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Gynecol Oncol. 2017 Jan;144(1):146-152. doi: 10.1016/j.ygyno.2016.11.023. Epub 2016 Nov 26.

Polymerase ε (POLE) ultra-mutation in uterine tumors correlates with T lymphocyte infiltration and increased resistance to platinum-based chemotherapy in vitro.

Author information

1
Department of Obstetrics, Gynecology and Reproductive Sciences, Yale University School of Medicine, 333 Cedar Street, PO Box 208063, New Haven, CT 06520-8063, USA.
2
Department of Obstetrics and Gynecology, ASST Spedali Civili di Brescia, Brescia, Italy.
3
Department of Molecular and Translational Medicine, Section of Pathology, University of Brescia, Brescia, Italy.
4
Department of Pathology, Yale University School of Medicine, 333 Cedar Street, PO Box 208063, New Haven, CT 06520-8063, USA.
5
Division of Gynecologic Oncology, University Campus Bio-Medico of Roma, Roma, Italy.
6
"Angelo Nocivelli" Institute of Molecular Medicine, University of Brescia, ASST Spedali Civili, Brescia, Italy.
7
Department of Obstetrics and Gynecology, Division of Gynecologic Oncology, University of Brescia, ASST Spedali Civili, Brescia, Italy.
8
Department of Obstetrics, Gynecology and Reproductive Sciences, Yale University School of Medicine, 333 Cedar Street, PO Box 208063, New Haven, CT 06520-8063, USA. Electronic address: alessandro.santin@yale.edu.

Abstract

OBJECTIVE:

Up to 12% of all endometrial-carcinomas (EC) harbor DNA-polymerase-ε-(POLE) mutations. It is currently unknown whether the favorable prognosis of POLE-mutated EC is derived from their low metastatic capability, extraordinary number of somatic mutations thus imparting immunogenicity, or a high sensitivity to chemotherapy.

METHODS:

Polymerase-chain-reaction-amplification and Sanger-sequencing were used to test for POLE exonuclease-domain-mutations (exons 9-14) 131 EC. Infiltration of CD4+ and CD8+ T-lymphocytes (TIL) and PD-1-expression in POLE-mutated vs POLE wild-type EC was studied by immunohistochemistry (IHC) and the correlations between survival and molecular features were investigated. Finally, primary POLE-mutated and POLE-wild-type EC cell lines were established and compared in-vitro for their sensitivity to chemotherapy.

RESULTS:

Eleven POLE-mutated EC (8.5%) were identified. POLE-mutated tumors were associated with improved progression-free-survival (P<0.05) and displayed increased numbers of CD4+ (44.5 vs 21.8; P=0.001) and CD8+ (32.8 vs 13.5; P<0.001) TILs when compared to wild-type POLE EC. PD-1 receptor was overexpressed in TILs from POLE-mutated vs wild-type-tumors (81% vs 28%; P<0.001). Primary POLE tumor cell lines were significantly more resistant to platinum-chemotherapy in-vitro when compared to POLE-wild-type tumors (P<0.004).

CONCLUSIONS:

POLE ultra-mutated EC are heavily infiltrated with CD4+/CD8+ TIL, overexpress PD-1 immune-check-point (i.e., features consistent with chronic antigen-exposure), and have a better prognosis when compared to other molecular subtypes of EC patients. POLE-mutated tumor-cell lines are resistant to platinum-chemotherapy in-vitro suggesting that the better prognosis of POLE-patients is not secondary to a higher sensitivity to chemotherapy but likely linked to enhanced immunogenicity.

KEYWORDS:

Cisplatin; Endometrial carcinoma; Polymerase ε; Uterine serous papillary cancer; Whole exome sequencing

PMID:
27894751
PMCID:
PMC5183545
DOI:
10.1016/j.ygyno.2016.11.023
[Indexed for MEDLINE]
Free PMC Article

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