APOBEC3 as a driver of genetic intratumor heterogeneity

ABSTRACT

Our recent study revealed that APOBEC3B is upregulated during the preinvasive stages of non-small cell lung cancer and breast cancer. In addition to its role in mediating single nucleotide variants, we propose that APOBEC3 promotes copy number intratumor heterogeneity prior to invasion, providing a substrate for cancer evolution.

KEYWORDS:

• APOBEC
• non-small cell lung cancer
• breast cancer
• intratumor heterogeneity
• chromosomal instability

Acknowledgments

We apologize to our colleagues for the omission of many important contributions to the field, and their references, due to space limitations.

Disclosure statement

S.F.B. holds a patent related to some of the work described targeting CIN and the cGAS-STING pathway in advanced cancer. He owns equity in, receives compensation from, and serves as a consultant and the Scientific Advisory Board and Board of Directors of Volastra Therapeutics Inc. C.S. acknowledges grant support from Pfizer, AstraZeneca, Bristol Myers Squibb, Roche-Ventana, Boehringer-Ingelheim, Invitae (previously Archer Dx Inc) - collaboration in minimal residual disease sequencing technologies, and Ono Pharmaceutical, and is an AstraZeneca Advisory Board member and Chief Investigator for the MeRmaiD1 clinical trial. C.S has consulted for Amgen, Pfizer, Novartis, GlaxoSmithKline, MSD, Bristol Myers Squibb, Celgene, Astra Zeneca, Illumina, Genentech, Roche-Ventana, GRAIL, Medicxi, Metabomed, Bicycle Therapeutics, Roche Innovation Centre Shanghai, and the Sarah Cannon Research Institute, C.S. has stock options in Apogen Biotechnologies, Epic Bioscience, GRAIL, and has stock options and is co-founder of Achilles Therapeutics. Patents: C.S. holds European patents relating to assay technology to detect tumour recurrence (PCT/GB2017/053289); to targeting neoantigens (PCT/EP2016/059401), identifying patent response to immune checkpoint blockade (PCT/EP2016/071471), determining HLA LOH (PCT/GB2018/052004), predicting survival rates of patients with cancer (PCT/GB2020/050221), identifying patients who respond to cancer treatment (PCT/GB2018/051912), a US patent relating to detecting tumour mutations (PCT/US2017/28013) and both a European and US patent related to identifying insertion/deletion mutation targets (PCT/GB2018/051892). No potential conflicts of interest were disclosed by the other authors.

Additional information

Funding

S.F.B. is supported by the Office of the Director, the NIH under Award Number National Institutes of Health DP5OD026395 High-Risk High-Reward Program, the NCI Breast Cancer SPORE (National Cancer Institute P50CA247749) and R01 (R01CA256188-01), the Burroughs Wellcome Fund Career Award for Medical Scientists, the Parker Institute for Immunotherapy at MSKCC, the Josie Robertson Foundation, and the MSKCC core grant P30-CA008748. J.B. and his team were funded by grants from the Danish Cancer Society (R1123-A7785-15-S2 and R167-A11068), the Novo Nordisk Fonden (16854 and Novo Nordisk Fonden 0060590), the Lundbeck foundation (Lundbeckfonden R266-2017-4289 and R322-2019-2577), the Swedish Research council (Swedish Research Council VR-MH 2014-46602-117891-30), The Swedish Cancer Foundation/Cancerfonden (The Swedish Cancer Foundation 170176), and the Danish national research foundation(project CARD, DNRF 125). N.K. receives funding from Cancer Research UK.C.S. is Royal Society Napier Research Professor (RP150154). This work was supported by the Francis Crick Institute that receives its core funding from Cancer Research UK (FC001169), the UK Medical Research Council FC001169, and the Wellcome Trust (FC001169). This research was funded in whole, or in part, by the Wellcome Trust (FC001169). For the purpose of Open Access, the author has applied a CC BY public copyright licence to any Author Accepted Manuscript version arising from this submission. C.S. is funded by Cancer Research UK (TRACERx, PEACE and CRUK Cancer Immunotherapy Catalyst Network), Cancer Research UK Lung Cancer Centre of Excellence (C11496/A30025), the Rosetrees Trust, Butterfield and Stoneygate Trusts, NovoNordisk Foundation (ID16584), Royal Society Professorship Enhancement Award (RP/EA/180007), the National Institute for Health Research (NIHR) Biomedical Research Centre at University College London Hospitals, the Cancer Research UK-University College London Centre, Experimental Cancer Medicine Centre, and the Breast Cancer Research Foundation (The Breast Cancer Research Foundation BCRF 20-157). This work was supported by a Stand Up To Cancer‐LUNGevity-American Lung Association Lung Cancer Interception Dream Team Translational Research Grant (Grant Number: SU2C-AACR-DT23-17 to S.M. Dubinett and A.E. Spira). Stand Up To Cancer is a division of the Entertainment Industry Foundation. Research grants are administered by the American Association for Cancer Research, the Scientific Partner of SU2C. CS is in receipt of an ERC Advanced Grant (PROTEUS) from the European Research Council under the European Union’s Horizon 2020 research and innovation programme (grant agreement No. H2020 European Research Council 835297);The Rosetrees Trust;The National Institute for Health Research (NIHR) Biomedical Research Centre at University College London Hospitals;The Cancer Research UK-University College London Centre;Parker Institute for Cancer Immunotherapy.