{"id":2252,"date":"2018-12-03T17:14:44","date_gmt":"2018-12-03T08:14:44","guid":{"rendered":"http:\/\/163.180.4.222\/lab\/?p=2252"},"modified":"2018-12-03T17:14:44","modified_gmt":"2018-12-03T08:14:44","slug":"the-paradox-of-mutations-and-cancer","status":"publish","type":"post","link":"https:\/\/biochemistry.khu.ac.kr\/lab\/?p=2252","title":{"rendered":"The paradox of mutations and cancer"},"content":{"rendered":"

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The past decade has witnessed the cataloging of genetic mutations in cancer genomes, providing new insights into how and in what ways cancer can develop and spread (1<\/em><\/a>,\u00a02<\/em><\/a>). The focus has been on defining specific \u201cdriver\u201d mutations, genetic errors in cancer cells that reveal basic biological processes gone awry that are required for cancer initiation and progression. These drivers are the target of new therapies\u2014this concept is central to precision oncology efforts to treat patients according to the genetic changes that are present in their tumors (3<\/em><\/a>). Along the way, it has also become apparent that cancer genomes harbor many additional \u201cpassenger\u201d mutations (4<\/em><\/a>). Patterns of driver and passenger DNA mutations derived from cancer genomes have provided clues about the different ways that cancer can manifest as a disease of genetic mutations (5<\/em><\/a>,\u00a06<\/em><\/a>). In some circumstances, they can be linked to strong environmental carcinogens (for example, mutation patterns caused by tobacco smoke, ultraviolet radiation, or the fungal toxin aflatoxin) (7<\/em><\/a>). Moreover, these forensic mutational patterns can be used to estimate how long it has taken for a tumor to develop (5<\/em><\/a>). On page 911 of this issue, Martincorena\u00a0et al.<\/em>\u00a0(8<\/em><\/a>) turned their attention toward the detection of mutations in normal tissue, addressing a long-standing paradox that mutations arise in normal tissues but do not necessarily lead to cancer.<\/p>\n

Martincorena\u00a0et al.<\/em>\u00a0found that a larger-than-anticipated fraction of cells of the esophagus harbor mutations in cancer driver genes, which increases with age. Although only nine individuals without evidence of cancer were studied, the results raise two important questions. What is the role of mutations in tumorigenesis, and what factors are required to progress to cancer, including additional mutations or local events in the microenvironment or immune system? The findings also reveal that genome integrity deteriorates with age and perhaps in tissue-specific ways, which could reflect distinct external exposures and tissue-specific properties.<\/p>\n

The authors compared the genome sequences of nondiseased esophagus and skin (9<\/em><\/a>) to mutations in 74 known cancer driver genes. The total number of mutations was higher in the skin, which is not unexpected because the outer layers of skin are continually exposed to a strong mutagen, ultraviolet light. However, it came as a surprise that esophageal epithelial cells have a higher number of driver mutations, particularly mutations in the\u00a0NOTCH1<\/em>\u00a0and\u00a0TP53<\/em>\u00a0genes, which often occur in esophageal squamous carcinoma (10<\/em><\/a>).<\/p>\n

It is intriguing to speculate how such driver cancer mutations might be induced in the esophagus. The authors propose that the accumulation of mutations increases with age, mainly owing to errors in intrinsic processes such as aberrant DNA replication or repair. It is also plausible that the complex mix of what we swallow daily could contribute to the high mutation burden. The cumulative lifetime probability of developing esophageal squamous carcinoma in the United States is about 1 in 125, which is substantially smaller than that which would be predicted by the occurrence of the observed\u00a0NOTCH1<\/em>\u00a0and\u00a0TP53<\/em>\u00a0mutations. This raises the question of what other events are needed to induce cancer. Alternatively, perhaps there are mechanisms that prevent cancer from developing.<\/p>\n

These findings suggest that the transition from healthy tissue to cancer may be more complicated than we have modeled (see the figure). A next step will be to survey the entire genome (rather than only selected driver genes), where we may find mutations in new genes as well as the elusive \u201cdark matter\u201d between genes. It is important to focus on this intergenic space to understand how regulation of the genome is disrupted through mutations or chemical modification, a hallmark of epigenetics. Larger comparative studies are also needed to more accurately estimate the actual distribution of mutational events in other tissues, particularly those with high cancer rates, such as the lung, and tissues with very low cancer rates, such as the heart. A long-term goal should be to generate a genetic atlas of mutations in tissues of healthy individuals, sampled across the age spectrum and from distinct ancestries. Armed with a more comprehensive catalog of aging-associated mutations, we should be in a better position to understand the trigger events for cancer.<\/p>\n

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