Sequential molecular changes and dynamic oxidative stress in high-grade serous ovarian carcinogenesis.
The mechanism of high-grade serous ovarian cancer (HGSC) development remains elusive. This review outlines recent advances in the understanding of sequential molecular changes associated with the development of HGSC, as well as describes oxidative stress-induced genomic instability and carcinogenesis. This article reviews the English language literature between 2005 and 2017. Clinicopathological features analysis provides a sequential progression of fallopian tubal epithelium to precursor lesions to type 2 HGSC. HGSC may develop over a long time after incessant ovulation and repeated retrograde menstruation via stepwise accumulation of genetic alterations, including PAX2, ALDH1A1, STMN1, EZH2 and CCNE1, which confer positive selection of cells with growth advantages through acquiring driver mutations such as BRCA1/2, p53 or PTEN/PIK3CA. Haemoglobin and iron-induced oxidative stress leads to the emergence of genetic alterations in fallopian tubal epithelium via increased DNA damage and impaired DNA repair. Serous tubal intraepithelial carcinoma (STIC), the likely precursor of HGSC, may be susceptible to DNA double-strand breaks, exhibit DNA replication stress and increase genomic instability. The induction of genomic instability is considered to be a driving mechanism of reactive oxygen species (ROS)-induced carcinogenesis. HGSC exemplifies the view of stepwise cancer development. We describe how genetic alterations emerge during HGSC carcinogenesis related to oxidative stress.
['Kobayashi|Hiroshi|H|', 'Ogawa|Kenji|K|', 'Kawahara|Naoki|N|', 'Iwai|Kana|K|', 'Niiro|Emiko|E|', 'Morioka|Sachiko|S|', 'Yamada|Yuki|Y|']
D000818:Animals D063646:Carcinogenesis D018284:Cystadenocarcinoma, Serous D005260:Female D042822:Genomic Instability D006801:Humans D009154:Mutation D010051:Ovarian Neoplasms D018384:Oxidative Stress D059016:Tumor Microenvironment
oxidative stress high-grade serous ovarian cancer serous tubal intraepithelial carcinoma Genomic mutations p53 mutations