A recent study from Sun et al. reveals a polygenic architecture for pan-cancer tumour mutational burden (TMB) and shows the identification of genes underpinning the associations between germline genetic variants and TMB in specific cancer types. Here we discuss the main findings of the Sun et al. study and the implications for further studies.
This is a preview of subscription content, access via your institution
Subscribe to Journal
Get full journal access for 1 year
only $4.96 per issue
All prices are NET prices.
VAT will be added later in the checkout.
Tax calculation will be finalised during checkout.
Get time limited or full article access on ReadCube.
All prices are NET prices.
Hellmann, M. D., Ciuleanu, T. E., Pluzanski, A., Lee, J. S., Otterson, G. A., Audigier-Valette, C. et al. Nivolumab plus ipilimumab in lung cancer with a high tumor mutational burden. N. Engl. J. Med. 378, 2093–2104 (2018).
Samstein, R. M., Lee, C. H., Shoushtari, A. N., Hellmann, M. D., Shen, R., Janjigian, Y. Y. et al. Tumor mutational load predicts survival after immunotherapy across multiple cancer types. Nat. Genet. 51, 202–206 (2019).
Sun, X., Xue, A., Qi, T., Chen, D., Shi, D., Wu, Y. et al. Tumor mutational burden is polygenic and genetically associated with complex traits and diseases. Cancer Res. 81, 1230–1239 (2021).
Zeng, J., de Vlaming, R., Wu, Y., Robinson, M. R., Lloyd-Jones, L. R., Yengo, L. et al. Signatures of negative selection in the genetic architecture of human complex traits. Nat. Genet. 50, 746–753 (2018).
Carrot-Zhang, J., Soca-Chafre, G., Patterson, N., Thorner, A. R., Nag, A., Watson, J. et al. Genetic ancestry contributes to somatic mutations in lung cancers from admixed Latin American populations. Cancer Discov. 11, 591–598 (2021).
Chen, J., Yang, H., Teo, A. S. M., Amer, L. B., Sherbaf, F. G., Tan, C. Q. et al. Genomic landscape of lung adenocarcinoma in East Asians. Nat. Genet. 52, 177–186 (2020).
Moamer, A., Hachim, I. Y., Binothman, N., Wang, N., Lebrun, J. J. & Ali, S. A role for kinesin-1 subunits KIF5B/KLC1 in regulating epithelial mesenchymal plasticity in breast tumorigenesis. EBioMedicine 45, 92–107 (2019).
Alexandrov, L. B., Ju, Y. S., Haase, K., Van Loo, P., Martincorena, I., Nik-Zainal, S. et al. Mutational signatures associated with tobacco smoking in human cancer. Science 354, 618–622 (2016).
Kucab, J. E., Zou, X., Morganella, S., Joel, M., Nanda, A. S., Nagy, E. et al. A compendium of mutational signatures of environmental agents. Cell 177, 821–836 e816 (2019).
Yoshida, K., Gowers, K. H. C., Lee-Six, H., Chandrasekharan, D. P., Coorens, T., Maughan, E. F. et al. Tobacco smoking and somatic mutations in human bronchial epithelium. Nature 578, 266–272 (2020).
Gandara, D. R., Paul, S. M., Kowanetz, M., Schleifman, E., Zou, W., Li, Y. et al. Blood-based tumor mutational burden as a predictor of clinical benefit in non-small-cell lung cancer patients treated with atezolizumab. Nat. Med. 24, 1441–1448 (2018).
Ethics approval and consent to participate
The authors declare no competing interests.
This work is partly supported by the Westlake Education Foundation.
Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
About this article
Cite this article
Sun, X., Yang, J. Towards the understanding of the genetics of somatic mutations. Br J Cancer 125, 627–628 (2021). https://doi.org/10.1038/s41416-021-01369-y