Editors' ChoiceCancer

Destiny or chance?

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Science Translational Medicine  06 Jan 2016:
Vol. 8, Issue 320, pp. 320ec2
DOI: 10.1126/scitranslmed.aad9762

Healthy cells are kept that way in part by molecular safety mechanisms that prevent genomic instability. When these guards are disrupted, malignant cells are born; however, the force behind these DNA injuries remains mysterious. Do our cells go awry due to assaults from genotoxic environmental factors such as chemicals or infectious agents or radiation? This is certainly the case in some tumors, such as lung cancers in smokers or skin malignancies caused by excessive sun exposure—and we can proactively avoid these risk factors. Alternatively, genetic errors may arise from random errors accumulating during DNA replication and chromosome segregation. Recent studies tackled these basic questions using large-scale genomics combined with cancer epidemiology.

Wu et al. report that approximately 80% of adult cancers may be blamed on extrinsic factors. According to their model of carcinogenesis, intrinsic mistakes do not explain the rising incidence of tumors in the human population. The investigators reviewed the mutational footprints left in malignant genomes by environmental cancer-causing factors and found that these genetic signatures occur commonly in human cancers. Although their model has limitations inherent to the mathematical description of live-cell processes, it fits the cancer epidemiology and genomic data remarkably well.

Childhood cancers are biologically different from adult tumors. Do extrinsic factors play an equally crucial role in pediatric malignancies? In an independent study, Zhang et al. comprehensively analyzed the landscape of congenital and acquired mutations in over 1000 children with cancer. 8.5% of their patients were born with potential cancer-associated gene mutations, which is close to the number of cancers not caused by extrinsic factors as predicted by Wu et al. Further, this study provided unexpected insights into pediatric cancer predisposition syndromes. Eight children had inherited monoallelic mutations of the adult-onset breast cancer genes BRCA1, BRCA2, and FANCN. These genes were mutated in children with a potpourri of pediatric cancers, from acute leukemia to brain malignancies, neuroblastoma, and osteosarcoma. Future studies will determine whether BRCA patients are truly at risk of childhood malignancies in addition to breast and ovarian cancers as young adults.

Genetic predisposition plays an essential role in a substantial number of cancers, but the majority of malignancies may reflect the toxic impact of environmental factors we can avoid. Therefore, optimistically speaking, we may be more empowered to prevent cancers from arising in the first place than we had realized.

S. Wu et al., Substantial contribution of extrinsic risk factors to cancer development. Nature 10.1038/nature16166 (2015). [Abstract]

J. Zhang et al., Germline mutations in predisposition genes in pediatric cancer. N. Engl. J. Med. 373, 2336­–2346 (2015). [Abstract]

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