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

• Published in: The American journal of pathology Vol. 181; no. 5; pp. 1807 - 1822
• Main Authors: Heselmeyer-Haddad, Kerstin, Berroa Garcia, Lissa Y, Bradley, Amanda, Ortiz-Melendez, Clarymar, Lee, Woei-Jyh, Christensen, Rebecca, Prindiville, Sheila A, Calzone, Kathleen A, Soballe, Peter W, Hu, Yue, Chowdhury, Salim A, Schwartz, Russell, Schäffer, Alejandro A, Ried, Thomas
• Format: Journal Article
• Language: English
• Published: Bethesda, MD Elsevier Inc 01.11.2012; American Society for Investigative Pathology
• Subjects: Adult; Aged; Biological and medical sciences; Biomarkers, Tumor - genetics; Breast Neoplasms - genetics; Breast Neoplasms - pathology; Carcinoma, Ductal, Breast - genetics; Carcinoma, Intraductal, Noninfiltrating - genetics; Carcinoma, Intraductal, Noninfiltrating - pathology; Chromosomal Instability - genetics; Clone Cells; Disease Progression; Female; Genes, Neoplasm - genetics; Genetic Heterogeneity; Genome, Human - genetics; Gynecology. Andrology. Obstetrics; Humans; In Situ Hybridization, Fluorescence; Investigative techniques, diagnostic techniques (general aspects); Mammary gland diseases; Medical sciences; Middle Aged; Neoplasm Invasiveness; Pathology; Pathology. Cytology. Biochemistry. Spectrometry. Miscellaneous investigative techniques; Ploidies; Proto-Oncogene Proteins c-myc - genetics; Regular; Single-Cell Analysis - methods; Tumors; Ductal carcinoma; Breast disease; Carcinoma in situ; Genomics; Breast tumor; Breast cancer; Malignant tumor; Mammary gland diseases; Heterogeneity; Anatomic pathology; C-Onc gene; Isolated cell; myc Gene; Genetics; Invasive cancer; Genome; Protooncogene; Cancer
• ISSN: 0002-9440; 1525-2191
• DOI: 10.1016/j.ajpath.2012.07.012

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.