Next-Generation Sequencing: Role in Gynecologic Cancers

Abstract

Next-generation sequencing (NGS) has risen to the forefront of tumor analysis and has enabled unprecedented advances in the molecular profiling of solid tumors. Through massively parallel sequencing, previously unrecognized genomic alterations have been unveiled in many malignancies, including gynecologic cancers, thus expanding the potential repertoire for the use of targeted therapies. NGS has expanded the understanding of the genomic foundation of gynecologic malignancies and has allowed identification of germline and somatic mutations associated with cancer development, enabled tumor reclassification, and helped determine mechanisms of treatment resistance. NGS has also facilitated rationale therapeutic strategies based on actionable molecular aberrations. However, issues remain regarding cost and clinical utility. This review covers NGS analysis of and its impact thus far on gynecologic cancers, specifically ovarian, endometrial, cervical, and vulvar cancers.

Clonal Evolution of TP53 c.375+1G>A Mutation in Pre- and Post- Neo-Adjuvant Chemotherapy (NACT) Tumor Samples in High-Grade Serous Ovarian Cancer (HGSOC)

“…The amount of mutations in TP53 implicated in splice junctions that interfere with correct protein translation, by introducing frameshift or aberrant spicing, has been probably underestimated in many studies, due to the restriction of genetic analyses in coding regions and in the DNA binding domain (DBD) of p53. Many rare genomic alterations, such as those affecting the splice site regions, have been unveiled by the application of NGS, thus expanding the potential repertoire for the use of target therapies and personalized therapy [24]. Aberrant splicing events are a common phenomenon in tumorigenesis described in each of the accepted hallmarks of cancer, particularly in apoptosis and metastasis formation, even if, their biological functions are still not completely clarified [56].…”

“…Next-generation sequencing (NGS) technology has expanded the knowledge of the complex genomic heterogeneity of ovarian cancer through the discovery of candidate targets for future therapeutic applications. In addition, the identification of germline and somatic mutations better define the subtype-specific molecular signatures, highlighting mechanisms of treatment resistance influencing ovarian and gynecologic malignancies [24]. This study, using targeted NGS, analyzed matched pre- and post-NACT ovarian tumor specimens and matched blood samples, from a patient with HGSOC characterized by a poor response to treatment and early death, within a 26 cancer-genes panel [23,25].…”

Dietary restriction protects against diethylnitrosamine-induced hepatocellular tumorigenesis by restoring the disturbed gene expression profile

“…During the past decade, next-generation sequencing (NGS) has become an efficient and accurate method in molecular diagnostics by providing comprehensive genomic aberrations in tumors for both research and clinical purposes2930. NGS encompasses a set of different techniques including whole genome/exome sequencing, RNA sequencing (RNA-Seq) and targeted sequencing of specific panels of genes31.…”

Nelfinavir induces cytotoxicity towards high-grade serous ovarian cancer cells, involving induction of the unfolded protein response, modulation of protein synthesis, DNA damage, lysosomal impairment, and potentiation of toxicity caused by proteasome inhibition

“…Despite increasing advancement in diagnostics and therapeutic avenues, platinum-based treatment following tumor-debulking surgery persists as the backbone of ovarian cancer treatment for over fifty years. Although 70% of patients respond favourably to the initial platinum-based therapy, flaring of microscopic residual disease and emergence of platinumresistance are inevitable within 18-24 months, which has contributed to an unimproved 5-year survival rate (47%) since the 1980s [2][3][4][5]. A maintenance therapy during the window of time between primary standard of care and the relapse of the disease may lead to improved patient survival.…”