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Cocktail & Poster Display session

10P - An adapted CGP-based model to interpret POLE mutations in endometrial cancer

Date

04 Oct 2023

Session

Cocktail & Poster Display session

Presenters

Rita Trozzi

Citation

Annals of Oncology (2023) 8 (suppl_1_S5): 1-55. 10.1016/esmoop/esmoop101646

Authors

R. Trozzi1, M. Ottaviani1, C. Nero1, S. Duranti2, F. Camarda1, I. Marino2, L. Giacò3, L. De Marco4, A. Preziosi3, A. Minucci5, M. de bonis4, A. Perrucci4, M.E. Onori4, G. Maneri4, F. Sillano4, D. Lorusso1, F. Fanfani1, T. Pasciuto3, I. Mozzetta4, G. Scambia1

Author affiliations

  • 1 Woman’s And Child Health And Public Health Sciences, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, 00168 - Rome/IT
  • 2 Scientific Directorate, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, 00168 - Rome/IT
  • 3 Fondazione Policlinico Universitario Agostino Gemelli IRCCS, 00168 - Rome/IT
  • 4 Fondazione Policlinico Universitario Agostino Gemelli IRCCS, 00168 - Rome/IT
  • 5 Laboratory Of Clinical Molecular And Personalized Diagnostics, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, 00168 - Rome/IT

Resources

This content is available to ESMO members and event participants.

Abstract 10P

Background

Endometrial cancer (EC) patients harbouring POLE mutations have been shown exceptionally good survival outcomes allowing de-escalation of adjuvant treatment. POLE encodes for the Pol ε catalytic subunit capable of correcting DNA synthesis errors; pathogenic mutations within the exonuclease domain (EDM) result in an ultramutated phenotype. So far, 11 POLE EDM variants have been recognized as hotspot mutations. Given the increasing availability in clinical practice of comprehensive genome profiling (CGP), the interpretation of non-hotspot EDM variants has become challenging.

Methods

EC patients enrolled in a CGP programme at Fondazione Policlinico Universitario Agostino Gemelli IRCCS were profiled using TSO500HT. VCF files containing identified variants were analyzed developing an in-house Python and R language script. The following parameters including the frequency of C > A, C > G, T > G substitutions, tumor mutational burden (TMB), the frequency of indels, and the presence of recurrent mutations were evaluated and a score to interpret POLE mutations was recalibrated from Castillo et al. published score on TCGA data.

Results

From January 2022 to May 2023, CGP was available for 392 EC patients. New thresholds for the frequency of C > A, C > G, T > G substitutions and indels were calculated based on the mean of the median values of each parameter comparing POLE EDM hotspots vs POLE benign variants and wild type (WT) cases. Overall, the score correctly identified the POLE hotspot mutations in 40/42 patients. One of the 2 misclassified cases was a FIGO stage IIIC1 case, displaying a TMB of 36.5; the other displayed a TMB of 87. 5 POLE EDM non-hotspot variants were identified (D287E, N363K, T278M, D262H, R375Q) and none of them reached a score ≥ 4. None of these cases displayed a COSMIC signature 10 as expected for POLE EDM hotspot cases. Among the co-mutations, ATM and APC variants were reported to be differentially expressed among POLE EDM hotspots and POLE EDM non-hotspots vs POLE benign and WT cases (ATM: 60%, 60% vs 10%, 11%; APC: 35%, 20% vs 3.8% and 0% respectively).

Conclusions

We adapted Castillo’s TCGA-based POLE score to a CGP assay. This approach could be helpful to interpret POLE EDM non hotspots variants emerging from wide routine genomic characterization.

Editorial acknowledgement

Clinical trial identification

Legal entity responsible for the study

The authors.

Funding

Has not received any funding.

Disclosure

C. Nero: Financial Interests, Personal, Other, Travel grant: Illumina. D. Lorusso: Financial Interests, Institutional, Funding: Clovis, GSK, MSD; Financial Interests, Personal, Funding: AstraZeneca, Clovis Oncology, MSD; Non-Financial Interests, Personal, Advisory Board: GCIG. G. Scambia: Non-Financial Interests, Personal, Advisory Board: Tesaro, Johnson & Johnson; Financial Interests, Institutional, Funding: MSD, Clovis Oncology. All other authors have declared no conflicts of interest.

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