Editors' ChoiceCancer

Does Cancer Know Which Way Is Up?

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Science Translational Medicine  07 Apr 2010:
Vol. 2, Issue 26, pp. 26ec56
DOI: 10.1126/scitranslmed.3001124

When it comes to cancer, sometimes what is not there is what counts. High-throughput gene expression analyses frequently have been used to identify previously unidentified genes involved in tumorigenesis, but this methodology is not designed to detect the presence of small intragenic deletions. Now, Rothenberg et al. have used 684 different cancer cell lines to identify rare homozygous genetic deletions that may be difficult to identify by conventional means.

Using a genome-wide screen for microdeletions, the group identified 211 genes that frequently harbored such small gaps—a collection that included the well-characterized CKDN2A/B and PTEN tumor-suppressor genes. Another notable category that commonly harbored microdeletions comprised genes that encode members of the cell polarity complexes PAR, CRB, and SCRIB, which mediate tight junctions between cells and perform myriad other functions. Advanced tumors often exhibit loss of cell polarity and cell–cell adhesion, which are properties that correlate with a tumor cell’s ability to invade other tissues. These polarity complex genes were most commonly altered in various squamous cell carcinomas and glioblastomas. The PARD3 gene—which encodes a key mediator of apical-basal cell polarity and is a member of the PAR complex—contained numerous alterations, including homozygous deletions, heterozygous deletions, and splice-site and missense mutations. Using PARD3 as a representative polarity complex gene, the investigators further analyzed the role of the corresponding protein in tumor cell proliferation and migration. In squamous carcinoma and glioblastoma cell lines, the absence of the PARD3 protein resulted in loss of contact inhibition in cancer cells as well as enhanced proliferation and migration. The results of this study, therefore, highlight the role of polarity complex genes in mediating cancer cell growth and suggest a critical role for genetic microdeletions in tumorigenesis.

S. M. Rothenberg et al., A genome-wide screen for microdeletions reveals disruption of polarity complex genes in diverse human cancers. Cancer Res. 70, 2158–2164 (2010). [Abstract]

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