Background Ovarian clear-cell and endometrioid carcinomas may arise from endometriosis, but the molecular events involved in this transformation have not been described. Methods We sequenced the whole transcriptomes of 18 ovarian clear-cell carcinomas and 1 ovarian clear-cell carcinoma cell line and found somatic mutations in ARID1A (the AT-rich interactive domain 1A [SWI-like] gene) in 6 of the samples. ARID1A encodes BAF250a, a key component of the SWI–SNF chromatin remodeling complex. We sequenced ARID1A in an additional 210 ovarian carcinomas and a second ovarian clear-cell carcinoma cell line and measured BAF250a expression by means of immunohistochemical analysis in an additional 455 ovarian carcinomas. Results ARID1A mutations were seen in 55 of 119 ovarian clear-cell carcinomas (46%), 10 of 33 endometrioid carcinomas (30%), and none of the 76 high-grade serous ovarian carcinomas. Seventeen carcinomas had two somatic mutations each. Loss of the BAF250a protein correlated strongly with the ovarian c...

https://www.nejm.org/doi/pdf/10.1056/NEJMoa1008433

ARID1A mutations in endometriosis-associated ovarian carcinomas.

Endometriosis

Molecular mechanisms of resistance and toxicity associated with platinating agents.

The pathogenesis of ovarian carcinoma, the most lethal gynecological malignancy, is unknown because of the lack of a tumor progression model. Based on a review of recent clinicopathological and molecular studies, we propose a model for their development. In this model, surface epithelial tumors are divided into two broad categories designated type I and type II tumors that correspond to two main pathways of tumorigenesis. Type I tumors tend to be low-grade neoplasms that arise in a stepwise manner from borderline tumors whereas type II tumors are high-grade neoplasms for which morphologically recognizable precursor lesions have not been identified, so-called de novo development. As serous tumors are the most common surface epithelial tumors, low-grade serous carcinoma is the prototypic type I tumor and high-grade serous carcinoma is the prototypic type II tumor. In addition to low-grade serous carcinomas, type I tumors are composed of mucinous carcinomas, endometrioid carcinomas, malignant Brenner tumors, and clear cell carcinomas. Type I tumors are associated with distinct molecular changes that are rarely found in type II tumors, such as BRAF and KRAS mutations for serous tumors, KRAS mutations for mucinous tumors, and β-catenin and PTEN mutations and microsatellite instability for endometrioid tumors. Type II tumors include high-grade serous carcinoma, malignant mixed mesodermal tumors (carcinosarcoma), and undifferentiated carcinoma. There are very limited data on the molecular alterations associated with type II tumors except frequent p53 mutations in high-grade serous carcinomas andmalignant mixed mesodermal tumors (carcinosarcomas). This model of carcinogenesis reconciles the relationship of borderline tumors to invasive carcinoma and provides a morphological and molecular framework for studies aimed at elucidating the pathogenesis of ovarian cancer.

/pdf/ovarian-tumorigenesis-a-proposed-model-based-on-vitkop4wmt.pdf

Ovarian Tumorigenesis : A Proposed Model Based on Morphological and Molecular Genetic Analysis

Ovarian clear cell carcinoma (OCCC) is an aggressive human cancer that is generally resistant to therapy. To explore the genetic origin of OCCC, we determined the exomic sequences of eight tumors after immunoaffinity purification of cancer cells. Through comparative analyses of normal cells from the same patients, we identified four genes that were mutated in at least two tumors. PIK3CA, which encodes a subunit of phosphatidylinositol-3 kinase, and KRAS, which encodes a well-known oncoprotein, had previously been implicated in OCCC. The other two mutated genes were previously unknown to be involved in OCCC: PPP2R1A encodes a regulatory subunit of serine/threonine phosphatase 2, and ARID1A encodes adenine-thymine (AT)-rich interactive domain-containing protein 1A, which participates in chromatin remodeling. The nature and pattern of the mutations suggest that PPP2R1A functions as an oncogene and ARID1A as a tumor-suppressor gene. In a total of 42 OCCCs, 7% had mutations in PPP2R1A and 57% had mutations in ARID1A. These results suggest that aberrant chromatin remodeling contributes to the pathogenesis of OCCC.

/pdf/frequent-mutations-of-chromatin-remodeling-gene-arid1a-in-4miq5uc6kx.pdf

Frequent mutations of chromatin remodeling gene ARID1A in ovarian clear cell carcinoma

Loss of heterozygosity (LOH) at locus 10q23.3 and mutation of the PTEN tumor suppressor gene occur frequently in both endometrial carcinoma and ovarian endometrioid carcinoma. To investigate the potential role of the PTEN gene in the carcinogenesis of ovarian endometrioid carcinoma and its related subtype, clear cell carcinoma, we examined 20 ovarian endometrioid carcinomas, 24 clear cell carcinomas, and 34 solitary endometrial cysts of the ovary for LOH at 10q23.3 and point mutations within the entire coding region of the PTEN gene. LOH was found in 8 of 19 ovarian endometrioid carcinomas (42.1%), 6 of 22 clear cell carcinomas (27.3%), and 13 of 23 solitary endometrial cysts (56.5%). In 5 endometrioid carcinomas synchronous with endometriosis, 3 cases displayed LOH events common to both the carcinoma and the endometriosis, 1 displayed an LOH event in only the carcinoma, and 1 displayed no LOH events in either lesion. In 7 clear cell carcinomas synchronous with endometriosis, 3 displayed LOH events common to both the carcinoma and the endometriosis, 1 displayed an LOH event in only the carcinoma, and 3 displayed no LOH events in either lesion. In no cases were there LOH events in the endometriosis only. Somatic mutations in the PTEN gene were identified in 4 of 20 ovarian endometrioid carcinomas (20.0%), 2 of 24 clear cell carcinomas (8.3%), and 7 of 34 solitary endometrial cysts (20.6%). These results indicate that inactivation of the PTEN tumor suppressor gene is an early event in the development of ovarian endometrioid carcinoma and clear cell carcinoma of the ovary.

/pdf/loss-of-heterozygosity-on-10q23-3-and-mutation-of-the-tumor-4vy25aar4c.pdf

Loss of Heterozygosity on 10q23.3 and Mutation of the Tumor Suppressor Gene PTEN in Benign Endometrial Cyst of the Ovary: Possible Sequence Progression from Benign Endometrial Cyst to Endometrioid Carcinoma and Clear Cell Carcinoma of the Ovary

Purpose
To study the MR characteristics of nonbenign uterine smooth muscle tumors.

Materials and Methods
Nine patients with pathologically proven leiomyosarcomas, and three patients with smooth muscle tumors of uncertain malignant potential (SMTUMP) were included in this study. Twelve cases of benign uterine leiomyomas and variants, in which gynecologists suspected leiomyosarcomas, were also analyzed. In each case we studied the size, location, signal intensity, and contrast enhancement of the tumors.

Results
Nine of the 12 nonbenign characters had more than 50% of high-intensity areas on T2-weighted images (T2WI), and some hyperintense foci on T1-weighted images (T1WI). In the contrast study, nine of 12 nonbenign characters had well-demarcated unenhanced areas. On the other hand, only two of 12 benign characters showed such a signal intensity pattern, and none of them had a pocket-like unenhanced area.

Conclusion
Although there were some exceptions, more than 50% of high signal on T2WI, and the presence of any small high-signal areas on T1WI with unenhanced pockets were considered MR-suggestive for SMTUMPs and leiomyosarcomas. J. Magn. Reson. Imaging 2004;20:998–1007. © 2004 Wiley-Liss, Inc.

https://onlinelibrary.wiley.com/doi/pdf/10.1002/jmri.20207

Smooth muscle tumors of uncertain malignant potential and leiomyosarcomas of the uterus: MR findings

Magnetic resonance (MR) imaging is useful not only for preoperative staging of gynecologic malignancies but also for prediction of the histopathologic features of a variety of intrapelvic tumors. Familiarity with the specific imaging findings that have been reported for the uterine cervix is a goal of radiologists. The typical MR imaging findings of uterine cervical lesions correspond to the histopathologic features. These lesions can be categorized as epithelial neoplasms, nonepithelial neoplasms, and nonneoplastic diseases. Cervical carcinoma accounts for most cases of malignant lesions and is staged by using the classification system established by the International Federation of Gynecology and Obstetrics. MR imaging allows differentiation between endophytic and exophytic growth and between normal and abnormal findings after hysterectomy and irradiation. Other epithelial neoplasms of the uterine cervix include adenoma malignum, which is a special type of cervical adenocarcinoma, as well as carcinoid tumor and malignant melanoma. Nonepithelial neoplasms of the uterine cervix include malignant lymphoma and leiomyoma. Nonneoplastic diseases of the uterine cervix include cervical pregnancy, cervicitis, nabothian cysts, polyps, and endometriosis. © RSNA, 2003

https://pubs.rsna.org/doi/pdf/10.1148/rg.232025065?frame=header

MR Imaging of the Uterine Cervix: Imaging-Pathologic

Magnetic resonance (MR) imaging is useful not only for preoperative staging of gynecologic malignancies but also for prediction of the histopathologic features of a variety of intrapelvic tumors. Familiarity with the specific imaging findings that have been reported for the uterine cervix is a goal of radiologists. The typical MR imaging findings of uterine cervical lesions correspond to the histopathologic features. These lesions can be categorized as epithelial neoplasms, nonepithelial neoplasms, and nonneoplastic diseases. Cervical carcinoma accounts for most cases of malignant lesions and is staged by using the classification system established by the International Federation of Gynecology and Obstetrics. MR imaging allows differentiation between endophytic and exophytic growth and between normal and abnormal findings after hysterectomy and irradiation. Other epithelial neoplasms of the uterine cervix include adenoma malignum, which is a special type of cervical adenocarcinoma, as well as carcinoid tumor and malignant melanoma. Nonepithelial neoplasms of the uterine cervix include malignant lymphoma and leiomyoma. Nonneoplastic diseases of the uterine cervix include cervical pregnancy, cervicitis, nabothian cysts, polyps, and endometriosis.

https://pubs.rsna.org/doi/pdf/10.1148/rg.232025065

MR imaging of the uterine cervix: imaging-pathologic correlation.

A series of 57 mucinous and 47 serous ovarian tumors (adenomas, tumors of borderline malignancy, and carcinomas) were examined by polymerase chain reaction-single strand conformation polymorphism analysis and direct sequencing for mutations in codons 12, 13, and 61 of K-ras gene. Higher incidence of K-ras mutations was observed in mucinous tumors compared to serous ones. Mutations were detected in 4 of 30 mucinous adenomas (13%), in 4 of 12 mucinous tumors of borderline malignancy (33%), and in 7 of 15 mucinous carcinomas (46%). Only 1 of 17 serous carcinomas (6%) had a mutation of K-ras in serous ovarian tumors. All mutations identified were in codon 12. Detailed analysis revealed that more K-ras mutations in mucinous adenomas were observed in intestinal type (identified in 4 of 13) than in endocervical type (identified in 0 of 17). Thus, K-ras gene codon 12 mutations in mucinous ovarian adenomas appear to be associated with the occurrence of intestinal type adenomas.

https://cancerres.aacrjournals.org/content/canres/54/1/33.full.pdf

Masato Nishida

Papers

Loss of Heterozygosity on 10q23.3 and Mutation of the Tumor Suppressor Gene PTEN in Benign Endometrial Cyst of the Ovary: Possible Sequence Progression from Benign Endometrial Cyst to Endometrioid Carcinoma and Clear Cell Carcinoma of the Ovary

Smooth muscle tumors of uncertain malignant potential and leiomyosarcomas of the uterus: MR findings

MR Imaging of the Uterine Cervix: Imaging-Pathologic

MR imaging of the uterine cervix: imaging-pathologic correlation.

Mutation of K-ras protooncogene is associated with histological subtypes in human mucinous ovarian tumors.