Single-cell genomic variation induced by mutational processes in cancer.

Area of Science:

• Genomics
• Cancer Biology
• Evolutionary Biology

Background:

• Genomic instability is a hallmark of cancer, contributing to tumor evolution.
• Cell-to-cell copy number alterations (CNAs) are key drivers of genomic instability.
• The impact of CNAs on cancer evolution and variation remains understudied.

Purpose of the Study:

• To investigate how cell-to-cell CNAs drive genomic and phenotypic variation in cancer.
• To identify specific mutational patterns associated with structural variation.
• To understand the evolutionary consequences of these variations in triple-negative breast cancer (TNBC) and high-grade serous ovarian cancer (HGSC).

Main Methods:

• Scaled single-cell whole-genome sequencing of 13,818 mammary epithelial cell genomes and 22,057 primary TNBC and HGSC genomes.
• Analysis of TP53-deficient and BRCA1/BRCA2-deficient cell lines.
• Identification and characterization of distinct structural variation patterns.

Main Results:

• Three distinct 'foreground' mutational patterns defined by cell-to-cell structural variation were identified.
• Clone-specific high-level amplifications, parallel haplotype-specific CNAs, and serrate structural variations were observed.
• These variations were linked to phenotypic and evolutionary consequences, including increased phenotypic variation and phylogenetic diversity.

Conclusions:

• Cell-to-cell structural variation significantly contributes to the origins of phenotypic and evolutionary diversity in TNBC and HGSC.
• Specific CNA patterns provide insights into the genomic and mutational states of individual cancer cells.
• Understanding these mechanisms is crucial for comprehending cancer evolution and developing targeted therapies.