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

• Published in: Genetics and molecular biology Vol. 43
• Main Authors: Rosa, Reginaldo Cruz Alves, Yurchenko, Andrey A, Chahud, Fernando, Ribeiro-Silva, Alfredo, Brunaldi, Mariângela Ottoboni, Silva Jr, Wilson Araújo, Kannouche, Patricia L, Nikolaev, Sergey, Ferraz, Victor Evangelista de Faria
• Format: Journal Article
• Language: English
• Published: Sociedade Brasileira de Genética 2020
• Subjects: Life Sciences; Endometrial cancer; Ultramutated phenotype; POLE exonuclease mutation; TMB; Targeted sequencing
• ISSN: 1415-4757; 1678-4685
• DOI: 10.1590/1678-4685-gmb-2020-0100

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.