Profiling cancer gene mutations in longitudinal epithelial ovarian cancer biopsies by targeted next-generation sequencing: A retrospective study

L. Beltrame, M. Di Marino, R. Fruscio, E. Calura, B. Chapman, L. Clivio, F. Sina, C. Mele, P. Iatropoulos, T. Grassi, V. Fotia, C. Romualdi, P. Martini, M. Noris, L. Paracchini, I. Craparotta, M. Petrillo, R. Milani, P. Perego, A. RavaggiA. Zambelli, E. Ronchetti, Maurizio D'Incalci, S. Marchini

Research output: Contribution to journalArticle

Abstract

Background: The majority of patients with stage III-IV epithelial ovarian cancer (EOC) relapse after initially responding to platinum-based chemotherapy, and develop resistance. The genomic features involved in drug resistance are unknown. To unravel some of these features, we investigated the mutational profile of genes involved in pathways related to drug sensitivity in a cohort of matched tumors obtained at first surgery (Ft-S) and second surgery (Sd-S). Patients and methods: Matched biopsies (33) taken at Ft-S and Sd-S were selected from the 'Pandora' tumor tissue collection. DNA libraries for 65 genes were generated using the TruSeq Custom Amplicon kit and sequenced on MiSeq (Illumina). Data were analyzed using a high-performance cluster computing platform (Cloud4CARE project) and independently validated. Results: A total of 2270 somatic mutations were identified (89.85% base substitutions 8.19% indels, and 1.92% unknown). Homologous recombination (HR) genes and TP53 were mutated in the majority of Ft-S, while ATM, ATR, TOP2A and TOP2B were mutated in the entire dataset. Only 2% of mutations were conserved between matched Ft-S and Sd-S. Mutations detected at second surgery clustered patients in two groups characterized by different mutational profiles in genes associated with HR, PI3K, miRNA biogenesis and signal transduction. Conclusions: There was a low level of concordance between Ft-S and Sd-S in terms of mutations in genes involved in key processes of tumor growth and drug resistance. This result suggests the importance of future longitudinal analyses to improve the clinical management of relapsed EOC.

Original languageEnglish
Pages (from-to)1363-1371
Number of pages9
JournalAnnals of Oncology
Volume26
Issue number7
DOIs
Publication statusPublished - Jul 1 2015

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Neoplasm Genes
Retrospective Studies
Biopsy
Mutation
Homologous Recombination
Drug Resistance
Genes
Computing Methodologies
Ovarian epithelial cancer
Neoplasms
p53 Genes
Platinum
MicroRNAs
Phosphatidylinositol 3-Kinases
Gene Library
Signal Transduction
Recurrence
Drug Therapy
Growth

Keywords

  • Epithelial ovarian cancer
  • Matched tumor biopsies
  • NGS

ASJC Scopus subject areas

  • Oncology
  • Hematology

Cite this

Profiling cancer gene mutations in longitudinal epithelial ovarian cancer biopsies by targeted next-generation sequencing : A retrospective study. / Beltrame, L.; Di Marino, M.; Fruscio, R.; Calura, E.; Chapman, B.; Clivio, L.; Sina, F.; Mele, C.; Iatropoulos, P.; Grassi, T.; Fotia, V.; Romualdi, C.; Martini, P.; Noris, M.; Paracchini, L.; Craparotta, I.; Petrillo, M.; Milani, R.; Perego, P.; Ravaggi, A.; Zambelli, A.; Ronchetti, E.; D'Incalci, Maurizio; Marchini, S.

In: Annals of Oncology, Vol. 26, No. 7, 01.07.2015, p. 1363-1371.

Research output: Contribution to journalArticle

Beltrame, L, Di Marino, M, Fruscio, R, Calura, E, Chapman, B, Clivio, L, Sina, F, Mele, C, Iatropoulos, P, Grassi, T, Fotia, V, Romualdi, C, Martini, P, Noris, M, Paracchini, L, Craparotta, I, Petrillo, M, Milani, R, Perego, P, Ravaggi, A, Zambelli, A, Ronchetti, E, D'Incalci, M & Marchini, S 2015, 'Profiling cancer gene mutations in longitudinal epithelial ovarian cancer biopsies by targeted next-generation sequencing: A retrospective study', Annals of Oncology, vol. 26, no. 7, pp. 1363-1371. https://doi.org/10.1093/annonc/mdv164
Beltrame, L. ; Di Marino, M. ; Fruscio, R. ; Calura, E. ; Chapman, B. ; Clivio, L. ; Sina, F. ; Mele, C. ; Iatropoulos, P. ; Grassi, T. ; Fotia, V. ; Romualdi, C. ; Martini, P. ; Noris, M. ; Paracchini, L. ; Craparotta, I. ; Petrillo, M. ; Milani, R. ; Perego, P. ; Ravaggi, A. ; Zambelli, A. ; Ronchetti, E. ; D'Incalci, Maurizio ; Marchini, S. / Profiling cancer gene mutations in longitudinal epithelial ovarian cancer biopsies by targeted next-generation sequencing : A retrospective study. In: Annals of Oncology. 2015 ; Vol. 26, No. 7. pp. 1363-1371.
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abstract = "Background: The majority of patients with stage III-IV epithelial ovarian cancer (EOC) relapse after initially responding to platinum-based chemotherapy, and develop resistance. The genomic features involved in drug resistance are unknown. To unravel some of these features, we investigated the mutational profile of genes involved in pathways related to drug sensitivity in a cohort of matched tumors obtained at first surgery (Ft-S) and second surgery (Sd-S). Patients and methods: Matched biopsies (33) taken at Ft-S and Sd-S were selected from the 'Pandora' tumor tissue collection. DNA libraries for 65 genes were generated using the TruSeq Custom Amplicon kit and sequenced on MiSeq (Illumina). Data were analyzed using a high-performance cluster computing platform (Cloud4CARE project) and independently validated. Results: A total of 2270 somatic mutations were identified (89.85{\%} base substitutions 8.19{\%} indels, and 1.92{\%} unknown). Homologous recombination (HR) genes and TP53 were mutated in the majority of Ft-S, while ATM, ATR, TOP2A and TOP2B were mutated in the entire dataset. Only 2{\%} of mutations were conserved between matched Ft-S and Sd-S. Mutations detected at second surgery clustered patients in two groups characterized by different mutational profiles in genes associated with HR, PI3K, miRNA biogenesis and signal transduction. Conclusions: There was a low level of concordance between Ft-S and Sd-S in terms of mutations in genes involved in key processes of tumor growth and drug resistance. This result suggests the importance of future longitudinal analyses to improve the clinical management of relapsed EOC.",
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T1 - Profiling cancer gene mutations in longitudinal epithelial ovarian cancer biopsies by targeted next-generation sequencing

T2 - A retrospective study

AU - Beltrame, L.

AU - Di Marino, M.

AU - Fruscio, R.

AU - Calura, E.

AU - Chapman, B.

AU - Clivio, L.

AU - Sina, F.

AU - Mele, C.

AU - Iatropoulos, P.

AU - Grassi, T.

AU - Fotia, V.

AU - Romualdi, C.

AU - Martini, P.

AU - Noris, M.

AU - Paracchini, L.

AU - Craparotta, I.

AU - Petrillo, M.

AU - Milani, R.

AU - Perego, P.

AU - Ravaggi, A.

AU - Zambelli, A.

AU - Ronchetti, E.

AU - D'Incalci, Maurizio

AU - Marchini, S.

PY - 2015/7/1

Y1 - 2015/7/1

N2 - Background: The majority of patients with stage III-IV epithelial ovarian cancer (EOC) relapse after initially responding to platinum-based chemotherapy, and develop resistance. The genomic features involved in drug resistance are unknown. To unravel some of these features, we investigated the mutational profile of genes involved in pathways related to drug sensitivity in a cohort of matched tumors obtained at first surgery (Ft-S) and second surgery (Sd-S). Patients and methods: Matched biopsies (33) taken at Ft-S and Sd-S were selected from the 'Pandora' tumor tissue collection. DNA libraries for 65 genes were generated using the TruSeq Custom Amplicon kit and sequenced on MiSeq (Illumina). Data were analyzed using a high-performance cluster computing platform (Cloud4CARE project) and independently validated. Results: A total of 2270 somatic mutations were identified (89.85% base substitutions 8.19% indels, and 1.92% unknown). Homologous recombination (HR) genes and TP53 were mutated in the majority of Ft-S, while ATM, ATR, TOP2A and TOP2B were mutated in the entire dataset. Only 2% of mutations were conserved between matched Ft-S and Sd-S. Mutations detected at second surgery clustered patients in two groups characterized by different mutational profiles in genes associated with HR, PI3K, miRNA biogenesis and signal transduction. Conclusions: There was a low level of concordance between Ft-S and Sd-S in terms of mutations in genes involved in key processes of tumor growth and drug resistance. This result suggests the importance of future longitudinal analyses to improve the clinical management of relapsed EOC.

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KW - Epithelial ovarian cancer

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