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

• Main Authors: Jake Leighton (Author), Min Hu (Author), Emi Sei (Author), Funda Meric-Bernstam (Author), Nicholas E. Navin (Author)
• Format: Book
• Published: Elsevier, 2023-01-01T00:00:00Z.
• Subjects: article
• Online Access: Connect to this object online.
• Notes: 2666-979X; 10.1016/j.xgen.2022.100215
• Keywords: single-cell genomics; triple-negative breast cancer; intratumor heterogeneity; mutational evolution; breast cancer; Genetics; QH426-470; Internal medicine; RC31-1245
• Source: Cell Genomics, Vol 3, Iss 1, Pp 100215- (2023)

Summary: Single-cell DNA sequencing (scDNA-seq) methods are powerful tools for profiling mutations in cancer cells; however, most genomic regions sequenced in single cells are non-informative. To overcome this issue, we developed a multi-patient-targeted (MPT) scDNA-seq 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 patients with triple negative-breast cancer (TNBC), which showed that 3 tumors were monoclonal and 2 tumors were polyclonal. From these 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 suggest that MPT can overcome a major technical obstacle for studying tumor evolution using scDNA-seq by profiling information-rich mutation sites.