WWOX: A Candidate Tumor Suppressor Gene Involved in Multiple Tumor Types

• Published in: Proceedings of the National Academy of Sciences - PNAS 2001-09, Vol.98 (20), p.11417-11422
• Main Authors: Adam J. W. Paige, Taylor, Karen J., Taylor, Claire, Hillier, Stephen G., Farrington, Susan, Scott, Diane, Porteous, David J., Smyth, John F., Gabra, Hani, J. E. Vivienne Watson
• Format: Article
• Language: English
• Subjects: Alternative Splicing; Amino Acid Sequence; Animals; Biological Sciences; Cancer; Carrier Proteins - genetics; Cell lines; chromosome 16; Colorectal Neoplasms - genetics; Complementary DNA; DNA; DNA - blood; Exons; Female; Gene Frequency; Genes; Genes, Tumor Suppressor; Genetic Variation; Genetics; Homozygote; Humans; Mice; Molecular Sequence Data; Mutation; Neoplasm Proteins - genetics; Ovarian Neoplasms - genetics; P1 artifical chromosomes; P1 artifitial chromosomes; Point Mutation; Polymerase chain reaction; Reference Values; Reverse transcriptase polymerase chain reaction; RNA; Sequence Alignment; Sequence Deletion; Studies; Tumor cell line; Tumor Cells, Cultured; Tumors; WWOX gene
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.191175898

We previously reported the construction of a P1-derived artificial chromosome (PAC) contig encompassing a set of homozygous deletions of chromosome 16q23-24.1 found in primary ovarian tumor material and several tumor cell lines. Using these PAC clones in a cDNA selection experiment, we have isolated a Sau3A fragment homologous to the WWOX transcript (GenBank accession no. AF211943) from normal human ovarian surface epithelial (HOSE) cells. We demonstrate the homozygous deletion of WWOX exons from ovarian cancer cells and three different tumor cell lines. We also identify an internally deleted WWOX transcript from a further primary ovarian tumor. In three of these samples the deletions result in frameshifts, and in each case the resulting WWOX transcripts lack part, or all, of the short chain dehydrogenase domain and the putative mitochondrial localization signal. Sequencing revealed several missense polymorphisms in tumor cell lines and identified a high level of single nucleotide polymorphism (SNP) within the WWOX gene. This evidence strengthens the case for WWOX as a tumor suppressor gene in ovarian cancer and other tumor types.