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Homozygous deletion of MKK4 in ovarian serous carcinoma
Kentaro Nakayama1, Naomi Nakayama, Ben Davidson
1Department of Pathology, Johns Hopkins Medical Institutions, Baltimore, Maryland 21231, USA.
Abstract:
Analysis of deleted chromosomal regions in tumors has historically led to the identification of tumor suppressor genes. In this study, we used digital karyotyping, a genome-wide, high-resolution technology, to search for chromosomal deletions in ovarian serous carcinoma, the most lethal gynecological malignancy in women. Five purified ovarian serous carcinomas were analyzed by digital karyotyping and small interstitial deletions at chromosome 17p were identified in two tumor samples. Aligning these two deletions identified an overlapping region that spanned 2.4 Mb which harbored a candidate tumor suppressor gene, mitogen-activated protein kinase kinase-4 (MKK4). Dual-color FISH analysis confirmed homozygous deletion of the MKK4 locus in both samples and RT-PCR demonstrated that both carcinomas lacked MKK4 transcript expression. Loss of heterozygosity of 17p occurred in 24 (86%) of 28 high-grade serous carcinomas including both cases with homozygous MKK4 deletion. Additionally, downregulation of MKK4 expression was found in 96 (75%) of 128 ovarian serous carcinomas as compared to benign ovarian tissues. These findings suggest that homozygous deletion or reduced expression of MKK4 may contribute to the development of ovarian serous carcinoma.
Insights
Researchers identified the MKK4 gene as a potential tumor suppressor in ovarian cancer. Homozygous deletion or reduced expression of MKK4 may contribute to this lethal gynecological malignancy.
Area of Science:
- Genomics
- Oncology
- Molecular Biology
Background:
- Tumor suppressor genes are often identified through analysis of chromosomal deletions in cancer.
- Ovarian serous carcinoma is the most lethal gynecological malignancy, necessitating the identification of its underlying genetic drivers.
Purpose of the Study:
- To identify chromosomal deletions in ovarian serous carcinoma using digital karyotyping.
- To investigate the role of the candidate tumor suppressor gene, mitogen-activated protein kinase kinase-4 (MKK4), in ovarian cancer development.
Main Methods:
- Digital karyotyping was employed to analyze chromosomal deletions in five ovarian serous carcinomas.
- Fluorescence in situ hybridization (FISH) and reverse transcription polymerase chain reaction (RT-PCR) were used to confirm MKK4 deletions and expression levels.
Main Results:
- Small interstitial deletions at chromosome 17p were found in two ovarian serous carcinoma samples.
- An overlapping deletion region identified a candidate tumor suppressor gene, MKK4.
- Homozygous deletion of MKK4 was confirmed, with absence of MKK4 transcript expression in these samples.
- Loss of heterozygosity at 17p was observed in 86% of high-grade serous carcinomas.
- MKK4 expression was downregulated in 75% of ovarian serous carcinomas compared to benign tissues.
Conclusions:
- Homozygous deletion or reduced expression of MKK4 may play a role in the pathogenesis of ovarian serous carcinoma.
- MKK4 is a potential tumor suppressor gene implicated in this malignancy.
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