Integrated single-cell genetic and transcriptional analysis suggests novel drivers of chronic lymphocytic leukemia

• DOI: 10.1101/gr.217331.116
• Publication Date: 2017-07-06T00:40:25Z
• Authors: Lili Wang; Jean Fan; Joshua M. Francis; George Georghiou; Sarah Hergert; Shuqiang Li; Rutendo Gambe; Chensheng W. Zhou; Chunxiao Yang; Sheng Xiao; Paola Dal Cin; Michaela Bowden; Dylan Kotliar; Sachet A. Shukla; Jennifer R. Brown; Donna Neuberg; Dario R. Alessi; Cheng-Zhong Zhang; Peter V. Kharchenko; Kenneth J. Livak; Catherine J. Wu
• Keywords: Adult; Male; 0303 health sciences; Transcription, Genetic; Research; High-Throughput Nucleotide Sequencing; Sequence Analysis, DNA; Middle Aged; Leukemia, Lymphocytic, Chronic, B-Cell; 3. Good health; Evolution, Molecular; 03 medical and health sciences; Case-Control Studies; Mutation; Biomarkers, Tumor; Humans; Female; Single-Cell Analysis

Intra-tumoral genetic heterogeneity has been characterized across cancers by genome sequencing of bulk tumors, including chronic lymphocytic leukemia (CLL). In order to more accurately identify subclones, define phylogenetic relationships, and probe genotype–phenotype we developed methods for targeted mutation detection in DNA RNA isolated from thousands single cells five CLL samples. By clearly resolving phylogenic uncovered mutated LCP1 WNK1 as novel drivers, supported functional evidence demonstrating their impact on pathways. Integrative analysis somatic mutations with transcriptional states prompts the idea that convergent evolution generates phenotypically similar distinct branches, thus creating a cohesive expression profile each sample despite presence heterogeneity. Our study highlights potential single-cell RNA-based sensitively determine mutational profiles individual cancer cells, leading increased understanding driving events malignancy.