Somatic mutation in cancer and normal cells

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Science  25 Sep 2015:
Vol. 349, Issue 6255, pp. 1483-1489
DOI: 10.1126/science.aab4082

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  • On the origin of mutational mosaicism in normal tissues
    • Indraneel Mittra, Dr. Ernest Borges Chair in Translational Research and Professor Emeritus, Department of Surgical Oncology, Tata Memorial Centre, Advanced Centre for Treatment, Research & Education in Cancer (ACTREC) Kharghar, Navi Mumbai

    There have been several recent publications in Science and other high ranking journals on the discovery of extensive somatic mutations in normal tissues (1-9). The common theme that emerges from these studies is that mutations increase with age and many more mutations are found in tissues exposed to environmental insults. Cancer genes are frequently mutated in normal tissues, providing clues to initiation of cancer. How do these mutations arise? Errors during DNA replication are one of the main suspects; but age related increase in mutations in brain cells (3) which do not divide and the fact that brain is not directly exposed to environmental mutagens suggests that other mechanisms are involved. Resent research has discovered that cell-free chromatin (cfCh) particles that are released from the billions of cells that die in the body everyday and enter into the blood circulation can illegitimately integrate themselves into healthy cells causing damage to their DNA by inflicting double stand breaks (10,11). These events may also occur locally following cell death in tissues with release of cfCh which integrate into genomes of neighbouring cells (10,12). cfCh integration and the resulting dsDNA breaks are most likely to be repaired by the error prone mechanism of NHEJ. I propose that mutations in normal tissues that have been discovered do not arise from the resident DNA, rather they arise from DNA segments carried from elsewhere via cfCh particles, with genes contained withi...

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    Competing Interests: None declared.

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