Homozygous deletion of MKK4 in ovarian serous carcinoma

Authors:
  • NNNaomi Nakayama
    Naomi Nakayama
  • BDBen Davidson
    Ben Davidson
  • HKHidetaka Katabuchi
    Hidetaka Katabuchi
  • RKRobert J. Kurman
    Robert J. Kurman
  • LSLe-Ming Shih
    Le-Ming Shih
  • TWTian-Li Wang
    Tian-Li Wang
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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 expre...