsatellite stability and other factors. However, there are still contradictions regarding the direction of action and the molecular mechanisms of this gene in EC. Future studies are needed to distinguish EC subtypes further and to verify their functions and specific molecular mechanisms in different EC subtypes. FANCC is a key component of the FA core complex that promotes two DNA damage repair processes, HR repair and TLS, which are essential for maintaining genomic stability ( 28 ). Research has found that the mutation rate of the FANCC gene in EC is 5.1 ( 21 ). EC is one of the most common uterine cancers (UC). In a study by Heald et al ( 29 ), four pathogenic or possibly pathogenic germline variants of the FANCC gene were identified by genetic testing of 953 patients with UC, indicating that variants in this gene may increase the risk of EC. FANCC gene deletion leads to stalling of the DNA replication fork, thereby increasing genomic instability ( 30 ), which drives EC development. Additionally, FANCC is involved in cell cycle regulation ( 31 ). FANCC mutations result in DNA damage repair defects, increased spontaneous chromosome breaks and G 2 /M phase arrest ( 28 , 32 ). Li et al ( 33 ) found that FANCC -deficient mice exhibited cell cycle abnormalities that promoted the malignant progression of endometrial cells. The FANCC gene is associated with multiple FA genes. For example, FANCC and FANCG jointly participate in the monoubiquitination of FANCD2 ( 32 ). Additionally, FANCC forms a complex with FANCE and FANCF (the FANCC-FANCE-FANCF complex) to regulate meiotic recombination ( 34 ). However, this functional synergistic mechanism has not been explored in EC models. Whether the FANCC gene has a specific effect on different EC subtypes requires further investigation. As a key component of the FA core complex ( 13 ), FANCA plays a crucial role in the repair of DSBs and ICL through the HR repair pathway in the S/G 2 phase of cells, which is essential for maintaining genome stability ( 35 , 36 ). In addition, FANCA participates in the mismatch repair (MMR) process by enhancing the interactions between MSH2 and MLH1 ( 37 ). Salomão et al ( 21 ) discovered a high mutation rate of FANCA in the upstream FA gene in EC, with mutation rates as high as 8.88%. Drusbosky et al ( 38 ) analyzed genomic data from 1,988 patients, of whom 12% exhibited high levels of MSI and a small number of patients were found to have pathogenic FANCA germline mutations. Kral et al ( 39 ) conducted germline genetic testing on 527 patients, of whom 284 had type I cancer and found that FANCA was a candidate susceptibility gene for EC. In addition, Drusbosky et al ( 38 ) and Liu et al ( 40 ) found that somatic mutations in the FANCA gene are also associated with EC. Atypical endometriosis (A-EMS) is associated with endometrial intraepithelial neoplasia. Recently, Wepy et al ( 41 ) revealed that 25% of 36 patients with A-EMS had concurrent EMS-related tumors, such as ipsilateral endometrioma, serous tumors, or clear cell tumors. A frameshift mutation in the FANCA gene (p.I865Kfs*20) was detected by second-generation sequencing in six patients with A-EMS. Although multiple studies ( 21 , 38 – 41 ) have suggested an association between FANCA abnormalities and EC, the specific mechanisms by which FANCA mutations contribute to EC remain unclear. According to current research, mutations in this gene may impair DNA damage repair by affecting the FA pathway or MMR, thereby increasing the risk of EC. Future studies should further refine EC subtypes to investigate the role of this gene and its specific mechanisms of action across different EC subtypes. FANCD2 plays a key role in DNA damage repair by interacting with FANCI to form the ID2 complex, which is critical for activating the FA pathway ( 42 ). Research has shown that the mutation rate of FANCD2 in EC is 9.07% ( 21 ). In addition, immunohistochemical results show that compared with normal tissue and atypical hyperplasia tissue, the expression level of FANCD2 is markedly upregulated in type I EC tissue. Knockdown of FANCD2 can lead to cell cycle arrest in the G 1 phase in EC cell lines, thereby inhibiting their proliferation and migration of EC cells ( 43 ). At the same time, Mhawech-Fauceglia et al ( 9 ) evaluated the expression of various DNA repair proteins in tumor cells from 357 EC patients (of these, 262 cases were type I EC, 76 cases were type II EC and 19 cases were carcinosarcoma) and found that FANCD2 overexpression was markedly associated with lymphatic invasion and the recurrence of high-grade EC. Cox regression and Kaplan-Meier analyses showed that high expression of FANCD2 was associated with poor overall survival in patients with EC. In addition, a study also found that FANCD2 expression positively associated with MSI in EC ( 44 ). This suggests that the overexpression of FANCD2 may lead to the accumulation of MSI in endometrial cells, leading to genomic instability and eventually to the occurrence of EC. After FANCD2 knockdown, the sensitivity of EC cells to paclitaxel, cisplatin and doxorubicin increased markedly, suggesting that FANCD2 promotes EC cells ( 45 ), highlighting its prognostic value in EC. In summary, high expression of FANCD2 may increase the risk of EC by affecting DNA damage repair and cell genome stability. In addition, overexpression of this gene is closely related to the poor prognosis of EC and FANCD2 may be a valuable biomarker for evaluating the prognosis of patients with EC. FANCI forms a heterodimer with FANCD2, which is then recruited to the site damaged by related proteins, thereby playing an important role in DNA damage repair ( 46 ). The absence of FANCI markedly downregulates the expression of core FA proteins such as FANCD2 and FANCB, leading to the accumulation of DNA damage within cells. Additionally, FANCI silencing partially reduced TP53 expression, causing cell cycle arrest at the G 1 phase ( 47 ). Research has shown that the mutation rate of FANCI in EC is 8.70% ( 21 ). This is consistent with the observation by Zhao et al ( 48 ) that the mutation rate of the FANCI gene in EC exceeded 8%. Pan-cancer research using The Cancer Genome Atlas (TCGA) has found that somatic mutations in FANCI exist in multiple types of cancer. Of the 517 EC, 43 cases (8.32%) harbored mutations. In addition, Fierheller et al ( 49 ) reported a case of ovarian cancer carrying FANCI c.1813C > T in a patient with extensive genome-wide SCNA ( 50 ). Dong et al ( 51 ) identified FANCI mutations in the HR repair gene mutation spectrum of patients with uterine serous carcinoma. This suggests that type II EC are associated with HR repair defects caused by FANCI mutations. In addition, Bi et al ( 52 ) analyzed the TCGA dataset of patients with EC and found that FANCI overexpression may be associated with a poor prognosis in EC. FANCI may become a valuable biomarker for assessing the prognosis of patients with EC. Further research is needed to investigate the effect of FANCI on type I EC and the regulatory role of TP53 in developing EC to clarify the function and underlying mechanisms of this gene in different EC subtypes and guide treatment strategies. FANCN, also known as PALB2, is closely associated with BRCA2 ( 53 ). The coiled-coil, WD40 and ChAM domains of PALB2 ensure the normal formation of RAD51 filaments and promote the correct binding of RAD51 to DNA, which is critical for the HR repair of DSBs ( 54 ). In addition, PALB2 interacts with BRCA1/2 to form the BRCA1-PALB2-BRCA2 axis, which promotes DSB repair, maintains genomic stability and is crucial for inhibiting tumor progression ( 55 ). Multiple studies have identified mutations that cause PALB2 loss of function in patients ( 56 – 61 ). Salomão et al ( 21 ) analyzed CBioportal data and found that the mutation rate of FANCN in EC was 6.62%. Johnatty et al ( 62 ) determined the role of PALB2 mutations in increasing the risk of EC using a multigene panel detection. In 2019, one patient with EC with a pathogenic PALB2 mutation was identified among 198 women in China ( 63 ). Sequencing analysis based on the TCGA-UCEC cohort revealed that the mutation frequency of the PALB2 gene in EC cases was markedly higher than that in the general population, more than doubling (0.32 vs. 0.14%). Researchers also identified a patient with a pathogenic PALB2 frameshift mutation (c.3116delA, p.Asn1039Ilefs) who was diagnosed with stage I endometrioid EC at 70 years of age ( 64 ). A PALB2 gene mutation [ NM_024675.3 (PALB2): c. (3113+1_3114-1)_ (3201+1_3202-1) del] was identified in the tumor tissue of a patient with serous EC; this mutation is considered pathogenic ( 65 ). In addition, Foo et al ( 66 ) used whole-exome sequencing (WES) to discover that PALB2 mutations in breast cancer patients can lead to multiple genomic SCNA. This suggests that the gene mutation may be associated with type II EC; however, further validation in patients with EC is required. Bowman-Colin et al ( 67 ) found that PALB2 coordinates with the cell cycle factor Trp53 to inhibit breast cancer formation in mice, suggesting that PALB2 mutations affect TP53 function and lead to cell cycle abnormalities. In summary, PALB2 mutations are associated with both type I and type II EC; however, further investigation is needed into the specific pathways through which this gene regulates HR repair in endometrial cells and its impact on endometrial cell cycle regulation. FANCO , also known as RAD51C , is a tumor suppressor gene. As a paralog of RAD51 , this gene plays a central role in the HR repair of ICLs and DSBs by forming RAD51B-RAD51C-RAD51D-XRCC2 and RAD51C-XRCC3 complexes, which are critical for maintaining replication fork integrity ( 68 – 70 ). Additionally, this gene participates in the regulation of DNA damage-induced cell cycle S-phase checkpoint by activating the phosphorylation of CHK2 ( 68 ). Salomão et al ( 21 ) analyzed CBioportal data and found that the mutation rate of FANCO in EC was 3.21%. Ring et al ( 71 ) detected three cases of serous EC carrying RAD51C mutations among 381 EC patients using a multi-gene panel, suggesting that mutations in this gene may be associated with type II EC (serous carcinoma). Kondrashova et al ( 64 ) analyzed 30 known and candidate EC risk genes in patients with EC (TCGA-UCEC study) and the general population (gnomAD database) using tumor sequencing data and reported a nine-fold increase in the frequency of pathogenic or possible pathogenic variations in the HR repair-related gene RAD51C (0.97 vs. 0.1%). This study underscores the potential role of RAD51C in EC development and highlights its potential as a candidate gene for the future exploration of EC risks. In conclusion, clinical genomic data suggest that RAD51C mutation is associated with type II EC (especially serous carcinoma), but its role and related mechanisms in type I EC remain unclear. Additionally, the CHK2 phosphorylation regulatory pathway also needs to be further verified in endometrial cell models. FANCJ , also known as BACH1 and BRCA1 interacting protein 1 (BRIP1), is a key downstream gene of the FA pathway. This gene can bind to the carboxyl-terminus of BRCA1 to promote HR repair ( 72 ). Moreover, this gene can be recruited to DNA break sites and, together with CTLP, promotes DNA end resection and repair of ICL and DSBs ( 73 , 74 ). It also participates in cell-cycle regulation through phosphorylation and dephosphorylation states ( 75 ). Salomão et al ( 21 ) analyzed data from CBioportal and found that the mutation rate of FANCJ in EC was 7.37%. Heeke et al ( 60 ) used NGS600 sequencing to detect an FANCJ mutation rate of 0.14% in 1,475 patients with EC. At the same time, studies have shown that BRIP1 has a higher mutation frequency in type II cancer than in type I cancer ( 76 ). Ring et al ( 71 ) reported the presence of a harmful germline mutation in BRIP1 in 13 non-LS EC patients (p.Lys705Thrfs*10). de Jonge et al ( 77 ) reported BRIP1 mutations c.632delC and P.Ro211fs in two EC patients with HR repair deficits. A frameshift mutation (p.Q554Hfs*35) in FANCJ was identified as pathogenic in high-grade EC ( 78 ). In addition, it has been found that FANCJ mutant mice show an increase in spontaneous MSI ( 79 ). This suggests that this may be related to type I EC. In summary, clinical genomic data suggest that BRIP1 mutations are associated with EC and that the mutation frequency is higher in type II than in type I. However, the functional mechanism in type I EC remains unclear. Further research is needed to investigate the mechanism of FANCJ -mediated MSI in endometrial cells and the specific role of its phosphorylation in cell cycle regulation. FANCS/BRCA1 and FANCD1/BRCA2 play key roles in DNA damage response through HR repair. BRCA1 is mainly localized at DNA damage sites, where it binds to PALB2 to initiate DNA end excision and promotes RAD51 loading. Additionally, BRCA1, in conjunction with BARD1, enhances the activity of the RAD51 recombinase, whereas BRCA2 protects against stagnant DNA replication bifurcations ( 80 , 81 ). In addition, BRCA1/2 interacts with TP53 to regulate cell cycle progression. Functional deficiency can lead to genomic instability, ultimately promoting cancer occurrence and development ( 82 , 83 ). Studies have shown that FANCS/BRCA1 and FANCD1/BRCA2 mutations are markedly associated with EC. Data analysis from CBioportal showed that the mutation rate of FANCS in EC was 9.26% and that of FANCD1 was 15.31% ( 21 ). In a large cohort study of BRCA1/2 mutation carriers, de Jonge et al ( 84 ) found that compared with the general population and non- BRCA1/2 gene mutation carriers, BRCA1/2 mutation carriers had a two- to three-fold increased risk of developing EC and BRCA1 gene mutation carriers had the highest risk of developing rare serous and p53-abnormal EC subgroups. A recent study identified 35 patients with BRCA1/2 copy number loss and eight patients with BRCA1/2 somatic mutations among 187 high-grade ECs using shallow whole-genome sequencing ( 85 ). In addition, in a study by Smith et al ( 86 ), MSI or SCNA pathogenic BRCA1/2 mutations were identified in 13 of 769 patients with high MSI or SCNA levels, whereas TP53 mutations were identified in all patients. de Jonge et al ( 77 ) identified pathogenic variants of BRCA1 and BRCA2 in eight ECs with HR repair defects: BRCA1 , c.4327C>T, p.Arg1443*; BRCA2 , c.6373dupA, p. Thr2125fs c.6306_6413del; and BRCA2 , p.Ser2103_Val2138del. In summary, the clinical data suggest that BRCA1/2 mutations are associated with both Type I and Type II EC, with a more significant association with high-grade EC (Type II). However, the mechanisms underlying these mutations in high-risk subtypes, such as serous carcinoma, require further clarification. Additionally, the synergistic regulation of the cell cycle by BRCA1/2 and TP53 , as well as the mechanisms related to MSI and SCNA caused by BRCA1/2 mutations, require further validation in endometrial cells. FANCR/RAD51 is an essential recombinase involved in HR repair that forms nuclear protein filaments by binding to single-stranded DNA, promoting the pairing of RAD51 with DNA sequences and participating in homologous search and chain exchange, which are essential for the maintenance of HR repair and genome stability ( 87 ). Bioportal data analysis shows that the mutation rate of FANCR in EC is 3.40% ( 21 ). Auguste et al ( 88 ) evaluated the degree of DNA damage in 116 patients with high-grade EC using immunohistochemistry. The results showed that complete deletion of RAD51 resulted in severe DNA damage in 28 patients. In addition, several studies have suggested that RAD51 135G/C and 135C/C polymorphisms may be related to the occurrence and development of EC ( 89 – 91 ). Michalska et al ( 92 ) suggested that the 135C/C polymorphism may be more closely associated with EC. Additionally, Krupa et al ( 93 ) found that the RAD51 C/C genotype was closely associated with the incidence of EC in patients with higher levels of basal DNA damage. In summary, existing clinical data suggest that the absence of FANCR / RAD51 is associated with high-grade EC (Type II), however, the role of this gene in Type I EC and the underlying mechanisms remain unclear. Furthermore, the specific molecular pathways through which RAD51 135G/C and 135C/C polymorphisms influence EC susceptibility require further validation. FANCU, also known as XRCC2, plays a vital role in the HR repair of ICLs and DSBs ( 94 , 95 ). XRCC2 is a potential tumor suppressor gene in mammals. Mutations in this gene can lead to defects in DNA damage repair and SCNA, thereby disrupting genomic stability ( 96 , 97 ). Bioportal data analysis showed that the FANCE mutation rate in EC was 3.02% ( 21 ). Nero et al ( 98 ) performed genome sequencing of 137 patients with recurrent EC and identified XRCC2 mutations in 2.9% of the patients. Taylor et al ( 99 ) identified one XRCC2 gene frameshift mutation case in 50 cases of MSI-H endometrioid adenocarcinoma. Additionally, XRCC2 SNP-41657C/T (rs718282) and 4234G/C (rs3218384) increased EC susceptibility ( 100 , 101 ). In summary, the current study indicated that FANCU/XRCC2 mutations and SNP polymorphisms increase the risk of EC. However, the specific pathogenic mechanisms by which XRCC2 mutations drive the development of endometrioid adenocarcinoma and how SNP polymorphisms in this gene contribute to EC require further clarification. Additionally, the mechanism by which XRCC2 deletion leads to SCNA requires further validation in endometrial cells. FANCW, also known as RFWD3, is an E3 ubiquitin ligase that promotes the timely removal of RPA and RAD51 from DNA damage sites and plays a crucial role in DNA HR repair and maintenance of genome stability ( 102 ). RFWD3 is also necessary to maintain a normal cell cycle and participate in the DDR by positively regulating p53. Knockdown of the RFWD3 gene may lead to cell-cycle arrest ( 103 , 104 ). Mutations in the FANCW gene have been identified in various cancers, including EC, ovarian cancer and bladder cancer. Compared with other types of cancer (2.23% in ovarian cancer and 3.89% in bladder cancer), the mutation frequency of this gene in EC is relatively high (4.73%) ( 21 ). However, the mechanisms by which RFWD3 regulates the participation of p53 in cell cycle regulation and causes genomic instability due to mutations in endometrial cells require further validation.

Endometrial cancer (EC) is one of the most prevalent gynecological malignancies worldwide ( 1 ); its global incidence has increased annually over the past 20 years. Although >50% of women diagnosed with EC are aged 50–69 years, the diagnosis rate in women aged <50 years has shown an increasing trend. Although the overall mortality rate has slightly decreased in recent years, EC remains one of the leading causes of cancer-related deaths among postmenopausal women in a number of countries ( 2 – 4 ). Traditionally, EC has been classified into two main types: Endometrioid (type I) and non-endometrioid (type II). Type I is a low-grade tumor associated with high estrogen levels, with the histological type of endometrioid adenocarcinoma (EAC) accounting for ~80% of all EC cases. Of the patients, 95% have a good prognosis. By contrast, type II is a highly aggressive, high-grade tumor, including serous carcinoma of the uterus, clear cell carcinoma and carcinosarcoma, with a poor prognosis ( 5 – 9 ). Type II carcinomas and 25% of high-grade type I carcinomas exhibit extensive somatic copy number alterations (SCNA), frequent TP53 mutations and other molecular manifestations, whereas most type I carcinomas exhibit microsatellite instability (MSI) ( 10 ), indicating that genomic instability and cell cycle abnormalities may be closely related to the development of EC. Normal function and growth of cells depend on the orderly progression of the cell cycle. In both unicellular and multicellular eukaryotes, the cell cycle is regulated by a complex network of regulatory mechanisms ( 11 ). In this complex network, genes involved in the DNA damage repair pathway play an important role and abnormalities in these genes may affect endometrial cell genome stability and/or lead to the failure of cell cycle regulation, increased susceptibility to EC and even ultimately trigger EC. The Fanconi anemia (FA) pathway plays a crucial role in DNA interstrand cross-linking (ICL) repair and the maintenance of genomic integrity ( 12 ). FA genes participate in DNA damage response (DDR) through the FA and homologous recombination (HR) pathways ( 13 ). FA gene deletions or variants may lead to DNA damage repair defects, causing genomic instability such as SCNA and MSI, or cell cycle abnormalities, ultimately leading to the development of EC. The present comprehensive review aimed to summarize the association between FA genes and EC occurrence, explore the potential relationship, open new avenues for future research on EC and FA genes and provide potential insights into the treatment of EC.

EC is the most prevalent cancer of the female reproductive tract and its incidence is increasing worldwide. Although the prognosis of patients with early- and low-grade EC is usually good, the outcomes of patients with advanced disease, deep muscle infiltration or metastasis and recurrence remain poor. The limited understanding of EC pathogenesis has hindered the development of effective diagnostic and therapeutic strategies. Based on the current WES of clinical EC patients with deletions or mutations in the FA gene, the present review identified a strong association between FA gene defects and EC, particularly high-grade EC ( Table IV ). The FA pathway is the core mechanism by which cells respond to inter-chain cross-linking (ICL) damage and maintain genomic stability and integrity ( Fig. 1 ). In EC, defects in the FA gene lead to genomic instability and/or an abnormal cell cycle, thereby promoting tumorigenesis and progression ( Fig. 2 ). Currently, research on the role of FA in EC primarily relies on clinical sample analysis and there is a lack of FA gene-deficient EC mouse models to validate the pathogenic mechanisms. In addition, the role of the FA gene in different EC subtypes and the associated mechanisms require further clarification. In this context, future studies should focus on establishing appropriate FA gene-deficient mouse models and refining EC subtypes to elucidate the complex pathogenesis of EC. The present review described the pathogenesis of EC in terms of FA pathway abnormalities. An in-depth understanding of the molecular mechanisms of EC pathogenesis may facilitate the development of targeted therapies that specifically target key genes, leading to a more accurate treatment for EC, which may substantially improve the quality of life and survival of patients with high-grade and advanced EC. The present review provided new insights into the genetic factors and pathogenesis of EC and will facilitate the development of new EC treatments in the future.

FA is rare a chromosomal disorder characterized by genomic instability and an increased susceptibility to cancer caused by mutations in the FA gene. By contrast, the FA pathway, a DNA damage repair pathway involving multiple FA genes, is crucial for normal DNA repair processes and maintenance of genomic stability ( 14 ). To date, 22 genes involved in the FA pathway have been identified and can be categorized into upstream, midstream and downstream components. The upstream genes include the lesion recognition gene FANCM , FA core complex-related genes ( FANCA, FANCB, FANCC, FANCE, FANCF, FANCG and FANCL ) and the E2 ubiquitin ligase-related gene FANCT/UBE2T . Midstream genes include FANCD2 and FANCI , which form the FANCI-FANCD2 (ID2) complex. The downstream genes included HR repair-related genes ( FANCD1/BRCA2, FANCJ/BRIP1, FANCN/PALB2, FANCO/RAD51C, FANCR/RAD51, FANCS/BRCA1, FANCU/XRCC2 and FANCW/RFWD3 ), nucleolytic incision-related genes ( FANCQ/XPF and FANCP/SLX4 ) and trans-lesion synthesis (TLS)-related genes FANCV/REV7 ( 15 ). The entire FA core complex consists of seven FA proteins (FANCA, FANCB, FANCC, FANCE, FANCF, FANCG and FANCL) and FANCA-associated peptides FAAP100, FAAP24 and FAAP20 ( 16 , 17 ). FAAP24 can target FANCM to form the FANCM-FAAP24 complex, recognize ICL and promote the recruitment of the FA core complex to DNA damage sites to participate in DNA damage repair ( 18 ). This core complex has E3-ubiquitin ligase activity and is essential for DNA damage repair by mediating mono-ubiquitination of the ID2 complex in response to DNA damage ( 15 ). The ID2 complex plays a critical role in the FA pathway and is recruited to the ICL site before FANCD2 mono-ubiquitination, thus participating in pathway activation ( 19 ). Additionally, downstream FA genes coordinate the three key DNA repair processes: Nucleolytic incision, TLS and HR, all of which are essential for ICL repair ( 20 ). The FA pathway plays a key role in DNA damage repair and participates in DNA damage repair and the maintenance of genome stability by interacting with other DNA repair pathways. Defective DNA repair increases genomic instability, which may lead to cancer development. Several FA genes are closely associated with EC ( 21 ). To elucidate the roles of FA genes in EC, the upstream ( Table I ), midstream ( Table II ) and downstream genes ( Table III ) of the EC-associated FA pathway were considered entry points and the underlying mechanisms contributing to EC development and progression were explored.