Characterization of BRCA1-deficient premalignant tissues and cancers identifies Plekha5 as a tumor metastasis suppressor

Nat Commun. 2020 Sep 25;11(1):4875. doi: 10.1038/s41467-020-18637-9.

Abstract

Single-cell whole-exome sequencing (scWES) is a powerful approach for deciphering intratumor heterogeneity and identifying cancer drivers. So far, however, simultaneous analysis of single nucleotide variants (SNVs) and copy number variations (CNVs) of a single cell has been challenging. By analyzing SNVs and CNVs simultaneously in bulk and single cells of premalignant tissues and tumors from mouse and human BRCA1-associated breast cancers, we discover an evolution process through which the tumors initiate from cells with SNVs affecting driver genes in the premalignant stage and malignantly progress later via CNVs acquired in chromosome regions with cancer driver genes. These events occur randomly and hit many putative cancer drivers besides p53 to generate unique genetic and pathological features for each tumor. Upon this, we finally identify a tumor metastasis suppressor Plekha5, whose deficiency promotes cancer metastasis to the liver and/or lung.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • BRCA1 Protein / genetics*
  • BRCA1 Protein / metabolism*
  • Breast Neoplasms / genetics
  • Cell Line, Tumor
  • DNA Copy Number Variations
  • Disease Models, Animal
  • Genetic Heterogeneity
  • Genetic Predisposition to Disease / genetics*
  • Humans
  • Intracellular Signaling Peptides and Proteins / genetics
  • Intracellular Signaling Peptides and Proteins / metabolism*
  • Liver / pathology
  • Lung / pathology
  • Mice
  • Mice, Knockout
  • Mutation
  • Precancerous Conditions / genetics*
  • Precancerous Conditions / pathology
  • Transcriptome

Substances

  • BRCA1 Protein
  • BRCA1 protein, human
  • Intracellular Signaling Peptides and Proteins
  • PLEKHA5 protein, human
  • Plekha5 protein, mouse