Single-cell genetic analysis of ductal carcinoma in situ and invasive breast cancer reveals enormous tumor heterogeneity yet conserved genomic imbalances and gain of MYC during progression.
Ductal carcinoma in situ (DCIS) is a precursor lesion of invasive ductal carcinoma (IDC) of the breast. To understand the dynamics of genomic alterations in this progression, we used four multicolor fluorescence in situ hybridization probe panels consisting of the oncogenes COX2, MYC, HER2, CCND1, and ZNF217 and the tumor suppressor genes DBC2, CDH1, and TP53 to visualize copy number changes in 13 cases of synchronous DCIS and IDC based on single-cell analyses. The DCIS had a lower degree of chromosomal instability than the IDC. Despite enormous intercellular heterogeneity in DCIS and IDC, we observed signal patterns consistent with a nonrandom distribution of genomic imbalances. CDH1 was most commonly lost, and gain of MYC emerged during progression from DCIS to IDC. Four of 13 DCISs showed identical clonal imbalances in the IDCs. Six cases revealed a switch, and in four of those, the IDC had acquired a gain of MYC. In one case, the major clone in the IDC was one of several clones in the DCIS, and in another case, the major clone in the DCIS became one of the two major clones in the IDC. Despite considerable chromosomal instability, in most cases the evolution from DCIS to IDC is determined by recurrent patterns of genomic imbalances, consistent with a biological continuum.
Genetics Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USA. heselmek@mail.nih.gov
Kerstin
K
Heselmeyer-Haddad
Lissa Y
LY
Berroa Garcia
Amanda
A
Bradley
Clarymar
C
Ortiz-Melendez
Woei-Jyh
WJ
Lee
Rebecca
R
Christensen
Sheila A
SA
Prindiville
Kathleen A
KA
Calzone
Peter W
PW
Soballe
Yue
Y
Hu
Salim A
SA
Chowdhury
Russell
R
Schwartz
Alejandro A
AA
Schäffer
Thomas
T
Ried
D000328:Adult; D000368:Aged; D014408:Biomarkers, Tumor / Q000235:genetics; D001943:Breast Neoplasms / Q000235:genetics* / Q000473:pathology; D018270:Carcinoma, Ductal, Breast / Q000235:genetics*; D002285:Carcinoma, Intraductal, Noninfiltrating / Q000235:genetics* / Q000473:pathology; D043171:Chromosomal Instability / Q000235:genetics*; D002999:Clone Cells; D018450:Disease Progression; D005260:Female; D052138:Genes, Neoplasm / Q000235:genetics; D018740:Genetic Heterogeneity; D015894:Genome, Human / Q000235:genetics; D006801:Humans; D017404:In Situ Hybridization, Fluorescence; D008875:Middle Aged; D009361:Neoplasm Invasiveness; D011003:Ploidies; D016271:Proto-Oncogene Proteins c-myc / Q000235:genetics*; D059010:Single-Cell Analysis / Q000379:methods*
D014408:Biomarkers, Tumor; D016271:Proto-Oncogene Proteins c-myc