Involvement of pelvic inflammation-related mismatch repair abnormalities and microsatellite instability in the malignant transformation of ovarian endometriosis

Hum Pathol. 2012 Nov;43(11):1964-72. doi: 10.1016/j.humpath.2012.02.005. Epub 2012 May 22.


Inflammation in the ovary, including ovulation and pelvic inflammatory disease, has been proposed to play a role in the pathogenesis of ovarian cancer. Endometriotic lesions trigger a local inflammatory reaction and have been reported to be associated with an increased risk of epithelial ovarian cancer. However, the precise molecular mechanisms of ovarian cancer arising from endometriosis are still to be elucidated. To clarify the involvement of mismatch repair (MMR) abnormalities in the inflammation-associated malignant transformation of endometriosis, the immunohistochemical expression of mismatch repair proteins (human mutL homolog 1 [hMLH1] and human mutS homolog 2 [hMSH2]) was examined in 27 cases of ovarian endometriosis, 25 cases of ovarian carcinoma accompanied by endometriosis, and 39 cases of solitary ovarian carcinoma. In addition, the relationship between mismatch repair abnormalities including the microsatellite instability, PTEN (phosphatase and tensin homolog) mutation, and clinicopathologic parameters was analyzed. The expression of mismatch repair proteins was stepwisely decreased in endometriosis, ovarian carcinoma accompanied by endometriosis, and ovarian carcinoma. Tumors harboring multiple microsatellite instability (high-frequency microsatellite instability [MSI-H]) were detected in 4 (14.8%) of 27 cases of endometriosis and 7 (30.4%) of 23 cases of ovarian carcinomas. The frequency of PTEN mutations was higher in MSI-H cases than in microsatellite instability-stable (MSI-S) cases. In 2 cases of ovarian carcinoma accompanied by endometriosis, the decreased expression of mismatch repair proteins and MSI-H was observed in both the endometriosis and carcinoma lesions. Clinicopathologically, the MSI-H cases were associated with elevated serum levels of C-reactive protein and higher white blood cell counts. These findings suggest that mismatch repair abnormalities might be involved in the malignant transformation of ovarian endometriosis and that inflammation induces mismatch repair abnormalities during ovarian carcinogenesis arising from endometriosis.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adaptor Proteins, Signal Transducing / genetics
  • Adaptor Proteins, Signal Transducing / metabolism
  • Brain Neoplasms
  • Cell Transformation, Neoplastic*
  • Colorectal Neoplasms
  • Cystadenocarcinoma, Serous / complications
  • Cystadenocarcinoma, Serous / genetics
  • Cystadenocarcinoma, Serous / metabolism
  • Cystadenocarcinoma, Serous / pathology*
  • DNA Mutational Analysis
  • DNA, Neoplasm / analysis
  • Disease Progression
  • Endometriosis / complications
  • Endometriosis / genetics
  • Endometriosis / metabolism
  • Endometriosis / pathology*
  • Female
  • Humans
  • Microsatellite Instability*
  • MutL Protein Homolog 1
  • MutL Proteins
  • Neoplasm Proteins / genetics
  • Neoplasm Proteins / metabolism
  • Neoplastic Syndromes, Hereditary
  • Nuclear Proteins / genetics
  • Nuclear Proteins / metabolism
  • Ovarian Neoplasms / complications
  • Ovarian Neoplasms / genetics
  • Ovarian Neoplasms / metabolism
  • Ovarian Neoplasms / pathology*
  • PTEN Phosphohydrolase / genetics
  • PTEN Phosphohydrolase / metabolism
  • Pelvic Inflammatory Disease / complications
  • Pelvic Inflammatory Disease / genetics
  • Pelvic Inflammatory Disease / metabolism
  • Pelvic Inflammatory Disease / pathology*
  • Point Mutation


  • Adaptor Proteins, Signal Transducing
  • DNA, Neoplasm
  • MLH1 protein, human
  • Neoplasm Proteins
  • Nuclear Proteins
  • PMS1 protein, human
  • PTEN Phosphohydrolase
  • PTEN protein, human
  • MutL Protein Homolog 1
  • MutL Proteins

Supplementary concepts

  • Turcot syndrome