Molecular biomarkers for facilitating genome‑directed precision medicine in gynecological cancer (Review)

Abstract

Prominent recent advancements in cancer treatment include the development and clinical application of next-generation sequencing (NGS) technologies, alongside a diverse array of novel molecular targeting therapeutics. NGS has enabled the high-speed and low-cost sequencing of whole genomes in individual patients, which has opened the era of genome-based precision medicine. The development of numerous molecular targeting agents, including anti-VEGF antibodies, poly (ADP-ribose) polymerase inhibitors and immune checkpoint inhibitors, have all improved the efficacy of systemic cancer therapy. Accumulating bench and translational research evidence has led to identification of various cancer-related biomarker profiles. In particular, companion diagnostics have been developed for some of these biomarkers, which can be clinically applied and are now widely used for guiding cancer therapies. Selecting biomarkers accurately will improve therapeutic efficacy, avoid overtreatment, enable earlier diagnosis and reduce the cost of preventing and treating gynecological cancer. Therefore, biomarkers are fast becoming indispensable tools in the practice of genome-directed precision medicine. In the present review, the current evidence of cancer-related biomarkers in the field of gynecological oncology, their molecular interpretations and future perspectives are outlined. The aim of the present review is to provide potentially useful information for the formulation of clinical trials.

Keywords: PARP inhibitor; biomarker; companion diagnostic; gynecological cancer; immune checkpoint inhibitor.

Figure 1.

ProMisE molecular classification of EC (7). dMMR, POLE-mutated, p53 abnormal and p53 wild-type tumors are identified using the respective molecular methods. POLE-mutated tumors show the most favorable prognosis, followed by p53 wild-type, dMMR and p53 abnormal tumors showing the worst prognosis. EC, endometrial cancer; IHC, immunohistochemistry; dMMR, deficient mismatch repair; pMMR, proficient mismatch repair; POLE, DNA polymerase ε.

Figure 2.

Proposed molecular mechanism of BRCA-related carcinogenesis. Tumors with loss of heterozygosity in BRCA1 or 2 show HRD, which causes the accumulation of DNA damage, leading to cell cycle arrest and apoptosis induced by wild-type p53. Acquisition of p53 aberrations overcomes cell cycle arrest and circumvents apoptosis, resulting in BRCA-related carcinogenesis. BRCA, breast cancer gene; BRCC, BRCA1/BRCA2-containing complex; DSB, double-strand DNA break; SSB, single-strand DNA break; HRD, homologous recombination deficiency; PARPi, poly-(ADP ribose) polymerase inhibitor.

Figure 3.

Mechanism underlying tumor sensitivity to ICI. Tumors with dMMR show high MSI and TMB, which causes T-cell infiltration and activates the PD1/PD-L1-mediated immune checkpoint pathway, consequently acquiring sensitivity to immune checkpoint blockade. dMMR, deficient mismatch repair; MSI, microsatellite instability; TMB, tumor mutation burden; ICI, immune checkpoint inhibitor; PD1, programmed cell death protein 1; PD-L1, programmed death-ligand 1.

Figure 4.

HPV-induced cervical carcinogenic pathways. Persistent infection with high-risk HPVs leads to the overexpression of E6 and E7, which degrade and inactivate p53 and Rb, respectively. This results in cervical carcinogenesis through multiple downstream pathways. The presence of high-risk HPV DNA corresponds to future long-term risk for developing ≥CIN3 (CIN3 or worse), whilst abnormal cytology corresponds to immediate risk of existing ≥CIN3. Degradation of Rb by E7 and upregulation of E2F result in a feedback loop, leading to the overexpression of p16, which supports the pathological diagnosis of ≥CIN2 (CIN2 or worse). HPV, human papillomavirus; Rb, retinoblastoma; CIN, cervical intraepithelial neoplasia; Dx, diagnosis.