Cellular Mechanism of Gene Mutations and Potential Therapeutic Targets in Ovarian Cancer.

KRAS locates on chromosome12p12 and encodes a 21-KD protein (p21RAS) which involves in MAP-kinase signal transduction pathway. As a member of the Ras gene family and an important oncogene, the KRAS gene plays an essential role in cellular proliferation, apoptosis, and carcinogenesis. KRAS mutations promote tumorigenesis and result in uncontrolled proliferation and differentiation of cells by activating the MAPK/ERK pathway which is triggered by MEK, MAPK/ERK-kinase. 7 , 8 The KRAS mutations are the most common RAS isoforms, including KRas4A and KRas4B, which are encoded by alternative fourth exons and the common activating mutations occur in exons 1 or 2. 115 , 116 The inherited variant which is located in the 3ʹUTR of KRAS gene (rs61764370 T > G) is associated with an increased risk of OC, breast cancer, and lung cancer. 117 KRAS mutation plays a key role in LGSOC and mucinous OC subtypes. The sequencing analysis showed KRAS gene mutation was the most frequent in borderline serous tumor, LGSOC, and mucinous carcinomas. KRAS mutation rate was reported as 33~41%, 35~54%, and 57.1%, respectively, in contrast with their low or absent expression in HGSOC ( Table 1 ). 7 , 118 The mutations of KRAS were even more than 70% in the recurrent LGSOC. The frequent occurrence of KRAS mutations in this subtype of tumors led to the presumption that the development of LGSOC begins in a stepwise mode from serous cystadenoma or adenofibroma, borderline serous tumor, and serous carcinoma, and its carcinogenic processes are closely related to RAS signaling. 7 KRAS mutation in borderline serous OC may be associated with peritoneal implant. 119 In research of 142 patients of primary epithelial OC without borderline tumor detected KRAS in exon 2 and 3, 9.9% KRAS mutations were observed, 13 mutations in exon 2 and only one in exon 3. In those mutations, six patients included both P53 and KRAS mutations, and all 14 KRAS mutations were missense mutations to lead to an exchange of the coding amino-acid. 120 Another recent study of 15 Korean patients with OCCC detected 20% KRAS mutations. 121 In OCs, KRAS mutations occur mostly on codon 12, the most common being the G12V point mutation, followed by G12D and G12S. A study on 63 Rome patients with OCCC also detected 13% KRAS mutations, and the results showed a higher incidence in codon 12 mutations (90%), G12V (43%), G12D (29%), G12S (14%), and G12A (14%), respectively. There is only one mutation at G13D of codon 13 93 ( Figure 1B ). Mucinous OCs begin in slow stepwise fashion: a mucinous adenoma progresses to mucinous borderline tumor to mucinous carcinoma. 122 In mucinous OCs, KRAS mutations occur frequently, which is more frequently than non-mucinous OCs. 123 Besides, the KARS mutations, as a tumorigenic, have been detected in adjacent mucinous cystadenoma and mucinous borderline tumor areas of mucinous carcinoma. 124 This may lead to the formation of ovarian borderline mucinous cystadenoma, but not advance the result to cystadenocarcinoma. 125 The direct sequencing method was used to analyze the mutation of KRAS exon 2, codons 11–14 in ovarian tissues. In normal ovarian tissue, there was no detected KRAS mutation. While, in mucinous neoplastic tissues, codon 12 mutations were detected about 53.45%, codon 13 mutations were detected about 24.14%, and codon 14 mutations were detected about 3.45%. Besides, previous studies have indicated that codon 12 was the most ordinary KRAS mutation in mucinous borderline tumor and mucinous carcinoma, codon 13 was the most ordinary KRAS mutation in mucinous adenoma. 123 , 126 In general, KRAS mutations were associated with better differentiated carcinomas in all types and not related with the patient overall survival. 120

Ovarian cancer (OC) is well recognized as the most lethal gynecologic malignancy, with an estimated 295,414 newly diagnosed cases, resulting in 184,799 deaths in 2018 worldwide. 1 Epithelial ovarian cancer is a heterogeneous disease comprising of five main subtypes including: high-grade serous ovarian carcinoma (HGSOC), low-grade serous ovarian carcinoma (LGSOC), endometrioid ovarian cancer (EnOC), ovarian clear cell carcinoma (OCCC), and mucinous. HGSOC is most commonly observed, accounting for approximately 70% among all cases. 2 Sixty percent of patients with OC are diagnosed at an advanced stage because of asymptomatic status and limited screening marker, and the rate of 5-year overall survival is less than 30%. 3 The commonly adopted strategy for OC primary treatment is surgical removal of the tumor, followed by consistent chemotherapy. It has been found that 20–30% of patients have no response to initial treatment or progress within 6 months after primary chemotherapy due to being insensitive to the chemotherapeutic drugs. 4 Therefore, there is a crucial need to develop newer and more effective therapeutic regimens to overcome chemoresistance in metastatic or recurrent ovarian cancer and to achieve durable clinical prognosis. Research has revealed that most advanced patients expressed different genetic abnormalities. Those gene mutations will guide treatment decisions and novel effective chemotherapeutic agents that target these aberrant genes, to improve the poor prognosis in OC. Liquid biopsy, based on minimally invasive and serial blood tests, has the advantage of following tumor evolution in real time, offering novel insights on precision medicine. The major components of liquid biopsy analysis involve circulating tumor cells (CTCs), circulating tumor DNA (ctDNA), circulating cell-free microRNAs (miRNAs), and circulating exosomes. 5 As a biomarker, it has already been implemented in ovarian cancer diagnosis, prognosis, and response to treatment. The aim of this review is to discuss the recent advances of TP53, BRCA1/2, PIK3CA, and KRAS gene mutations in ovarian cancer. In addition, the potential functional targeted therapy and the biomarker that might eventually be clinically actionable and applied in liquid biopsy are also reviewed.

The TP53, located chromosome 17P13.1, is composed of 19,198 nucleotides spanning 11 exons. 11 TP53, as a “the guardian of the genome” or “cellular gatekeeper”, 12 , 13 plays an important roles in tumor suppression, by regulating the expression of downstream genes to induce a series of cellular responses, such as cell cycle arrest or apoptosis in different types of stress (eg, nutrient deprivation, telomere erosion, hypoxia, DNA damage, ribosomal stress, and oncogene activation) 6 , 14 ( Figure 1 ). In general, protein levels of p53 keep low or undetectable owing to its negative regulator MDM2, which binds to the amino terminus of p53 and targets p53 for proteasome-mediated degradation. 6 DNA damage and stresses disrupt P53-MDM2 binding to increase p53 levels. 15 Loss of its apoptosis activity can cause tumor development and chemoresistance. 16 Figure 1 Mutational landscape of epithelial ovarian cancer. ( A ) Mutations in significantly mutated genes in epithelial ovarian cancer and selected known oncogenes and tumor suppressors. Genes mutations are shown in subtype of epithelial ovarian cancer. ( B ) Variants for P53, BRCA1/2, PIK3CA, and KRAS, color-coded by subtype of epithelial ovarian cancer. Splice site mutations are indicated as involving the acceptor site (exon – nucleotide position of mutation). Mutational landscape of epithelial ovarian cancer. ( A ) Mutations in significantly mutated genes in epithelial ovarian cancer and selected known oncogenes and tumor suppressors. Genes mutations are shown in subtype of epithelial ovarian cancer. ( B ) Variants for P53, BRCA1/2, PIK3CA, and KRAS, color-coded by subtype of epithelial ovarian cancer. Splice site mutations are indicated as involving the acceptor site (exon – nucleotide position of mutation). P53 is a tetramer formed by four p53 molecules which self-assemble on two DNA half-sites. It contains three major functional domains, including N terminus contains a transactivation domain, C terminus consists of oligomerization and regulatory domains. The core domain contains a sequence-specific DNA binding domain. 17 The next generation sequencing (NGS) has revealed that approximately 95% of the tumor-associated mutation is located in the core DNA-binding domain. 18 P53 mutations lead to inactivity of wild-type (WT) P53 function, at the same time it can produce a new protein with new functions, which is called gain-of-function (GOF). These GOF P53 mutations result in mutation P53 accumulating at high levels in cells, contributing to carcinogenesis, multidrug resistance, poor prognosis, and metastasis. 19 , 20 P53 mutated tumor cells are the absence of a functional G1-checkpoint and depend completely on their G2-checkpoint for cell cycle arrest and DNA repair. 21 In OC, a recently whole-genome sequencing of DNA found mainly P53 mutation is missense mutation. The missense mutation occurs predominantly in exons 5–10. 22 There have been some hotspots (R175, G245, R248, R249, R273, Y220 and R282) identified, and four (R273, R248, R175, and Y220) of those are the most frequent mutations. The most common codons of mutation are R273C, R273H, and R273L mutants. 23 The R273 and R248 mutants seem more effective than the other mutants on the migration and invasion of OC 14 , 24 ( Figure 1B ). In research on 245 primary OC patients, 68 revealed active function of p53 and 177 inactive function of p53, in all 177 patients with P53 mutations, 128 harbored missense, 30 frameshift, 11 nonsense, and only eight splice variants ( Figure 1A ). One hundred and thirty-four patients had p53 splice variants in 245 ovarian cancers and the mutations expressions were associated with the functional p53 status. 25 Using NGS, more than 90% of HGSOC reveal expression of P53 mutation, which is associated with metastatic progression and resistance of chemotherapy. 26 More remarkably, there was a high prevalence of the P53 mutations in stage 1 or 2 HGSOC. 23 Interestingly, LGSOC, that have poor response to platinum-based chemotherapy, is more typically WT- P53 than HGSOC. 27 However, the WT-P53 is found to be dysfunctional by indirectdegradation through several different mechanisms. Restoring the function of WT-P53 can inhibit tumor growth, but the effect of TP53 recovery on tumor growth seems to depend on the stage of cancer progression. 18

A number of studies on ctDNA, representing a small percentage of cfDNA that is shed in circulation by tumor cells and carries tumor specific mutations, attempted to evaluate its clinical value in OC. The research demonstrated 44% of the OCs involved in the study had detected P53 mutations in tumor tissue. In OCs with advanced disease, the rate of P53 mutation was 28.6%. 20 P53 mutants were undetectable in plasma after surgery, but in one patient the P53 mutant again became detectable 16 months after surgery and the patient died 2 months later. 5 , 139 The detection of mutant P53 in cfDNA might be an important strategy for future diagnosis and monitoring of the treatment efficacy. Another recent study attempted to evaluate somatic P53 mutations in patients with serous OC by ddPCR. The research has suggested that P53 mutations were investigated in serial ctDNA samples of HGSOC. Besides, the presence of P53 mutation allele fractions in ctDNA, when compared to serum CA-125 levels, could indicate a much earlier response to chemotherapy. 140 Using methylation specific PCR (MSP), the BRCA hypermethylation was detected in cfDNA of early stage (stage I, II) epithelial OC patients. The results showed that the consistency of tumor and plasma/serum DNA methylation pattern in 82% of matched samples was observed. Detecting BRCA1/2 mutation in the patients with OC can provide valuable information in diagnostic, prognostic, and predictive disease progression. 5 The reversion of BRCA1/2 mutations in ctDNA was investigated as an indicator of response to platinum-based and PARPi-based chemotherapy or following treatment with PARPi or platinum compounds after disease progression. 141 , 142 PIK3CA mutation is frequent in OCCC, and 16.7% of those had detected in the plasma DNA. PIK3CA-H1047R is a hotspot and can be detected in most of the OCCC patients with PIK3CA mutation. KRAS-G12D can be detected in part of patients with KRAS mutation. Detection of PIK3CA-H1047R and KRAS-G12D in cfDNA by ddPCR would be useful for the early diagnosis of ovarian clear cell carcinoma, to monitor its response to the therapy, and for predicting its recurrence. 9 Liquid biopsy, as a promising non-invasive diagnostic, prognostic, and predictive strategy, provides an easily accessible source of DNA derived from the OC.

The PIK3CA gene is located at the chromosomes 3 (3q26.3) and encodes the p110α catalytic subunit of the PI3K. The PI3K pathway is a family of lipid kinases in the early stages of a signaling cascade, which is frequently altered in cancer. 88 , 89 The overexpression of mutation PIK3CA activates its downstream effector AKT that leads to increased activity of mTOR, promoting cell survival, proliferation, oncogenic transformation, and suppressing apoptosis. 88 , 90 , 91 The PI3K/AKT plays a central role in glucose metabolism, and mTOR is a serine/threonine kinase which acts as an effector in the PI3K/AKT pathway. 89 , 92 The PIK3CA mutation clearly identified as mechanisms of inducing oncogenic PI3K signaling ( Figure 4 ). Figure 4 The mechanisms of PI3K/Akt/mTOR pathway and MAPK pathway, and inhibitors in ovarian cancer clinical development. Illustration the therapy strategy via inhibiting the PI3K/Akt/mTOR pathway (green) and MAPK pathway (amaranth) in ovarian cancer patients with PIK3CA and KRAS gene mutation. The orange represents a different inhibitory effect of repressing tumor growth by targeting different sites on the PI3K/Akt/mTOR pathway. For patients with PIK3CA gene mutation, clinical treatment drugs are mainly divided into PI3K inhibitor, AKT inhibitor, and mTOR inhibitor. The blue represents a different inhibitor target MAPK pathway in ovarian cancer patients with KRAS gene mutation. The therapy strategy includes restricting KRAS bound to GTP and targeting its downstream signaling pathway. The mechanisms of PI3K/Akt/mTOR pathway and MAPK pathway, and inhibitors in ovarian cancer clinical development. Illustration the therapy strategy via inhibiting the PI3K/Akt/mTOR pathway (green) and MAPK pathway (amaranth) in ovarian cancer patients with PIK3CA and KRAS gene mutation. The orange represents a different inhibitory effect of repressing tumor growth by targeting different sites on the PI3K/Akt/mTOR pathway. For patients with PIK3CA gene mutation, clinical treatment drugs are mainly divided into PI3K inhibitor, AKT inhibitor, and mTOR inhibitor. The blue represents a different inhibitor target MAPK pathway in ovarian cancer patients with KRAS gene mutation. The therapy strategy includes restricting KRAS bound to GTP and targeting its downstream signaling pathway. The PIK3CA gene results in somatic mutations in a majority of human cancer, including OC. The research evidence revealed that the PI3K/AKT signaling was deregulated in a significant fraction of OC and associated with a poor survival rate. The NGS technology has revealed that most of the PIK3CA mutations were confined to exons 9 and 20. 93 , 94 The most common codons of mutation are H1047R, E545G, E545GK, and E545A mutants ( Figure 1B ). Interestingly, PIK3CA mutations are much more prevalent in the rare subtypes of OC. The previous reports showed activating PIK3CA mutations was high frequency in OCCC and EnOC in relation to endometriosis 95 , 96 ( Table 1 ). A research suggested 10 of 11 endometriosis-associated EnOC had PIK3CA mutations in exon 9 and eight of 10 OCCC in exon 20. 97 Oncogenic mutations are rare, with only 2.9% in HGSOC, while oncogenic amplifications in PIK3CA occur in 25% cases. The researcher examined the results of a multiplatform profiling panel, such as DNA sequencing, immunohistochemistry, fluorescent or chromogenic in situ hybridization, and RNA fragment analysis, confirming that the PIK3CA/Akt/mTOR pathway was altered in 61% OCCC. 98 Whole-genome sequencing was performed in 55 Japanese women diagnosed with OCCC. Twenty-three cases had alteration in these genes, including mutations of PIK3CA (35%), PIK3R1 (7%), and PTEN (2%), and amplifications of PIK3R2 (5%), AKT1 (4%), and AKT2 (9%). 99 These differences between OC subtypes suggested that subtype-specific treatment strategies might be needed to improve OC outcomes. Some studies suggested the mutation of PIK3CA was considered an early event in the transformation of endometriosis into OCCC. 96 The higher frequent expression of PIK3CA mutation in OCCC is regarded as its specific biological behavior with foci of endometriosis. 98 , 100–102 The PI3K/Akt pathway has been reported as a collaboration with other gene expression in tumorigenesis. A study showed that mutations of PIK3CA were detected in 40% (17/42) of OCCC and a majority (71%) of these were found in ARID1A-deficient (which encodes a member of the SWI/SNF family protein BAF250a) carcinomas. 103 Remarkable, a study suggested that P53 suppresses PIK3CA transcription through the direct junction with its promoter in ovarian surface epithelial cells. Intriguingly, this study revealed that cisplatin simultaneously attenuated PIK3CA expression and activated P53 expression in sensitive tumors but not in the resistant tumors, which only expressed a low level of P53 activation. But the precise principle of P53-PIK3CA remains elusive at molecular level. 90

BRCA1/2 genes locate on chromosomes 17 (17q21) and 13 (13q12.3), as tumor suppressor genes, which play an important role in regulating the cell cycle and DNA repair system. 52 BRCA1 is a pleiotropic DNA damage response protein with checkpoint activation, DNA repair, and is involved in pro-survival and apoptotic pathways. BRCA2 is a mediator of the core mechanism of homologous recombination. Both BRCA genes have distinctive primary sequences. BRCA mutation leads to similar pathophysiological effects and cancer spectra and to increased cancer predisposition. 53 , 54 For large regions of the human genome, the mutation in different regions are associated with different types of malignancies. A previous study shows that the 3ʹ region mutation of BRCA1 is related to a lower risk of OC, while mutation in the 3ʹ region downstream is related to a higher risk. 4 , 55 In recent years, studies of BRCA mutation have been carried out all over the world. Germline and somatic BRCA mutations were detected in plasma ctDNA of OC by using NGS technology. The indels mutation is the most common in the BRCA genes in OCs ( Figure 1A ), pathogenic germline variants of BRCA1/2 in patients of OC are described in Figure 1B . In a study of eastern England, approximately 8% of HGSOC and EnOC were identified with mutation in BRCA1/2, and the prevalence increased to 12% in patients diagnosed under the age of 70 years, but fell to 1% in those aged over 70 years. 56 In a Scottish study, the prevalence of pathogenic BRCA1/2 mutation among non-mucinous epithelial OC fell from 13.1% to 8.2% in patients diagnosed over the age of 70 years. 57 In a study across the North West of England, the prevalence of BRCA1/2 mutation in epithelial OC by testing germline DNA exceeded 10%, and was consistently over 10% in patients diagnosed under the age of 60 years and over the age of 60 years with either breast and/or OC family history. 58 In a Europe series approximately 20% of epithelial OC were shown to a mutation of BRCA1/2, and the prevalence increased to 31.9% in women with a family history of breast or ovarian cancer, but fell to 10.6% in women diagnosed over 60 years old. 59 So, the age at diagnosis, family history of breast and/or OC, breast cancer history or a Manchester BRCA Score of ≥15 points are related to a >10% prevalence of BRCA1/2 mutation in epithelial OC. 58 Another newstudy assessed the frequency and predictors of BRCA1/2 mutation by using NGS in HGSOC in Serbia. 60 Factors that predicted BRCA1/2 mutations included breast and OC in the same patient, age of epithelial OC, menstrual status, and family history of cancer. Family history of breast or OC diagnosed <50 years among first/second-degree relatives was the most significant factor associated with BRCA1/2 in HGSOC patients. Moreover, it indicated a negative family history will not safely exclude all germline BRCA1/2 mutations and that more than 10% of BRCA1/2 mutation carriers would not be identified. Using those to predict the appropriate risk, then BRCA mutation testing is important to assess the strategy of treatment and prognosis for epithelial OC patients. A great number of studies reported that BRCA1 mutation displayed lower BRCA1 and higher BRCA2 expression. Low BRCA1-expression showed a favorable overall survival in OC. The expression of BRCA2 was associated with poor tumor differentiation as it increases with tumor grade. In contrast to patients with no residual disease, the expression of BRCA2 is higher in patients with any residual disease. Low expression of BRCA1/2 in OC reduces DNA damage repair ability via homologous recombination to result in a better response to platinum-based chemotherapy and Poly (ADP-ribose) polymerase (PARP) inhibition. 61 The patients of OC with mutation of BRCA2 are particularly sensitive to platinum. Therefore, the platinum-based chemotherapeutic regimens are a widely recommended treatment in BRCA-related OC. However, other studies revealed that some BRCA-related OC with previous platinum-sensitivity can become platinum resistant, owing to a reversion of the BRCA mutation by secondary intragenic mediating. 62 , 63 Currently, as an encouraging but complex research field in targeted therapy for OC, PARP inhibitors are in a variety of clinical testing as part of Phase I, II, or III study. The present opinions of PARP inhibitors are discussed later. Finally, the prognosis of BRCA-related OC is optimistic. BRCA mutated OC have a better prognostic outcome and higher chemotherapy sensitivity than those cancers without BRCA dysfunction. 64 A retrospective study showed that OC patients with BRCA2 mutation appeared to have higher progression-free survival rates than ovarian cancer patients with a BCRA1 mutation or without BRCA-related dysfunction. 65 But the controversial conclusion needs to be further explored.

Multiple studies have reported the significant association between gene mutations and clinical phenotype of cancers, implying the prospect to use the loci of gene mutations as prognosis and therapeutic targets. 6–9 Four gene mutations are most commonly reported to be highly associated with epithelial OC, including: TP53, BRCA1/2, PIK3CA, and KRAS. The frequency of these mutations varies among different subtypes of epithelial OC ( Table 1 ). The expression of P53 mutation is the most common mutation in HGSOC. The P53 mutation rate increases to 54.5% in HGSOC. BRCA1/2 genes are responsible for the majority of hereditary OC. The BRCA mutation rate increases to 40% in recurrent HGSOC. PIK3CA mutations have a high frequency in OCCC and the EnOC in relation to endometriosis. The KRAS mutation plays a key role in the LGSOC and mucinous OC. The potential mechanisms between the mutations and OC are described as: loss of function of genes regulating tumor suppression, abnormalities of DNA repair genes, apoptosis, gain in function of oncogenes, and epigenetic inactivation. 10 Table 1 The Frequency of the Four Gene Mutations Among Epithelial Ovarian Cancer Subtype Frequency of Genetic Alterations Ref. TP53 BRCA1/2 PIK3CA KRAS HGSOC 96% 22%~40% 2.9% 5.9% [ 23 , 143–145 ] LGSOC 8.3 10% 12.5% 54% [ 7 , 61 , 146 , 147 ] EnOC 5–54.5% 11.1% 31.4% 10.3% [ 61 , 97 , 120 , 148 , 149 ] OCCC 10% 4.5% 51% 15% [ 61 , 93 , 99 , 121 , 150 ] Mucinous 56.8% 0 13.5% 57.1~64.9% [ 120 , 126 , 151 , 152 ] Abbreviations: HGSOC, high-grade serous ovarian carcinoma; LGSOC, low-grade serous ovarian carcinoma; EnOC, endometrioid ovarian carcinoma; OCCC, ovarian clear cell carcinoma. The Frequency of the Four Gene Mutations Among Epithelial Ovarian Cancer Abbreviations: HGSOC, high-grade serous ovarian carcinoma; LGSOC, low-grade serous ovarian carcinoma; EnOC, endometrioid ovarian carcinoma; OCCC, ovarian clear cell carcinoma.

Currently, no therapies that directly target KRAS oncoprotein are available in the clinic because of the high affinity for GTP. 127 Previously, KRAS has been known as difficult to target for cancer treatment. Recently, the detection of KRAS mutations in numerous tumors has led to the development of new therapeutic agents that aimed to either directly inhibit mutated-KRAS, target its downstream signaling pathway, or exploit synthetic lethality partners of mutant KRAS 128 , 129 ( Figure 4 ). In studies on direct inhibition of KRAS activity, strategies of directly restricting and binding KRAS to its functional domains have been proposed. ARS853 could specifically target combination to the G12C mutant of KRAS, significantly restricting the binding of KRAS to GTP, then reducing the phosphorylation level of KRAS and inhibiting the interaction between KRAS and downstream signaling molecules. 130 Meanwhile, the exosomes secreted by normal fibroblast-like mesenchymal cells are engineered and encapsulated with siRNA or shRNA for delivery of KRAS G12D mutants. By targeting wild-type KRAS, the growth of lung cancer and colorectal cancer can be significantly inhibited. This provides a reliable method for direct targeting therapy of KRAS mutant tumors. 131 , 132 The KRAS related downstream signaling contains the RAF-MEK-MEK pathway. Besides, KRAS mutated tumor cells are often accompanied with other signaling molecules mutations, such as PIK3CA, PTEN, P53, which play a key role in tumorigenesis. Selumetinib (AZD6244) is the second generation of MEK1/2 inhibitors, which can specifically inhibit the phosphorylation of ERK1/2, a direct substrate of MEK1/2, thereby inhibiting cell growth. 133 A study of 15 patients with epithelial OC genotype-matched in phase I or II trials, including 14 patients with KRAS mutation treatment in combination to selumetinib, suggested seven partial responses, seven with stable disease and one with disease progression. 134 Moreover, the higher sensitivity to MEK inhibitors was observed in the OC patients with KRAS mutation. A phase II trial of Selumetinib suggested that the response rate for recurrent low-grade serous cancer was 15%. 135 Synthetic lethal strategy, which is raised to inhibit both downstream active pathway and feedback regulation pathway of KRAS, so as to achieve the therapeutic effect of inhibiting tumor cell growth. Cyclin dependent kinase 1(CDK1), such as AZD5483, has a synthetic lethal effect on KRAS-mutated tumor by blocking cells at G0/G1 phase. The anticancer effect has been further confirmed in colorectal cancer and pancreatic cancer in vivo. 136 Recently research reported that frequent mutation of KRAS have been observed in ovarian mucinous carcinomas. The results suggested that combined MEK inhibitor (pimasertib) and PI3K/mTOR inhibitor (SAR245409, voxtalisib) exhibited synergistic anti-tumor effects in ovarian mucinous carcinomas with KRAS and/or PIK3CA mutation. 137 Recently, a great number of synthetic lethal sites have been identified, including serine/threonine kinase 33, PLK1 (polo like kinase 1), Bcl-xL (B-cell lymphoma-extra-large), AK1 (TGF-beta activated kinase 1), and GATA2 (GATA binding protein 2). 138 All of these provide new strategies and options for the treatment of KRAS mutant tumors ( Table 2 ).

OC is a complex and polygenic mutation disease. Specific gene mutations have been revealed to drive OC pathogenesis and development. The usability of genome sequencing has provided exact data of gene mutations in ovarian carcinomas to develop some accurate treatment strategies. In a certain extent biologically targeted therapies and some targeted drugs combinations have improved prognosis. Recently, numerous gene mutation studies have offered some potential predictive biomarkers or therapeutics in OC. But few available effective therapies are currently used widely in the clinic. In this review, we highlight the advance in P53, BRAC1/2, PIK3CA, and KRAS gene mutations in OC and summarize the potential targets for novel therapeutic strategies based on the above gene mutant. In the future, to improve OC targeting, we need a deeper delve to identify carcinogenesis and interactions of gene mutations. There is still future research to be done in order to prospect for gene therapy which can solve the treatment of OC. With development of whole gene sequencing technology, liquid biopsy and gene-editing technologies will reveal a more complete genomic landscape which can detect OC in the early stage and establish novel treatments.