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PIK3CA mutations and loss of ARID1A protein expression are early events in the development of cystic ovarian clear cell adenocarcinoma

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Abstract

Somatic mutations of PIK3CA and ARID1A are the most common genetic alterations observed in ovarian clear cell adenocarcinomas (CCA). In a previous report, we showed that PIK3CA gene mutations and loss of ARID1A expression occur early during the development of CCA. In the present study, using direct genomic DNA sequencing for exons 9 and 20 of PIK3CA and immunohistochemistry for ARID1A protein expression, we analyzed the association of these molecular alterations with various clinicopathological parameters in a total of 90 cases of primary ovarian CCA, including 42 previously examined cases. The presence of PIK3CA mutations, identified in 34 (39%) of the 88 informative cases, was significantly associated with a grossly cystic tumor, the presence of adjacent endometriosis, prominent papillary architecture of tumor growth, the presence of hyalinized and mucoid stroma, and the absence of clear cell adenofibroma components (P < 0.05, each). There was no significant association of PIK3CA mutations with other clinical variables, such as age, clinical stage, or clinical outcome of the patients. The intensity of immunoreactivity for ARID1A was assigned as negative, weakly positive, and strongly positive in 44%, 22%, and 33% of tumors, respectively. Compared to tumors immunoreactive for ARID1A, ARID1A-negative tumors were significantly associated with the presence of adjacent endometriosis (P = 0.025), but there was no statistically supported association with other examined clinicopathological parameters. Compared with CCAs strongly positive for ARID1A, CCAs negative for ARID1A more frequently harbor PIK3CA mutations (P = 0.013). PIK3CA gene mutations and ARID1A immunohistochemistry lacked prognostic significance. These data further support the idea that these molecular alterations occur as very early events during tumor development of ovarian CCA.

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Acknowledgments

This work was supported in part by a grant-in-aid for promotion of defense medicine from the Ministry of Defense, Japan (S.Y., O.M.), by a grant-in-aid for cancer research from the Ministry of Health, Labor, and Welfare, Japan (H.T.), and by a grant from the Foundation for Promotion of Cancer Research (S.Y. and H.T.). We are grateful to Ms. Kozue Suzuki, Department of Basic Pathology, National Defense Medical College, Saitama, Japan, for her technical assistance.

Conflicts of interest

The authors declare no actual or potential conflicts of interest associated with this study.

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Authors and Affiliations

  1. Department of Basic Pathology, National Defense Medical College, 3-2 Namiki, Tokorozawa, Saitama, 359-8513, Japan

    Sohei Yamamoto & Osamu Matsubara

  2. Department of Obstetrics and Gynecology, National Defense Medical College, 3-2 Namiki, Tokorozawa, Saitama, 359-8513, Japan

    Masashi Takano

  3. Department of Laboratory Medicine, National Defense Medical College Hospital, 3-2 Namiki, Tokorozawa, Saitama, 359-8513, Japan

    Seiichi Tamai

  4. Department of Pathology and Clinical Laboratories, National Cancer Center Hospital, 5-1-1 Tsukiji, Chuo-ku, Tokyo, 104-0045, Japan

    Hitoshi Tsuda

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  1. Sohei Yamamoto
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  2. Hitoshi Tsuda
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  5. Osamu Matsubara
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Correspondence to Sohei Yamamoto.

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Yamamoto, S., Tsuda, H., Takano, M. et al. PIK3CA mutations and loss of ARID1A protein expression are early events in the development of cystic ovarian clear cell adenocarcinoma. Virchows Arch 460, 77–87 (2012). https://doi.org/10.1007/s00428-011-1169-8

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  • DOI: https://doi.org/10.1007/s00428-011-1169-8

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