title: Tumor Evolution in Two Patients with Basal-like Breast Cancer: A Retrospective Genomics Study of Multiple Metastases.
abstract: BACKGROUND
  Metastasis is the main cause of cancer patient deaths and remains a poorly characterized process. It is still unclear when in tumor progression the ability to metastasize arises and whether this ability is inherent to the primary tumor or is acquired well after primary tumor formation. Next-generation sequencing and analytical methods to define clonal heterogeneity provide a means for identifying genetic events and the temporal relationships between these events in the primary and metastatic tumors within an individual.
  
  
  RESULTS
  We performed DNA whole genome and mRNA sequencing on two primary tumors, each with either four or five distinct tissue site-specific metastases, from two individuals with triple-negative/basal-like breast cancers. As evidenced by their case histories, each patient had an aggressive disease course with abbreviated survival. In each patient, the overall gene expression signatures, DNA copy number patterns, and somatic mutation patterns were highly similar across each primary tumor and its associated metastases. Almost every mutation found in the primary was found in a metastasis (for the two patients, 52/54 and 75/75). Many of these mutations were found in every tumor (11/54 and 65/75, respectively). In addition, each metastasis had fewer metastatic-specific events and shared at least 50% of its somatic mutation repertoire with the primary tumor, and all samples from each patient grouped together by gene expression clustering analysis. TP53 was the only mutated gene in common between both patients and was present in every tumor in this study. Strikingly, each metastasis resulted from multiclonal seeding instead of from a single cell of origin, and few of the new mutations, present only in the metastases, were expressed in mRNAs. Because of the clinical differences between these two patients and the small sample size of our study, the generalizability of these findings will need to be further examined in larger cohorts of patients.
  
  
  CONCLUSIONS
  Our findings suggest that multiclonal seeding may be common amongst basal-like breast cancers. In these two patients, mutations and DNA copy number changes in the primary tumors appear to have had a biologic impact on metastatic potential, whereas mutations arising in the metastases were much more likely to be passengers.
authors.affiliation: Department of Genetics, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, United States of America.|Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, United States of America.
authors.forename: Katherine A
authors.initials: KA
authors.lastname: Hoadley
authors.affiliation: Department of Genetics, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, United States of America.|Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, United States of America.
authors.forename: Marni B
authors.initials: MB
authors.lastname: Siegel
authors.affiliation: McDonnell Genome Institute, Washington University in St. Louis, St. Louis, Missouri, United States of America.
authors.forename: Krishna L
authors.initials: KL
authors.lastname: Kanchi
authors.affiliation: McDonnell Genome Institute, Washington University in St. Louis, St. Louis, Missouri, United States of America.
authors.forename: Christopher A
authors.identifier: http://orcid.org/0000-0003-4266-6700
authors.initials: CA
authors.lastname: Miller
authors.affiliation: McDonnell Genome Institute, Washington University in St. Louis, St. Louis, Missouri, United States of America.
authors.forename: Li
authors.initials: L
authors.lastname: Ding
authors.affiliation: Department of Genetics, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, United States of America.|Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, United States of America.
authors.forename: Wei
authors.initials: W
authors.lastname: Zhao
authors.affiliation: Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, United States of America.
authors.forename: Xiaping
authors.initials: X
authors.lastname: He
authors.affiliation: Department of Genetics, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, United States of America.|Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, United States of America.
authors.forename: Joel S
authors.identifier: http://orcid.org/0000-0003-2080-6901
authors.initials: JS
authors.lastname: Parker
authors.affiliation: McDonnell Genome Institute, Washington University in St. Louis, St. Louis, Missouri, United States of America.|Department of Mathematics, Washington University in St. Louis, St. Louis, Missouri, United States of America.
authors.forename: Michael C
authors.identifier: http://orcid.org/0000-0002-5694-2668
authors.initials: MC
authors.lastname: Wendl
authors.affiliation: McDonnell Genome Institute, Washington University in St. Louis, St. Louis, Missouri, United States of America.
authors.forename: Robert S
authors.initials: RS
authors.lastname: Fulton
authors.affiliation: McDonnell Genome Institute, Washington University in St. Louis, St. Louis, Missouri, United States of America.
authors.forename: Ryan T
authors.initials: RT
authors.lastname: Demeter
authors.affiliation: McDonnell Genome Institute, Washington University in St. Louis, St. Louis, Missouri, United States of America.
authors.forename: Richard K
authors.identifier: http://orcid.org/0000-0002-1992-1358
authors.initials: RK
authors.lastname: Wilson
authors.affiliation: Division of Hematology-Oncology, Department of Medicine, School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, United States of America.
authors.forename: Lisa A
authors.initials: LA
authors.lastname: Carey
authors.affiliation: Department of Genetics, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, United States of America.|Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, United States of America.|Department of Pathology and Laboratory Medicine, School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, United States of America.
authors.forename: Charles M
authors.identifier: http://orcid.org/0000-0001-9827-2247
authors.initials: CM
authors.lastname: Perou
authors.affiliation: McDonnell Genome Institute, Washington University in St. Louis, St. Louis, Missouri, United States of America.
authors.forename: Elaine R
authors.initials: ER
authors.lastname: Mardis
mesh_terms: D000368:Aged; D001943:Breast Neoplasms / Q000235:genetics* / Q000556:secondary; D018450:Disease Progression; D005260:Female; D023281:Genomics; D006801:Humans; D008875:Middle Aged; D009154:Mutation; D018295:Neoplasms, Basal Cell / Q000235:genetics* / Q000556:secondary; D012189:Retrospective Studies