Tumor heterogeneity is one of the characteristics of malignant tumors, which refers to the molecular biology or genetic changes in the daughter cells of tumors after multiple divisions and proliferation during the growth process, resulting in differences in tumor growth rate, invasion ability, drug sensitivity, prognosis and other aspects. Ovarian cancer is the leading cause of death from gynecologic malignancies, and its treatment approach has evolved into a complex framework designed to reflect the spatial and temporal heterogeneity of ovarian cancer, a disease that encompasses several subtypes. Molecular heterogeneity in these subtypes results in varying degrees of inherent resistance to conventional platinum-based chemotherapy. A recent review published in the journal Nat Rev Clin Oncol summarized the clinical and biological heterogeneity of ovarian cancer and how it forms and continues to form therapeutic algorithms, and defines the current therapeutic landscape [1]. In the previous issue, we reported on "Clinical, histological, and pathological heterogeneity in ovarian cancer". In this issue, we focus on the "Genomic Characteristics of Spatial and Temporal Heterogeneity in Ovarian Cancer" for readers.
High-grade serous ovarian cancer (HGSOC)
HGSOC is characterized by the presence of TP53 mutations in nearly all patients (96%), as well as recurrent somatic changes in genes such as NF1, BRCA1, and BRCA2 (collectively referred to as BRCA1/2), RB1, and CDK12. In addition, HGSOC exhibits a high degree of chromosomal instability and homologous recombination defects (HRDs) [2]. TP53-encoded tumor suppressor works in response to a variety of stress signals by regulating specific cellular responses, including transient cell cycle arrest, cell senescence, apoptosis, autophagy, and DNA damage repair (DDR)] [3]. Mutations in TP53 often occur in regions encoding DNA-binding domains. In HGSOCs lacking TP53 mutations, the increase in the copy number of MDM2 or MDM4 leads to the dysfunction of p53, and the proteins encoded by these two are involved in the regulation and degradation of p53 [4].
Homologous recombination repair (HRR) is a process involving multiple interrelated pathways responsible for the repair of DNA double-strand breaks and interstrand cross-links [4]. A variety of proteins, such as BRCA1/2, maintain genome stability by repairing DNA damage, thereby promoting cell survival and replication. In HGSOC, HRD is present in approximately 50 percent of cases, of which approximately 25 percent are due to germline and somatic mutations in BRCA1/2, while the remainder are due to alterations in other genes, such as EMSY, RAD51, ATM, ATR, various FANC genes, BARD1, BRIP1, PALB2, RB1, NF1, and CDKN2A [5-7].
Alterations in TP53 and BRCA1/2 together promote chromosomal instability, leading to a widespread accumulation of copy number alterations (CNAs), which may be an adaptive response to tumors. There is evidence that CNAs in the genome, as well as doubling of the genome as a whole, may be associated with advanced stages of the disease, which may be an adaptive survival mechanism [8]. CNAs involved in the amplification and overexpression of the CCNE1 genomic region are known to lead to unplanned DNA replication, centrosome amplification, and chromosomal instability [8,9]. In HGSOC, up to 20 percent of cases exhibit amplification or overexpression of CCNE1, which is associated with resistance to platinum agents and PARP inhibitors [10].
In addition, other genetic mutations have been identified in HGSOC, including AURKA, ERBB3, CDK2, MTOR, BRD4, and MYC1 [11]. Signaling proteins involved in the pathogenesis of this subtype include FOXM1 (84%), Rb1 (67%), PI3K (45%), and Notch1 (22%)[9].
Based on gene expression analysis of immune cell and matrix activation, HGSOC is divided into four subtypes: differentiated, immunoresponsive, mesenchymal, and proliferative [5]. Although these subtypes are associated with overall survival (OS) prognosis [6], this classification has not been incorporated into routine clinical practice due to the lack of standardized subtype classification algorithms and the ability to predictively guide treatment decisions.
A genome sequencing study revealed the presence of seven CNA signals in HGSOC that could predict a patient's OS and the probability of recurrence after platinum-based chemotherapy [12]. Most HGSOCs express multiple signals at the same time, suggesting significant heterogeneity between tumors. This information provides clarity into the mutational mechanisms that affect the DNA integrity of HGSOC signatures and opens up new avenues for translational-clinical study design [9].
Endometrioid ovarian cancer (EOVC) vs. ovarian clear cell carcinoma (OCCC)
There is some overlap between EOVC, OCCC and HGSOC. Alterations in the TP53 gene have been observed in poorly differentiated EOVCs and OCCCs, accounting for 6 to 26 percent and 8.5 to 21.6 percent, respectively [13,14]. In addition, mutations in the mismatch repair (MMR) gene have been reported in both subtypes, which are typically present in individuals with Lynch syndrome [13].
In addition to TP53, variants in other genes have been identified in EOVC, many of which overlap with mutational signatures in endometrial cancer, such as CTNNB1 (16 to 63 percent), KRAS (12 to 26 percent), PTEN (14 to 29 percent), POLE (3 to 10 percent), SOX8 (19 percent), FBXW7 (13 percent), and ERBB2 (8 percent) [13]. Notably, ARID1A mutations are common in EOVC (30%-55%) and are involved in the evolution from endometriosis to EOVC. Mutations or amplifications of PIK3CA are associated with low FIGO levels and early disease stages [13].
In OCCC, common somatic driver mutations are ARID1A (49%), PIK3CA (49%), and TERT (20%). These tumors usually appear at an early stage and are more strongly associated with endometriosis. Alterations in ARID1A have been associated with chemoresistance in OCCC and other solid cancer types [15,16]. In addition, OCCCs (16 percent) with TP53 mutations constitute the HGSOC-like subgroup, and these tumors tend to present with a mesenchymal phenotype, advanced disease, and a poor prognosis [15]. Notably, all OCCCs are characterized by upregulation of HNF1B (95 percent) and genes associated with oxidative stress signaling [17]. These molecular features help us identify epithelial and mesenchymal-like subsets [14].
Low-grade serous ovarian cancer (LGSOC)
Approximately 60% of LGSOCs are altered (including mutations, fusions, and deletions) that affect the MAPK pathway (e.g., KRAS, NRAS, or BRAF). Alterations in the KRAS gene have been associated with improved platinum-based sensitivity, and patient survival [18]. In addition, genetic mutations affecting the AKT-mTOR pathway, such as EIF1AX (10%) and USP9X (11%), have been identified [18]. Compared with HGSOC, LGSOC exhibits IGF1 overexpression, a relatively low frequency of TP53 mutations, and a rare BRCA1/2 mutation [18,19].
Mucinous ovarian cancer (MOC)
KRAS mutations occur in about 46% of MOCs, usually in the early stages of cancer. In contrast, other types of alterations, such as TP53 mutations (52 percent) and HER2 amplification (19 percent), occur more often in advanced stages of cancer [20,21]. In addition, this subtype is characterized by high microsatellite instability, MET overexpression, and CTNNB1 and APC mutations. Notably, both CTNNB1 and APC genes are closely related to the WNT signaling pathway, which further reveals the complexity and specificity of this cancer subtype.
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Disclaimer: This article is published with the support of AstraZeneca and is intended for healthcare professionals only
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