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

• Published in: International journal of molecular sciences Vol. 19; no. 5; p. 1510
• Main Authors: Garziera, Marica, Cecchin, Erika, Canzonieri, Vincenzo, Sorio, Roberto, Giorda, Giorgio, Scalone, Simona, De Mattia, Elena, Roncato, Rossana, Gagno, Sara, Poletto, Elena, Romanato, Loredana, Sartor, Franca, Polesel, Jerry, Toffoli, Giuseppe
• Format: Journal Article
• Language: English
• Published: Switzerland MDPI AG 18-05-2018; MDPI
• Subjects: Aged; Bioinformatics; Case Report; Female; Frameshift Mutation; Gene deletion; Genetic markers; Humans; Immunohistochemistry; INDEL Mutation; Insertion; Markers; Middle Aged; Mutation; Neoplasms, Cystic, Mucinous, and Serous - genetics; Neoplasms, Cystic, Mucinous, and Serous - pathology; Ovarian cancer; Ovarian Neoplasms - genetics; Ovarian Neoplasms - pathology; p53 Protein; Patients; Platinum; Precision medicine; Proteins; Therapeutic applications; Tumor Suppressor Protein p53 - chemistry; Tumor Suppressor Protein p53 - genetics; Tumor Suppressor Protein p53 - metabolism; Tumors; high-grade serous ovarian cancer (HGSOC); next-generation sequencing (NGS); TP53 gene mutations
• ISSN: 1422-0067; 1661-6596; 1422-0067
• DOI: 10.3390/ijms19051510

Somatic mutations in
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
, 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
somatic mutations in untreated tumors from six distinct patients diagnosed with HGSOC were identified:
c.728_739delTGGGCGGCATGA (p.Met243_Met247del, in-frame insertion or deletion (INDEL);
c.795_809delGGGACGGAACAGCTT (p.Gly266_Phe270del, in-frame INDEL);
c.826_827GC>AT (p.Ala276Ile, missense);
c.1022insT (p.Arg342Profs*5, frameshift INDEL);
c.1180delT (p.Ter394Aspfs*28, frameshift INDEL); and
c.573insT (p.Gln192Serfs*17, frameshift INDEL). Novel
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
somatic mutations provides an opportunity to translate NGS technology into personalized medicine and identify new potential targets for therapeutic applications.