Identification of Novel Somatic TP53 Mutations in Patients with High-Grade Serous Ovarian Cancer (HGSOC) Using Next-Generation Sequencing (NGS)

Abstract

Somatic mutations in <i>TP53</i> are a hallmark of high-grade serous ovarian cancer (HGSOC), although their prognostic and predictive value as markers is not well defined. Next-generation sequencing (NGS) can identify novel mutations with high sensitivity, that may be repurposed as potential druggable anti-cancer targets and aid in therapeutic decisions. Here, a commercial NGS cancer panel comprising 26 genes, including <i>TP53</i>, was used to identify new genetic markers of platinum resistance and patient prognosis in a retrospective set of patients diagnosed with epithelial ovarian cancer. Six novel <i>TP53</i> somatic mutations in untreated tumors from six distinct patients diagnosed with HGSOC were identified: <i>TP53</i> c.728_739delTGGGCGGCATGA (p.Met243_Met247del, in-frame insertion or deletion (INDEL); <i>TP53</i> c.795_809delGGGACGGAACAGCTT (p.Gly266_Phe270del, in-frame INDEL); <i>TP53</i> c.826_827GC>AT (p.Ala276Ile, missense); <i>TP53</i> c.1022insT (p.Arg342Profs*5, frameshift INDEL); <i>TP53</i> c.1180delT (p.Ter394Aspfs*28, frameshift INDEL); and <i>TP53</i> c.573insT (p.Gln192Serfs*17, frameshift INDEL). Novel <i>TP53</i> variants were validated by classical sequencing methods and their impact on protein expression in tumors explored by immunohistochemistry. Further insights into the potential functional effect of the mutations were obtained by different in silico approaches, bioinformatics tools, and structural modeling. This discovery of previously unreported <i>TP53</i> somatic mutations provides an opportunity to translate NGS technology into personalized medicine and identify new potential targets for therapeutic applications.