Identification of novel somatic TP53 mutations in patients with high-grade serous ovarian cancer (HGSOC) using next-generation sequencing (NGS)

Research output: Contribution to journalArticle

4 Citations (Scopus)

Abstract

Somatic mutations in TP53 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 TP53, 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 TP53 somatic mutations in untreated tumors from six distinct patients diagnosed with HGSOC were identified: TP53 c.728_739delTGGGCGGCATGA (p.Met243_Met247del, in-frame insertion or deletion (INDEL); TP53 c.795_809delGGGACGGAACAGCTT (p.Gly266_Phe270del, in-frame INDEL); TP53 c.826_827GC>AT (p.Ala276Ile, missense); TP53 c.1022insT (p.Arg342Profs*5, frameshift INDEL); TP53 c.1180delT (p.Ter394Aspfs*28, frameshift INDEL); and TP53 c.573insT (p.Gln192Serfs*17, frameshift INDEL). Novel TP53 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 TP53 somatic mutations provides an opportunity to translate NGS technology into personalized medicine and identify new potential targets for therapeutic applications.

Original languageEnglish
Article number1510
JournalInternational Journal of Molecular Sciences
Volume19
Issue number5
DOIs
Publication statusPublished - May 18 2018

Fingerprint

deletion
sequencing
mutations
Ovarian Neoplasms
Tumors
insertion
grade
cancer
Mutation
Bioelectric potentials
Bioinformatics
Platinum
Medicine
Genes
markers
Neoplasms
Proteins
tumors
Precision Medicine
prognosis

Keywords

  • High-grade serous ovarian cancer (HGSOC)
  • Next-generation sequencing (NGS)
  • TP53 gene mutations

ASJC Scopus subject areas

  • Catalysis
  • Molecular Biology
  • Spectroscopy
  • Computer Science Applications
  • Physical and Theoretical Chemistry
  • Organic Chemistry
  • Inorganic Chemistry

Cite this

@article{a3fbdab3a513494c96115c7daa1c9366,
title = "Identification of novel somatic TP53 mutations in patients with high-grade serous ovarian cancer (HGSOC) using next-generation sequencing (NGS)",
abstract = "Somatic mutations in TP53 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 TP53, 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 TP53 somatic mutations in untreated tumors from six distinct patients diagnosed with HGSOC were identified: TP53 c.728_739delTGGGCGGCATGA (p.Met243_Met247del, in-frame insertion or deletion (INDEL); TP53 c.795_809delGGGACGGAACAGCTT (p.Gly266_Phe270del, in-frame INDEL); TP53 c.826_827GC>AT (p.Ala276Ile, missense); TP53 c.1022insT (p.Arg342Profs*5, frameshift INDEL); TP53 c.1180delT (p.Ter394Aspfs*28, frameshift INDEL); and TP53 c.573insT (p.Gln192Serfs*17, frameshift INDEL). Novel TP53 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 TP53 somatic mutations provides an opportunity to translate NGS technology into personalized medicine and identify new potential targets for therapeutic applications.",
keywords = "High-grade serous ovarian cancer (HGSOC), Next-generation sequencing (NGS), TP53 gene mutations",
author = "Marica Garziera and Erika Cecchin and Vincenzo Canzonieri and Roberto Sorio and Giorgio Giorda and Simona Scalone and {De Mattia}, Elena and Rossana Roncato and Sara Gagno and Elena Poletto and Loredana Romanato and Franca Sartor and Jerry Polesel and Giuseppe Toffoli",
year = "2018",
month = "5",
day = "18",
doi = "10.3390/ijms19051510",
language = "English",
volume = "19",
journal = "International Journal of Molecular Sciences",
issn = "1661-6596",
publisher = "MDPI AG",
number = "5",

}

TY - JOUR

T1 - Identification of novel somatic TP53 mutations in patients with high-grade serous ovarian cancer (HGSOC) using next-generation sequencing (NGS)

AU - Garziera, Marica

AU - Cecchin, Erika

AU - Canzonieri, Vincenzo

AU - Sorio, Roberto

AU - Giorda, Giorgio

AU - Scalone, Simona

AU - De Mattia, Elena

AU - Roncato, Rossana

AU - Gagno, Sara

AU - Poletto, Elena

AU - Romanato, Loredana

AU - Sartor, Franca

AU - Polesel, Jerry

AU - Toffoli, Giuseppe

PY - 2018/5/18

Y1 - 2018/5/18

N2 - Somatic mutations in TP53 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 TP53, 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 TP53 somatic mutations in untreated tumors from six distinct patients diagnosed with HGSOC were identified: TP53 c.728_739delTGGGCGGCATGA (p.Met243_Met247del, in-frame insertion or deletion (INDEL); TP53 c.795_809delGGGACGGAACAGCTT (p.Gly266_Phe270del, in-frame INDEL); TP53 c.826_827GC>AT (p.Ala276Ile, missense); TP53 c.1022insT (p.Arg342Profs*5, frameshift INDEL); TP53 c.1180delT (p.Ter394Aspfs*28, frameshift INDEL); and TP53 c.573insT (p.Gln192Serfs*17, frameshift INDEL). Novel TP53 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 TP53 somatic mutations provides an opportunity to translate NGS technology into personalized medicine and identify new potential targets for therapeutic applications.

AB - Somatic mutations in TP53 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 TP53, 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 TP53 somatic mutations in untreated tumors from six distinct patients diagnosed with HGSOC were identified: TP53 c.728_739delTGGGCGGCATGA (p.Met243_Met247del, in-frame insertion or deletion (INDEL); TP53 c.795_809delGGGACGGAACAGCTT (p.Gly266_Phe270del, in-frame INDEL); TP53 c.826_827GC>AT (p.Ala276Ile, missense); TP53 c.1022insT (p.Arg342Profs*5, frameshift INDEL); TP53 c.1180delT (p.Ter394Aspfs*28, frameshift INDEL); and TP53 c.573insT (p.Gln192Serfs*17, frameshift INDEL). Novel TP53 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 TP53 somatic mutations provides an opportunity to translate NGS technology into personalized medicine and identify new potential targets for therapeutic applications.

KW - High-grade serous ovarian cancer (HGSOC)

KW - Next-generation sequencing (NGS)

KW - TP53 gene mutations

UR - http://www.scopus.com/inward/record.url?scp=85047350941&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85047350941&partnerID=8YFLogxK

U2 - 10.3390/ijms19051510

DO - 10.3390/ijms19051510

M3 - Article

C2 - 29783665

AN - SCOPUS:85047350941

VL - 19

JO - International Journal of Molecular Sciences

JF - International Journal of Molecular Sciences

SN - 1661-6596

IS - 5

M1 - 1510

ER -