Lectures and seminars OnkPat Extra Seminar: Tracing cancer causes using single-cell genome sequencing

Host: Martin Enge, Department of Oncology-Pathology 

Abstract

Studying the processes that drive cancer initiation directly in patient samples is inherently challenging, as the disease is already established by the time it is detected. To overcome this limitation, our group uses somatic DNA mutations as an endogenous historical record of cellular life histories. We have developed single-cell genome sequencing approaches to quantify mutation accumulation in individual cells and to reconstruct tumor phylogenies, enabling the identification and molecular characterization of the cell-of-origin. Combined with mutational signature analysis, this framework allows us to infer the biological and environmental processes that contribute to cancer initiation.

In this talk, I will highlight how this strategy revealed a causal link between a mutagenic E. coli strain, carried by approximately one in five individuals, and the development of colorectal cancer. I will also discuss how single-cell genomics can be used to study why cancers arise in children, despite the limited age-related damage in their cells, providing new insights into the earliest steps of tumorigenesis.

Related publications

Mutational signature in colorectal cancer caused by genotoxic pks+ E. coli.
Pleguezuelos-Manzano C, Puschhof J, Rosendahl Huber A, van Hoeck A, Wood HM, Nomburg J, Gurjao C, Manders F, Dalmasso G, Stege PB, Paganelli FL, Geurts MH, Beumer J, Mizutani T, Miao Y, van der Linden R, van der Elst S, , Garcia KC, Top J, Willems RJL, Giannakis M, Bonnet R, Quirke P, Meyerson M, Cuppen E, van Boxtel R, Clevers H
Nature 2020 Apr;580(7802):269-273

Improved detection of colibactin-induced mutations by genotoxic E. coli in organoids and colorectal cancer.
Rosendahl Huber A, Pleguezuelos-Manzano C, Puschhof J, Ubels J, Boot C, Saftien A, Verheul M, Trabut LT, Groenen N, van Roosmalen M, Ouyang KS, Wood H, Quirke P, Meijer G, Cuppen E, Clevers H, van Boxtel R
Cancer Cell 2024 Mar;42(3):487-496.e6

Transient Differentiation-State Plasticity Occurs during Acute Lymphoblastic Leukemia Initiation.
Poort VM, Hagelaar R, van Roosmalen MJ, Trabut L, Buijs-Gladdines JGCAM, van Wijk B, Meijerink J, van Boxtel R
Cancer Res 2024 Aug;84(16):2720-2733

Elevated Mutational Age in Blood of Children Treated for Cancer Contributes to Therapy-Related Myeloid Neoplasms.
Bertrums EJM, Rosendahl Huber AKM, de Kanter JK, Brandsma AM, van Leeuwen AJCN, Verheul M, van den Heuvel-Eibrink MM, Oka R, van Roosmalen MJ, de Groot-Kruseman HA, Zwaan CM, Goemans BF, van Boxtel R
Cancer Discov 2022 Aug;12(8):1860-1872

Antiviral treatment causes a unique mutational signature in cancers of transplantation recipients.
de Kanter JK, Peci F, Bertrums E, Rosendahl Huber A, van Leeuwen A, van Roosmalen MJ, Manders F, Verheul M, Oka R, Brandsma AM, Bierings M, Belderbos M, van Boxtel R
Cell Stem Cell 2021 Oct;28(10):1726-1739.e6