Clinicopathologic and biological analysis of PIK3CA mutation in ovarian clear cell carcinoma

• Published in: Human pathology Vol. 43; no. 12; pp. 2197 - 2206
• Main Authors: Rahman, Munmun, MBBS, Nakayama, Kentaro, MD, PhD, Rahman, Mohammed Tanjimur, MBBS, Nakayama, Naomi, MD, Ishikawa, Masako, MD, PhD, Katagiri, Atsuko, MD, Iida, Kouji, BSc, Nakayama, Satoru, MD, Otsuki, Yoshiro, MD, Shih, Ie-Ming, MD, PhD, Miyazaki, Kohji, MD, PhD
• Format: Journal Article
• Language: English
• Published: New York, NY Elsevier Inc 01-12-2012; Elsevier; Elsevier Limited
• Subjects: Adenocarcinoma, Clear Cell - genetics; Adenocarcinoma, Clear Cell - mortality; Adenocarcinoma, Clear Cell - pathology; Adult; Aged, 80 and over; Biological and medical sciences; BRAF; Cell Line, Tumor; Chemotherapy; Class I Phosphatidylinositol 3-Kinases; Female; Female genital diseases; Gynecology. Andrology. Obstetrics; Humans; Investigative techniques, diagnostic techniques (general aspects); KRAS; Medical sciences; Middle Aged; Mutation; Ovarian cancer; Ovarian clear cell carcinoma; Ovarian Neoplasms - genetics; Ovarian Neoplasms - mortality; Ovarian Neoplasms - pathology; Pathology; Pathology. Cytology. Biochemistry. Spectrometry. Miscellaneous investigative techniques; Phosphatidylinositol 3-Kinases - genetics; Phosphatidylinositol 3-Kinases - metabolism; Phosphorylation; PIK3CA; Prognosis; Proteins; Proto-Oncogene Proteins c-akt - metabolism; TOR Serine-Threonine Kinases - metabolism; Tumors; Japan; Ovarian clear cell carcinoma; KRAS; BRAF; Mutation; PIK3CA; Enzyme; Transferases; Biology; Malignant tumor; Female genital diseases; 1-Phosphatidylinositol 3-kinase; K ras Gene; Ovarian diseases; Anatomic pathology; BRAF Gene; Histopathology; C-Onc gene; Genetics; Protooncogene; Cancer
• ISSN: 0046-8177; 1532-8392
• DOI: 10.1016/j.humpath.2012.03.011

Summary Somatic mutations of PIK3CA (phosphoinositide-3-kinase) have recently been shown playing an important role in the pathogenesis of ovarian clear cell carcinoma. In this study, the frequency of PIK3CA mutations and the relationship of PIK3CA mutations with clinicopathologic and biological variables were investigated in ovarian clear cell carcinomas from Japanese patients. Mutational analysis of PIK3CA was performed in 56 primary ovarian clear cell carcinomas from Japanese women. The relationship of these mutations with various clinicopathologic and biological variables (phosphorylated AKT and phosphorylated mTOR (mammalian target of rapamycin) expression by immunohistochemistry) was determined. To clarify the roles of PI3K/AKT activation in ovarian clear cell carcinomas harboring PIK3CA mutations, we inactivated the PI3K/AKT/mTOR pathway in ovarian carcinoma cells with LY294002, temsirolimus and NVP-BEZ235. Missense mutations of PIK3CA were found in 16 (28.6%) of 56 ovarian clear cell carcinomas, but no mutation was found in 15 ovarian high-grade serous carcinomas. PIK3CA mutations were significantly associated with a favorable overall survival of patients with ovarian clear cell carcinoma ( P < .05). There was no significant association between PIK3CA mutations and phosphorylated AKT or phosphorylated mTOR immunointensity status. No relationship was found between PIK3CA mutation status and sensitivity to PI3K/AKT/mTOR inhibitors in ovarian clear cell carcinoma cells. No association of PIK3CA mutations was found between positive phosphorylated AKT and positive phosphorylated mTOR, which suggests that the PI3K/AKT/mTOR pathway may be activated by other molecular mechanisms. Although PIK3CA mutations were associated with a more favorable prognosis, they did not predict the sensitivity of ovarian clear cell carcinoma cells to PI3K/AKT/mTOR inhibitors.