Between 5 and 15% or approximately 10% of ovarian cancers are determined by germline mutations in different genes with activity in oncogenesis processes. Among these, the most frequently involved are the BRCA1 and BRCA2 genes, but there are also other well-known ones: CHEK2, BARD1, PALB2, RAD51, and TP53.

BRCA1 and BRCA2

BRCA1 (BReast CAncer gene 1) and BRCA2 (BReast CAncer gene 2) are tumor suppressor genes that play a role in genomic stability and DNA repair. BRCA1 and BRCA2 are involved in homologous recombination, a key pathway for repairing double-strand DNA breaks ^[1][20]. BRCA1 and BRCA2 encode large proteins expressed in several tissues throughout S and G2 stages of the cell cycle ^[2][21].

The BRCA1 gene is located on chromosome 17q21 and encodes a protein of 1863 aminoacids. At the N-terminal end of the protein, there is a RING (Really Interesting New Gene) domain, which is required for the interaction with BARD1 (BRCA1 Associated RING Domain protein 1). At the C-terminal end, there are two domains (BRCT) that mediate the interaction with proteins, such as ABRAXAS (BRCA1 A Complex Subunit), CtIP, (C-terminal binding protein 1 interacting protein), and BRIP1 (BRCA1 interacting protein C-terminal helicase 1). The coiled-coil domain, which is important for the interaction with BRCA1 through PALB2, and two nuclear localization signals (NLS), essential for BRCA1 function, can be found in the central region ^[3][22]. Most BRCA1 mutations are frameshift insertions or deletions, nonsynonymous truncations, and disruptions of splice site resulting in non-functional proteins ^[4][23]. Most frequent mutations are found in the regions that correspond to BRCT and RING domains and in the exons 11-13 that encode NLS. BRCA1 mutations have been associated with breast and ovarian cancers, as well as prostate, pancreas, gastric, and colorectal cancers.

The BRCA2 gene is located on chromosome 13q12.3 and encodes a protein of 3418 amino acids ^[5][24]. BRCA2 contains two DNA-binding domains ^[6][25]. The central region contains BRC repeats that bind to RAD51 ^[7][26]. C-terminus contains two NLS and an additional RAD51 interaction site (TR2) ^[8][27].

Most BRCA2 mutations are frameshift insertions, deletions, and nonsense mutations, and they result in premature truncation or non-functional protein ^[6][25]. The most commonly mutated site is exon 11, which encodes the BRC repeats ^[9][28]. Mutations in the BRCA2 gene predispose to breast, ovarian, and prostate cancer, but they have also been associated with ocular or cutaneous melanoma and gastric, pancreatic, gallbladder, and bile duct cancer ^[10][29].

BRCA-associated breast cancers have demonstrated a dependence on alternate DNA repair processes through base excision repair, which requires poly (ADP-ribose) polymerase 1 (PARP-1) ^[11][30]. BRCA mutations follow an autosomal dominant inheritance pattern.

PALB2

The PALB2 (partner and localizer of BRCA2) gene is located on chromosome 16p12.2 and encodes a protein that interacts with BRCA1 and BRCA2, forming a complex that is crucial for DNA repair through homologous recombination ^[12][31]. The coiled-coil domain at the N-terminal end of the protein interacts with BRCA1. The WD40 domain, which interacts with BRCA2, DNA polymerase, RAD51, RAD51C, and the ubiquitin ligase RNF168, is located at the C-terminal end of the protein ^[13][14][32,33]. The ChAM domain, which contributes to the formation of PALB2-BRCA2-RAD51, is found in the middle region ^[15][34]. The protein has two DNA-binding domains. Moreover, it interacts directly with RAD51 ^[16][35]. Breast, ovarian, and pancreatic cancer have all been linked to heterozygous germline mutations in the PALB2 gene ^[17][36]. Biallelic mutations in PALB2 are involved in a subtype of Fanconi anemia ^[18][19][37,38].

RAD51

RAD51 is a gene located on chromosome 15q15.1 involved in homologous recombination and DNA repair processes ^[20][39]. The gene in question produces a protein that belongs to the RAD51 protein family. RAD51 family members are highly similar to bacterial RecA and Saccharomyces cerevisiae Rad51 ^[21][40]. RAD51 protein plays a central role in homologous recombination, a mechanism that ensures accurate repair of DNA double-strand breaks. It acts by assembling into a filamentous structure on single-stranded DNA regions, facilitating the search for and pairing with homologous DNA sequences for repair. This protein interacts with the ssDNA-binding protein RPA, RAD52, BRCA1, and BRCA2 ^[22][41]. It has been shown that BRCA2 controls its intracellular location as well as its capacity to bind DNA. Following BRCA2 inactivation, the loss of these regulators may be a crucial event triggering genomic instability. Mutations in RAD51 have been associated with an increased susceptibility to certain types of cancer, particularly breast and ovarian cancer.

CHEK2

CHEK2 (Checkpoint Kinase 2) gene is located on chromosome 22q12.1, and it encodes a protein involved in cell cycle regulation and DNA repair processes. As a checkpoint kinase, CHEK2 plays a critical role in monitoring DNA integrity and ensuring proper cell division. It functions by inhibiting the entry of the cell into mitosis by stopping it in stage G1 in response to DNA damage. The role of the gene is to alter the intercellular signal in cases of DNA damage, thereby inducing a prompt phosphorylation response. Specifically, in situations where the action of this gene is inactivated, various types of cancer will occur, including breast, ovarian, prostate, and colorectal cancer ^[23][42]. The types of cancer that can result from gene mutations are both sporadic and hereditary. The 1100delC mutation variant was observed in Cowden syndrome and Li Fraumeni syndrome ^[24][43]. The gene is activated by the phosphorylation of Thr68 by ATM, which produces the dimerization of the gene, giving it the ability to function as a kinase. Subsequently, the gene reacts with phosphatase CDC25, protein kinase Ser/THr NEK6, transcription factor FOXM1, protein p53, and BRCA1 or BRCA2. Alterations in the CHEK2 or TP53 genes have been linked to reduced sensitivity to anthracycline-based chemotherapy in breast cancer patients. Another study in Chinese women with breast cancer demonstrated that H371Y carriers may have a better response to neoadjuvant chemotherapy ^[25][44].

The TP53 gene

The TP53 gene, often referred to as p53, is a pivotal tumor suppressor gene that plays a crucial role in maintaining genomic stability and preventing the development of cancer. Its position can be found on the short arm of chromosome 17 (17p13.1).

It serves as a nuclear transcriptional regulator intricately involved in numerous cellular processes. Through its direct interaction with DNA, p53 exerts precise control over the expression of a vast array of target genes, thus upholding cellular homeostasis and safeguarding the integrity of the genome. Notably, p53’s role encompasses multifaceted functions, including activation of DNA repair mechanisms following instances of DNA damage, imposition of cell growth arrest through modulation of the G1/S transition, which allows for the execution of DNA repair processes, and initiation of programmed cell death, or apoptosis, in cases of irreparable DNA damage ^[26][45].

Structurally, the p53 protein exhibits four discernible functional domains: an N-terminal domain governing transcriptional activation, a central DNA-binding domain endowed with sequence specificity, a tetramerization domain, and a C-terminal regulatory domain. Beyond its recognized capacity for transcriptional activation, p53 has also been associated with transcriptional repression; however, the binding sites implicated in the regulation of its downregulated target genes remain relatively less characterized.

The induction of p53 activation transpires through a myriad of stimuli, encompassing UV- or gamma-irradiation-induced DNA damage, inappropriate activation of proto-oncogenes, mitogenic signaling cascades, stress elicited within the ribosomal or nucleolar milieu, and instances of hypoxia. Upon attaining an activated state, p53 orchestrates an array of cellular responses contingent upon the specific cellular context. These responses encompass cell cycle arrest, senescence, cellular differentiation, apoptosis, and ferroptosis. The mechanism underlying such varied outcomes resides in p53’s aptitude for stimulating the expression of a diverse spectrum of genes vital for these cellular activities.

TPp53 is known in the transcription of p21, an orchestrator of p53-mediated cell cycle arrest in the G1 phase, which culminates in cellular senescence. In parallel, p53 also triggers the expression of key elements, such as Puma, Bax, and miR-34, which collectively underpin p53’s ability to elicit apoptosis. Intriguingly, recent investigations have unveiled p53’s role in inducing ferroptosis—a specialized form of cell demise characterized by reactive oxygen species—via the activation of SLC7A11, a pivotal component of the cystine/glutamate antiporter ^[27][46].

ARID1A gene

ARID1A, also known as AT-rich interactive domain-containing protein 1A, is a tumor suppressor gene located on chromosome 1p36.11. Inactivating mutations in the ARID1A gene, which result in the loss of protein expression, have been found in cases of ovarian cancer, especially clear cell carcinoma ^[28][47]. This gene encodes ARID1A protein, a member of the SWI/SNF family involved in transcriptional activation through chromatin remodeling. Chromatin remodeling is a process that regulates the structure and accessibility of DNA, which in turn affects gene expression. Mutations in the ARID1A gene can lead to disruptions in the regulation of genes involved in cell growth, differentiation, and DNA repair, contributing to the development of cancer.

The role of ARID1A in cancer is exercised by the involvement in EZH2 methyltransferase activity, the PI3K/AKT/mTOR pathway, the regulation of p53 targets, DNA damage checkpoints, and the tumor immune response ^[29][48].

Other cancers associated with Other cancers associated with mutations that lead to loss-of-function in the ARID1A gene are endometrial cancers, gastric cancers, bladder cancers, hepatocellular cancers, melanomas, colon cancers, and lung cancers ^[30][49].

Candidate genes in the context of ovarian cancer refer to specific genes that are hypothesized to play a significant role in the development, progression, or susceptibility to ovarian cancer. These genes are identified through various scientific methods and investigations that aim to uncover genetic factors associated with the disease. Candidate genes are selected based on their biological functions, potential relevance to cancer biology, and evidence from research studies indicating their involvement in ovarian cancer ^[31][50].

The process of identifying candidate genes involves a combination of genetic, molecular, and clinical research, as it is a dynamic process. Candidate genes are often selected based on their known or suspected functions related to cancer biology. For example, genes involved in cell cycle regulation, DNA repair, apoptosis, and signaling pathways that contribute to tumorigenesis are frequently considered ^[32][51].

For example, PTEN is a crucial tumor suppressor gene frequently implicated in ovarian cancer. It regulates cell growth, division, and apoptosis by inhibiting the PI3K-AKT signaling pathway. Loss of PTEN function, often due to mutations or epigenetic silencing, can lead to uncontrolled cell growth and survival.

PTEN exerts its tumor-suppressive influence through the orchestrated action of two principal domains: the phosphatase domain and the C2 domain. In its capacity as a tumor suppressor, PTEN carries out its regulatory role by means of its 3’-phosphatase activity, which engenders the dephosphorylation of phosphatidylinositol (3,4,5)-trisphosphate (PIP3). This dephosphorylation event culminates in the restraint of AKT activity, thereby orchestrating downstream modulation of the entire signaling cascade. Delving further into the molecular intricacies, the PTEN protein exhibits a dual aptitude: lipid phosphatase activity, which is pivotal in halting cell-cycle progression at the G1/S checkpoint, and protein phosphatase activity, which is instrumental in repressing certain processes, such as focal adhesion assembly, cellular spreading, and migration. Furthermore, this dualistic activity extends to the inhibition of the MAPK signaling pathway, which is prompted by growth factor stimuli ^[33][52].

KRAS and BRAF

Mutations in KRAS and BRAF genes are commonly observed in mucinous ovarian carcinomas. These genes are part of the MAPK signaling pathway, which regulates cell growth, differentiation, and survival. Aberrations in KRAS and BRAF contribute to dysregulated cellular processes in ovarian cancer ^[34][53].

FOXL2

FOXL2 mutations are frequently found in adult granulosa cell tumors, a rare subtype of ovarian cancer. FOXL2 is a transcription factor involved in ovarian development and folliculogenesis. Mutations in FOXL2 can lead to dysregulated gene expression and cell growth in granulosa cell tumors ^[35][54].

CCNE1

Cyclin E1 (CCNE1) is involved in cell cycle regulation and progression. Amplification and overexpression of CCNE1 have been observed in a subset of high-grade serous ovarian carcinomas, contributing to uncontrolled cell proliferation and genomic instability ^[36][55].

In the realm of ovarian cancer, prognostic genes are those whose expression levels or genetic alterations are associated with the anticipated clinical outcomes for patients. These genes can provide valuable insights into disease progression, patient survival, and response to treatments. Some genes are considered risk genes, having a negative influence on the clinical outcome, while others are considered protective genes, the presence of which positively influences the evolution of the disease. Several prognostic genes have been identified through extensive research in ovarian cancer.

AP3D1 and LRFN4 are genes associated with increased risk, and elevated expression of these genes is linked to diminished survival rates among individuals with ovarian cancer. The presence of AP3D1 and LRFN4 has been found to contribute to the initiation and progression of various cancers and diseases ^[37][56].

Notably, in cases of colorectal cancer, the absence of the optic nerve element prompts evasion of the immune system and an inherent resistance to immunotherapy. Intriguingly, the optic nerve element unexpectedly interacts with AP3D1, thereby preventing the sorting and degradation of palmitoylated IFNGR1 lysosomes. This interaction serves to preserve the integrity of signaling related to interferon gamma and major histocompatibility complex (MHC)-I, which are crucial components of the immune response ^[38][57].

DCAF10, FBXO16, PTPN2, SAYSD1, and ZNF426 are genes that confer protection to ovarian cancer patients, with their heightened expression correlating with improved survival rates. These genes exhibit a restraining influence on the development of numerous cancers and diseases ^[37][38][56,57].

Notably, FBXO16 serves as a tumor suppressor, and it functions within the skp1-cullin1-f-box protein complex. This complex targets nuclear β-catenin for proteasome degradation through the 26S proteasome system. Deficiency of FBXO16 results in elevated β-catenin levels, subsequently fostering certain processes, such as cancer cell invasion, tumor proliferation, and epithelial–mesenchymal transition. In the realm of breast cancer, FBXO16 holds potential as a clinical target and prognostic biomarker across diverse molecular subtypes. Additionally, research has indicated that augmenting the count of cytotoxic Tim-3+/CD8+ T cells can enhance effective anti-tumor immunity. PTPN2 emerges as an attractive target for tumor immunotherapy in immune cells, further underscoring its significance ^[39][58].

CCDC80, also known as LRP1B (Low-Density Lipoprotein Receptor-Related Protein 1B), is gaining recognition as a candidate gene in ovarian cancer prognosis. LRP1B is a transmembrane receptor involved in cellular processes like endocytosis, cell signaling, and cell adhesion. Recent studies have suggested that CCDC80/LRP1B may function as a tumor suppressor in certain contexts. Downregulation or loss of CCDC80 expression has been associated with multiple cancer types, including ovarian cancer, and it has been linked to poorer outcomes.

In the context of ovarian cancer, CCDC80’s role in mediating cell adhesion and migration is of particular interest. Its downregulation may contribute to enhanced tumor cell invasiveness and metastasis. Studies exploring the clinical relevance of CCDC80 in ovarian cancer patients are underway; they aim to elucidate its impact on disease progression and patient survival ^[40][59].

FBXO16, an F-box protein, has garnered attention for its tumor-suppressive properties. F-box proteins are key components of ubiquitin ligase complexes that target specific proteins for degradation, thereby regulating various cellular processes. FBXO16 has been identified as a potential tumor suppressor in various cancer types, including ovarian cancer.

Research has highlighted FBXO16’s involvement in the regulation of β-catenin, a key player in the Wnt signaling pathway that influences cell proliferation, differentiation, and migration. FBXO16 helps target nuclear β-catenin for degradation, thereby curbing its oncogenic potential. Loss of FBXO16 could lead to increased β-catenin levels, contributing to cancer cell invasion, tumor growth, and metastasis.

FBXO16’s significance extends to potential clinical applications. It has been suggested that FBXO16 might serve as a clinical target for therapeutic intervention, particularly in breast cancer, where its role as a prognostic biomarker across distinct molecular subtypes is being explored ^[41][60].