CDKN2D-WDFY2 Is a Cancer-Specific Fusion Gene Recurrent in High-Grade Serous Ovarian Carcinoma

Kalpana Kannan, Cristian Coarfa, Kimal Rajapakshe, Shannon Hawkins, Martin M. Matzuk, Aleksandar Milosavljevic, Laising Yen

Research output: Contribution to journalArticle

18 Citations (Scopus)

Abstract

Ovarian cancer is the fifth leading cause of cancer death in women. Almost 70% of ovarian cancer deaths are due to the high-grade serous subtype, which is typically detected only after it has metastasized. Characterization of high-grade serous cancer is further complicated by the significant heterogeneity and genome instability displayed by this cancer. Other than mutations in TP53, which is common to many cancers, highly recurrent recombinant events specific to this cancer have yet to be identified. Using high-throughput transcriptome sequencing of seven patient samples combined with experimental validation at DNA, RNA and protein levels, we identified a cancer-specific and inter-chromosomal fusion gene CDKN2D-WDFY2 that occurs at a frequency of 20% among sixty high-grade serous cancer samples but is absent in non-cancerous ovary and fallopian tube samples. This is the most frequent recombinant event identified so far in high-grade serous cancer implying a major cellular lineage in this highly heterogeneous cancer. In addition, the same fusion transcript was also detected in OV-90, an established high-grade serous type cell line. The genomic breakpoint was identified in intron 1 of CDKN2D and intron 2 of WDFY2 in patient tumor, providing direct evidence that this is a fusion gene. The parental gene, CDKN2D, is a cell-cycle modulator that is also involved in DNA repair, while WDFY2 is known to modulate AKT interactions with its substrates. Transfection of cloned fusion construct led to loss of wildtype CDKN2D and wildtype WDFY2 protein expression, and a gain of a short WDFY2 protein isoform that is presumably under the control of the CDKN2D promoter. The expression of short WDFY2 protein in transfected cells appears to alter the PI3K/AKT pathway that is known to play a role in oncogenesis. CDKN2D-WDFY2 fusion could be an important molecular signature for understanding and classifying sub-lineages among heterogeneous high-grade serous ovarian carcinomas.

Original languageEnglish (US)
Article numbere1004216
JournalPLoS Genetics
Volume10
Issue number3
DOIs
StatePublished - 2014
Externally publishedYes

Fingerprint

gene fusion
Gene Fusion
carcinoma
cancer
Carcinoma
neoplasms
gene
Neoplasms
ovarian neoplasms
protein
Ovarian Neoplasms
Introns
introns
death
fallopian tubes
protein isoforms
Proteins
DNA
Fallopian Tubes
Genomic Instability

ASJC Scopus subject areas

  • Genetics
  • Molecular Biology
  • Ecology, Evolution, Behavior and Systematics
  • Cancer Research
  • Genetics(clinical)
  • Medicine(all)

Cite this

Kannan, K., Coarfa, C., Rajapakshe, K., Hawkins, S., Matzuk, M. M., Milosavljevic, A., & Yen, L. (2014). CDKN2D-WDFY2 Is a Cancer-Specific Fusion Gene Recurrent in High-Grade Serous Ovarian Carcinoma. PLoS Genetics, 10(3), [e1004216]. https://doi.org/10.1371/journal.pgen.1004216

CDKN2D-WDFY2 Is a Cancer-Specific Fusion Gene Recurrent in High-Grade Serous Ovarian Carcinoma. / Kannan, Kalpana; Coarfa, Cristian; Rajapakshe, Kimal; Hawkins, Shannon; Matzuk, Martin M.; Milosavljevic, Aleksandar; Yen, Laising.

In: PLoS Genetics, Vol. 10, No. 3, e1004216, 2014.

Research output: Contribution to journalArticle

Kannan, K, Coarfa, C, Rajapakshe, K, Hawkins, S, Matzuk, MM, Milosavljevic, A & Yen, L 2014, 'CDKN2D-WDFY2 Is a Cancer-Specific Fusion Gene Recurrent in High-Grade Serous Ovarian Carcinoma', PLoS Genetics, vol. 10, no. 3, e1004216. https://doi.org/10.1371/journal.pgen.1004216
Kannan, Kalpana ; Coarfa, Cristian ; Rajapakshe, Kimal ; Hawkins, Shannon ; Matzuk, Martin M. ; Milosavljevic, Aleksandar ; Yen, Laising. / CDKN2D-WDFY2 Is a Cancer-Specific Fusion Gene Recurrent in High-Grade Serous Ovarian Carcinoma. In: PLoS Genetics. 2014 ; Vol. 10, No. 3.
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