Forward-reverse mutation cycles between stages of cancer development

Hu, T.; Kumar, Y.; Shazia, I.; Duan, S.-J.; Li, Y.; Chen, L.; Chen, J.-F.; Yin, R.; Kwong, A.; Leung, G. K.-K.; Mat, W.-K.; Wu, Z.; Long, X.; Chan, C.-H.; Lee, P.; Ng, S.-K.; Ho, T. Y. C.; Yang, J.; Ding, X.; Tsang, S.-Y.; Zhou, X.; Zhang, D.-H.; International Cancer Genome Consortium,; Zhou, E.-X.; Xu, L.; Poon, W.-S.; Wang, H.-Y.; Xue, H.

doi:10.1101/198309

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bioRxiv · 10.1101/198309

Forward-reverse mutation cycles between stages of cancer development

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Abstract

Earlier, prominent occurrences of interstitial loss-of-heterozygosities (LOHs) were found in different cancers as a type of single-nucleotide-variations (SNVs), at rates far exceeding those of the commonly investigated gain-of-heterozygosities (GOHs) type of SNVs. Herein, such co-occurrences of LOHs and GOHs were confirmed in 102 cases of four cancer types analyzed with three different next-generation sequencing platforms, comparing non-tumor, paratumor, and tumor tissues with white-blood-cell controls; and in 246 pan-cancer cases of whole-genome tumor-control pairs. Unexpectedly, large numbers of SNVs enriched with CG>TG GOHs and copy-number-variations (CNVs) proximal to these GOHs were detected in the non-tumor tissues, which were extensively reversed in paratumors showing prominent TG>CG LOHs with proximal CNVs, and less so in tumors to form forward-reverse mutation cycles. Lineage effects in the reversions, likely resulting from directional selection, supported a sequential rather than parallel mode of evolution as described in a Stage Specific Populations model of cancer development.

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Hu, T., Kumar, Y., Shazia, I., Duan, S.-J., Li, Y., Chen, L., Chen, J.-F., Yin, R., Kwong, A., Leung, G. K.-K., Mat, W.-K., Wu, Z., Long, X., Chan, C.-H., Lee, P., Ng, S.-K., Ho, T. Y. C., Yang, J., Ding, X., Tsang, S.-Y., Zhou, X., Zhang, D.-H., International Cancer Genome Consortium,, Zhou, E.-X., Xu, L., Poon, W.-S., Wang, H.-Y., Xue, H.. 2017-10-05. Forward-reverse mutation cycles between stages of cancer development. https://doi.org/10.1101/198309

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