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Reconstructing mutational lineages in breast cancer by multi-patient-targeted single cell DNA sequencing

Leighton J et al.
BioRxiv (2022)

Single cell DNA sequencing (scDNA-seq) methods are powerful tools for profiling mutations in cancer cells, however most genomic regions characterized in single cells are non-informative. To overcome this issue, we developed a Multi-Patient-Targeted (MPT) scDNA-seq sequencing method. MPT involves first performing bulk exome sequencing across a cohort of cancer patients to identify somatic mutations, which are then pooled together to develop a single custom targeted panel for high-throughput scDNA-seq using a microfluidics platform. We applied MPT to profile 330 mutations across 23,500 cells from 5 TNBC patients, which showed that 3 tumors were monoclonal and 2 tumors were polyclonal. From this data, we reconstructed mutational lineages and identified early mutational and copy number events, including early TP53 mutations that occurred in all five patients. Collectively, our data suggests that MPT can overcome technical obstacles for studying tumor evolution using scDNA-seq by profiling information-rich mutation sites.


Leighton J, Hu M, Sei E, Meric-Bernstam F, Navin N


Phenotypic signatures of immune selection in HIV-1 reservoir cells
Weiwei Sun
Mutated cells mediate distinct inflammatory responses in clonal hematopoiesis
J. Brett Heimlich
scTAM-seq enables targeted high-confidence analysis of DNA methylation in single cells
Bianchi A
Genome Biology (2022)
Single cell genotypic and phenotypic analysis of measurable residual disease in acute myeloid leukemia
Troy T. Robinson
BioRxiv (2022)