Genetic and phenotypic diversity in breast tumor metastases.
Metastatic disease is the main cause of cancer-related mortality due to almost universal therapeutic resistance. Despite its high clinical relevance, our knowledge of how cancer cell populations change during metastatic progression is limited. Here, we investigated intratumor genetic and phenotypic heterogeneity during metastatic progression of breast cancer. We analyzed cellular genotypes and phenotypes at the single cell level by performing immunoFISH in intact tissue sections of distant metastatic tumors from rapid autopsy cases and from primary tumors and matched lymph node metastases collected before systemic therapy. We calculated the Shannon index of intratumor diversity in all cancer cells and within phenotypically distinct cell populations. We found that the extent of intratumor genetic diversity was similar regardless of the chromosomal region analyzed, implying that it may reflect an inherent property of the tumors. We observed that genetic diversity was highest in distant metastases and was generally concordant across lesions within the same patient, whereas treatment-naïve primary tumors and matched lymph node metastases were frequently genetically more divergent. In contrast, cellular phenotypes were more discordant between distant metastases than primary tumors and matched lymph node metastases. Diversity for 8q24 was consistently higher in HER2(+) tumors compared with other subtypes and in metastases of triple-negative tumors relative to primary sites. We conclude that our integrative method that couples ecologic models with experimental data in human tissue samples could be used for the improved prognostication of patients with cancer and for the design of more effective therapies for progressive disease.
Authors' Affiliations: Departments of Medical Oncology and Biostatistics and Computational Biology, Dana-Farber Cancer Institute; Department of Medicine, Brigham and Women's Hospital; Department of Medicine, Harvard Medical School; Department of Biostatistics, Harvard School of Public Health, Boston; Departments of Physics and Biology, Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology; Harvard Stem Cell Institute, Cambridge, Massachusetts; Department of Epidemiology and Biostatistics, Memorial Sloan-Kettering Cancer Center, New York, New York; Departments of Pathology and Oncology, Johns Hopkins University School of Medicine, Baltimore, Maryland; Department of Medical Oncology, Hospital Clinic, Institut d'Investigacions Biomediques August Pi i Sunyer, Barcelona, Spain; Department of Pathology, MizMedi Hospital, Seoul, South Korea; Department of Molecular Cell Biology, Weizmann Institute of Science, Rehovot, Israel; and Hubrecht Institute, Royal Netherlands Academy of Arts and Sciences and University Medical Center Utrecht, Utrecht, the Netherlands.
Vanessa
V
Almendro
Hee Jung
HJ
Kim
Yu-Kang
YK
Cheng
Mithat
M
Gönen
Shalev
S
Itzkovitz
Pedram
P
Argani
Alexander
A
van Oudenaarden
Saraswati
S
Sukumar
Franziska
F
Michor
Kornelia
K
Polyak
D001943:Breast Neoplasms / Q000235:genetics* / Q000473:pathology*; D005260:Female; D014644:Genetic Variation / Q000235:genetics*; D006801:Humans; D008198:Lymph Nodes / Q000473:pathology; D008207:Lymphatic Metastasis / Q000235:genetics / Q000473:pathology; D009362:Neoplasm Metastasis / Q000235:genetics* / Q000473:pathology*; D010641:Phenotype