Clinical impact of endometrial cancer stratified by genetic mutational profiles, pole mutation, and microsatellite instability

Tomoko Haruma, Takeshi Nagasaka, Keiichiro Nakamura, Junko Haraga, Akihiro Nyuya, Takeshi Nishida, Ajay Goel, Hisashi Masuyama, Yuji Hiramatsu

Research output: Contribution to journalArticle

3 Citations (Scopus)

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.

Original languageEnglish
Article numbere0195655
JournalPLoS One
Volume13
Issue number4
DOIs
Publication statusPublished - Apr 1 2018

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Microsatellite Instability
Endometrial Neoplasms
Microsatellite Repeats
Poles
microsatellite repeats
Repair
mutation
Mutation
neoplasms
DNA Mismatch Repair
Genes
Methylation
Polymerase chain reaction
prognosis
Biomarkers
promoter regions
Tumors
Proteins
bisulfites
resection

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)
  • Agricultural and Biological Sciences(all)

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Clinical impact of endometrial cancer stratified by genetic mutational profiles, pole mutation, and microsatellite instability. / Haruma, Tomoko; Nagasaka, Takeshi; Nakamura, Keiichiro; Haraga, Junko; Nyuya, Akihiro; Nishida, Takeshi; Goel, Ajay; Masuyama, Hisashi; Hiramatsu, Yuji.

In: PLoS One, Vol. 13, No. 4, e0195655, 01.04.2018.

Research output: Contribution to journalArticle

Haruma, Tomoko ; Nagasaka, Takeshi ; Nakamura, Keiichiro ; Haraga, Junko ; Nyuya, Akihiro ; Nishida, Takeshi ; Goel, Ajay ; Masuyama, Hisashi ; Hiramatsu, Yuji. / Clinical impact of endometrial cancer stratified by genetic mutational profiles, pole mutation, and microsatellite instability. In: PLoS One. 2018 ; Vol. 13, No. 4.
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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.",
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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

PY - 2018/4/1

Y1 - 2018/4/1

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.

AB - 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.

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