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Dec 9, 2013

Single Gene, Once under Radar, Helps Drive 1/100 Cancers

  • When studying genetic drivers of cancer, scientists often focus on genes that are mutated at a high rate, in single type of cancer. But an alternative approach is possible—focusing on genes that mutate at low rates, in many types of cancer. This alternative approach, taken by researchers centered at the Wellcome Trust Sanger Institute, has identified a gene that drives the development of tumors in over 1% of all cancer patients.

    The gene, CUX1, had already been suspected of playing an oncogenic role in human cancer development. The new work, however, marks the first time CUX1 has been evaluated so comprehensively, and so broadly linked to cancer development.

    The new work appeared December 8 in Nature Genetics, in an article entitled “Inactivating CUX1 mutations promote tumorigenesis.” In this article, the authors noted that sequencing studies typically lack the sensitivity to identify commonly mutated cancer genes, which means that cancer drivers mutated at low frequency often escape detection. Then the authors described how they addressed this issue by scrutinizing an extensive collection of 7,651 genome sequences (352 whole genomes, 7,299 exomes) derived from 28 tumor types to identify cancer driver genes characterized by loss-of-function mutations.

    This strategy involved searching for genes showing a significant enrichment for nonsense mutations. Fifty-four genes were identified, including genes known to drive tumorigenesis and genes not previously implicated as currently mutated tumor suppressors, contributing to a “hitherto unseen picture of the cancer gene landscape.”

    Of these 54 genes, the scientists focused on CUX1, which showed a 3.4-fold increase in the ratio of observed to expected nonsense mutations. Ultimately, reported the scientists, “overall nonsense and frameshift mutations in CUX1 were detected in 1–5% of tumors, spanning many types, with the highest frequency occurring in endometrial cancer.”

    Next the scientists silenced CUX1 in cultured cells to understand how inactivating it might lead to the development of tumors. They found that when CUX1 is deactivated, it had a knock-on effect on a biological inhibitor, PIK3IP1, reducing its inhibitory effects. This mobilizes an enzyme responsible for cell growth, phosphoinositide 3-kinase (PI3K), increasing the rate of tumor progression.

    “Our work harnesses the power of combining large-scale cancer genomics with experimental genetics,” said Dr. Chi C. Wong, first author from the Wellcome Trust Sanger Institute and a hematologist at Addenbrooke’s Hospital. “CUX1 defects are particularly common in myeloid blood cancers, either through mutation or acquired loss of chromosome 7q. As these patients have a dismal prognosis currently, novel targeted therapies are urgently needed.”

    Although the Nature Genetics article focused on CUX1, the article’s authors remain interested in the other genes that were identified in their study—the several dozen genes that, like CUX1, were found to mutate at a low frequency. These genes may also promote cancer development. To explore this possibility, the authors plan to silence these genes in mice to fully understand how their inactivation may lead to cancer development and the mechanisms by which this occurs.

    “Our research is a prime example of how understanding the genetic code of cancers can drive the search for targeted cancer therapies that work more effectively and efficiently,” said David J. Adams, Ph.D., lead author from the Wellcome Trust Sanger Institute. “This could improve the lives of thousands of people suffering from cancer.”



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