First description of ultramutated endometrial cancer caused by germline loss-of-function and somatic exonuclease domain mutations in POLE gene - Archive ouverte HAL Accéder directement au contenu
Article Dans Une Revue Genetics and Molecular Biology Année : 2020

First description of ultramutated endometrial cancer caused by germline loss-of-function and somatic exonuclease domain mutations in POLE gene

Reginaldo Cruz Alves Rosa
Andrey A Yurchenko
  • Fonction : Auteur
Fernando Chahud
  • Fonction : Auteur
Alfredo Ribeiro-Silva
  • Fonction : Auteur
Mariângela Ottoboni Brunaldi
  • Fonction : Auteur
Wilson Araújo Silva Jr
Sergey Nikolaev
  • Fonction : Auteur
Victor Evangelista de Faria Ferraz

Résumé

Endometrial cancer (EC) harboring heterozygous POLE proofreading inactivating mutations (POLE-exo*) is associated with an increased number of somatic mutations that result in a distinctive anti-tumor immune response. However, the consequences of such POLE mutations in the context of the missing wild-type allele have not yet been described in endometrial tumors. A 72-year-old woman harboring a germline monoallelic frameshift mutation (p.Pro269fsTer26) in POLE was diagnosed with an EC having a somatic heterozygous mutation in the exonuclease domain of POLE (S459F). Targeted gene sequencing revealed an ultramutated phenotype (381 mutations/Mb) in the tumor and a 2-fold excess of mutations on the DNA leading strand. Additionally, we observed a mutational signature similar to the COSMIC signature 10, a higher mutation rate in this tumor than in endometrial tumors with heterozygous POLE-exo*, and an increased number of T lymphocytes. This is the first report of an ultramutated EC harboring a somatic POLE-exo* mutation in association with a germline loss-of-function mutation in this gene. The absence of a wild type POLE allele led to a particularly high mutational burden.
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hal-03853568 , version 1 (15-11-2022)

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Reginaldo Cruz Alves Rosa, Andrey A Yurchenko, Fernando Chahud, Alfredo Ribeiro-Silva, Mariângela Ottoboni Brunaldi, et al.. First description of ultramutated endometrial cancer caused by germline loss-of-function and somatic exonuclease domain mutations in POLE gene. Genetics and Molecular Biology, 2020, 43, ⟨10.1590/1678-4685-gmb-2020-0100⟩. ⟨hal-03853568⟩
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