Genetically engineering tumors in mice, a technique that has    dominated cancer research for decades, may not replicate    important features of cancers caused by exposure to    environmental carcinogens, according to a new study led by UC    San Francisco scientists. In addition to pointing the way to    better understanding of environmental causes of cancer, the    findings may help explain why many patients do not benefit    from, or develop resistance to, targeted drug therapies.  
    In the new research, reported November 2, 2014 in the advance    online edition of     Nature, a team led by UCSF graduate student Peter M.K.    Westcott found that chemically induced lung tumors in mice    carry hundreds of point mutationsdeleterious alterations of    single letters in the genomethat are not present in tumors    induced by genetic engineering. The researchers demonstrated    that chemically induced tumors display a starkly different    mutational landscape even when chemicals cause a    tumor-initiating mutation that is identical to that created by    direct genetic manipulation.  
    Since the 1980s, when genetic engineering came along, the    mouse model community has been working on genetically    engineered canceryou put a gene in or take a gene out, and you    get a tumor, said Allan Balmain,    PhD, the Barbara Bass Bakar Distinguished Professor in Cancer    Genetics at UCSF and senior author of the study. But its only    now that were beginning to analyze what has happened between    that first engineered change and the ultimate development of an    aggressive tumor.  
    The new work made use of next-generation sequencing (NGS)    technology, which allows researchers to analyze the genomic    sequence of tumors or of normal tissue letter-by-letter. For    the Nature study, the group used a form of NGS known    as whole-exome sequencing, which comprehensively analyzes the    portion of the genome that contains the code for producing    proteins.  
    The findings dovetail well with those from NGS-based studies of    human tumors, such as The Cancer Genome Atlas (TCGA) initiative    spearheaded by the National Cancer Institute and National Human    Genome Research Institute, which have revealed mutational    signatures, some of which can be definitively tied to    environmental exposures. For example, distinctive patterns of    point mutations are now known to differentiate lung cancer in    smokers from that affecting non-smokers.  
    The results are also consistent with observations that tumors    arising in human organs that are most directly exposed to    environmental carcinogensthe skin, gastrointestinal system,    and lungsare more prone to point mutations than more    protected organs such as the brain, breast, and prostate    gland.  
    We humans smoke cigarettes, drink alcohol, and spend too much    time in the sun, all of which cause us to accumulate point    mutations that are major determinants of the behavior of    tumors, especially of how a tumor responds to therapy, said    Balmain, co-leader of the Cancer Genetics Program at UCSFs    Helen Diller Family    Comprehensive Cancer Center. All this heterogeneity is    being missed with genetically engineered tumors, because they    dont reflect these environmental effects.  
    But only a very small number of the 25 mutational signatures    revealed by NGS in human tumors so far have been convincingly    tied to environmental exposures, Balmain said, so there is much    to learn. Other very unusual, very specific signatures have    been seen in human studies that remain obscure. Theyre like a    smoking gunwe know theyre caused by something    environmental, but were not sure what.  
    To date most epidemiological research on environmental causes    of cancer has relied on patients and families to recall and    document dietary habits, alcohol and tobacco use, or    occupational exposures, and the rise of NGS offers an    opportunity to approach these questions more rigorously, said    Balmain.  
    To that end, Balmains research group is embarking on a    collaboration with the National Institute of Environmental    Health Sciences, which maintains a collection of thousands of    mouse and rat tumors caused by exposure to suspected human    carcinogens. Through NGS analyses of that collection, the    research team hopes to find mutational signatures that can be    correlated with those seen in human cancer.  
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Environmental Carcinogens Leave Distinctive Genetic Imprints in Tumors