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Clinical impact of endometrial cancer stratified by genetic mutational profiles, POLE mutation, and microsatellite instability.
PLoS One. 2018; 13(4):e0195655.Plos

Abstract

BACKGROUND

The molecular characterization of endometrial cancer (EC) can facilitate identification of various tumor subtypes. Although EC patients with POLE mutations reproducibly demonstrate better prognosis, the outcome of patients with microsatellite instability (MSI) remains controversial. This study attempted to interrogate whether genetic stratification of EC can identify distinct subsets with prognostic significance.

MATERIALS AND METHODS

A cohort of 138 EC patients who underwent surgical resection with curative intent was enrolled. Sanger sequencing was used to evaluate mutations in the POLE and KRAS genes. MSI analysis was performed using four mononucleotide repeat markers and methylation status of the MLH1 promoter was measured by a fluorescent bisulfite polymerase chain reaction (PCR). Protein expression for mismatch repair (MMR) proteins was evaluated by immunohistochemistry (IHC).

RESULTS

Extensive hypermethylation of the MLH1 promoter was observed in 69.6% ECs with MLH1 deficiency and 3.5% with MMR proficiency, but in none of the ECs with loss of other MMR genes (P < .0001). MSI-positive and POLE mutations were found in 29.0% and 8.7% EC patients, respectively. Our MSI analysis showed a sensitivity of 92.7% for EC patients with MMR deficiency, and a specificity of 97.9% for EC patients with MMR proficiency. In univariate and multivariate analyses, POLE mutations and MSI status was significantly associated with progression-free survival (P = 0.0129 and 0.0064, respectively) but not with endometrial cancer-specific survival.

CONCLUSIONS

This study provides significant evidence that analyses of proofreading POLE mutations and MSI status based on mononucleotide repeat markers are potentially useful biomarkers to identify EC patients with better prognosis.

Authors+Show Affiliations

Department of Obstetrics and Gynecology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, Japan.Department of Clinical Oncology, Kawasaki Medical School, Kurashiki, Japan.Department of Obstetrics and Gynecology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, Japan.Department of Obstetrics and Gynecology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, Japan.Department of Clinical Oncology, Kawasaki Medical School, Kurashiki, Japan.Department of Obstetrics and Gynecology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, Japan.Center for Gastrointestinal Research, Center for Translational Genomics and Oncology, Baylor Scott & White Research Institute, Dallas, Texas, United States of America. Charles A Sammons Cancer Center, Baylor University Medical Center, Dallas, Texas, United States of America.Department of Obstetrics and Gynecology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, Japan.Department of Obstetrics and Gynecology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, Japan.

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

29659608

Citation

Haruma, Tomoko, et al. "Clinical Impact of Endometrial Cancer Stratified By Genetic Mutational Profiles, POLE Mutation, and Microsatellite Instability." PloS One, vol. 13, no. 4, 2018, pp. e0195655.
Haruma T, Nagasaka T, Nakamura K, et al. Clinical impact of endometrial cancer stratified by genetic mutational profiles, POLE mutation, and microsatellite instability. PLoS One. 2018;13(4):e0195655.
Haruma, T., Nagasaka, T., Nakamura, K., Haraga, J., Nyuya, A., Nishida, T., Goel, A., Masuyama, H., & Hiramatsu, Y. (2018). Clinical impact of endometrial cancer stratified by genetic mutational profiles, POLE mutation, and microsatellite instability. PloS One, 13(4), e0195655. https://doi.org/10.1371/journal.pone.0195655
Haruma T, et al. Clinical Impact of Endometrial Cancer Stratified By Genetic Mutational Profiles, POLE Mutation, and Microsatellite Instability. PLoS One. 2018;13(4):e0195655. PubMed PMID: 29659608.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Clinical impact of endometrial cancer stratified by genetic mutational profiles, POLE mutation, and microsatellite instability. AU - Haruma,Tomoko, AU - Nagasaka,Takeshi, AU - Nakamura,Keiichiro, AU - Haraga,Junko, AU - Nyuya,Akihiro, AU - Nishida,Takeshi, AU - Goel,Ajay, AU - Masuyama,Hisashi, AU - Hiramatsu,Yuji, Y1 - 2018/04/16/ PY - 2017/12/09/received PY - 2018/03/27/accepted PY - 2018/4/17/entrez PY - 2018/4/17/pubmed PY - 2018/7/17/medline SP - e0195655 EP - e0195655 JF - PloS one JO - PLoS One VL - 13 IS - 4 N2 - BACKGROUND: The molecular characterization of endometrial cancer (EC) can facilitate identification of various tumor subtypes. Although EC patients with POLE mutations reproducibly demonstrate better prognosis, the outcome of patients with microsatellite instability (MSI) remains controversial. This study attempted to interrogate whether genetic stratification of EC can identify distinct subsets with prognostic significance. MATERIALS AND METHODS: A cohort of 138 EC patients who underwent surgical resection with curative intent was enrolled. Sanger sequencing was used to evaluate mutations in the POLE and KRAS genes. MSI analysis was performed using four mononucleotide repeat markers and methylation status of the MLH1 promoter was measured by a fluorescent bisulfite polymerase chain reaction (PCR). Protein expression for mismatch repair (MMR) proteins was evaluated by immunohistochemistry (IHC). RESULTS: Extensive hypermethylation of the MLH1 promoter was observed in 69.6% ECs with MLH1 deficiency and 3.5% with MMR proficiency, but in none of the ECs with loss of other MMR genes (P < .0001). MSI-positive and POLE mutations were found in 29.0% and 8.7% EC patients, respectively. Our MSI analysis showed a sensitivity of 92.7% for EC patients with MMR deficiency, and a specificity of 97.9% for EC patients with MMR proficiency. In univariate and multivariate analyses, POLE mutations and MSI status was significantly associated with progression-free survival (P = 0.0129 and 0.0064, respectively) but not with endometrial cancer-specific survival. CONCLUSIONS: This study provides significant evidence that analyses of proofreading POLE mutations and MSI status based on mononucleotide repeat markers are potentially useful biomarkers to identify EC patients with better prognosis. SN - 1932-6203 UR - https://www.unboundmedicine.com/medline/citation/29659608/Clinical_impact_of_endometrial_cancer_stratified_by_genetic_mutational_profiles_POLE_mutation_and_microsatellite_instability_ L2 - https://dx.plos.org/10.1371/journal.pone.0195655 DB - PRIME DP - Unbound Medicine ER -