Study Sheds New Light on the Progression and Invasiveness of Ductal Breast Cancer
Results published in The American Journal of Pathology
Results published in The American Journal of Pathology
Philadelphia, PA, October 16, 2012 – Ductal carcinoma in situ (DCIS) is considered a precursor lesion for invasive breast cancer if untreated, and is found in approximately 45% of patients with invasive ductal carcinoma (IDC). Patients with DCIS only (not accompanied by invasive disease) have a 5-year-survival of nearly 100%, compared to 89% for all stages of invasive breast cancer (24% for patients with distant metastasis). A new study has found that despite an enormous degree of intercellular heterogeneity in both DCIS and IDC, the evolution from noninvasive to invasive disease is determined by recurrent patterns of genomic imbalances in most cases. This study is published online in advance of the November issue of The American Journal of Pathology.
“For patients with cancer, the transition from locally controlled disease to a disseminated stage and metastases is probably the most critical threshold, because that transition makes surgical intervention considerably less likely to succeed,” says lead investigator Thomas Ried, Section Chief, Genetics Branch, Center for Cancer Research, National Cancer Institute (NCI), National Institutes of Health (NIH), Bethesda, MD. “We looked at gene copy number changes during the transition from DCIS to IDC and, if so, what patterns of genetic imbalances drive this process.”
The study was based on archived clinical samples for which the co-occurrence of DCIS and IDC in the same patient had been tracked at the National Naval Medical Center. It was led by researchers from the NCI and also included researchers from the National Center for Biotechnology Information, the National Naval Medical Center, Bethesda, MD, and Carnegie Mellon University, Pittsburgh, PA.
Investigators compared the genetic makeup of individual cells from 13 patients with DCIS and IDC and analyzed the gain or loss of specific genes that are frequently affected in DCIS and IDC. These genes included cancer promoting oncogenes and cancer suppressing tumor suppressor genes. Fluorescence in situ hybridization (FISH) probe panels, which use fluorescent copies or clones of the relevant DNA sections to identify gene copy numbers, were hybridized to intact cells prepared from histomorphologically identified areas from lesions from several patients. Subsequent hybridizations of multicolor probe panels resulted in multiplexing of probes that further allowed for simultaneous analysis of copy numbers of five oncogenes and three tumor suppressor genes within each cell analyzed.
A high degree of chromosomal instability from one cell to another was observed, reflected by the fact that identical signal clones were only present in less than 20% of the cells. Despite this instability, the distribution of gains and losses in most cases was consistent with known genetic aberration profiles for breast cancer, and investigators found patterns consistent with non-random distribution of genomic imbalances. CDH1, a tumor suppressor that triggers cancer invasion and metastases upon reduced expression, was most commonly lost in DCIS and IDC. MYC, a strong oncogene that drives cell proliferation and regulates cell growth and differentiation, was most frequently gained from DCIS to IDC. MYC appears to play a major role in the transition from “in situ” to invasive breast disease.
“DCIS and IDCs are genetically related lesions as they both have similar imbalance patterns. However, according to their aberration patterns, the DCIS lesions are far further advanced than other precursor lesions with more stable genomes, such as colorectal polyps or cervical dysplasias,” notes Dr. Ried. “The considerable degree of intercellular heterogeneity in the DCIS convincingly attests to the fact that chromosomal instability precedes the transition to invasive disease.”
Dr. Ried observes that the advanced aberration profiles of DCIS associated with IDC make it unlikely that progression to invasive disease can be prevented with measures other than surgery, radiation, and adjuvant hormonal therapy.
“This of course raises the question of what precisely determines this critical transition between pre-invasive and invasive disease. Identifying the differences in the full catalog of genes in DCIS and IDC could have the potential of identifying a gene expression signature that is ultimately responsible for invasion and progression,” he concludes.
# # #
Notes for editors
“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,” by Kerstin Heselmeyer-Haddad, Lissa Y. Berroa Garcia, Amanda Bradley, et al. DOI: http://dx.doi.org/10.1016/j.ajpath.2012.07.012. It appears in The American Journal of Pathology, Volume 181, Issue 5 (November 2012) published by Elsevier.
Full text of the article is available to credentialed journalists upon request; contact David Sampson at +1-215-239-3171 o firstname.lastname@example.org. Journalists wishing to interview the authors may contact the NCI Press Officers at +1-301-496-6641, +1-301-451-7440 (fax) or email@example.com.
About The American Journal of Pathology
The American Journal of Pathology (http://ajp.amjpathol.org), official journal of the American Society for Investigative Pathology, seeks to publish high-quality, original papers on the cellular and molecular biology of disease. The editors accept manuscripts that advance basic and translational knowledge of the pathogenesis, classification, diagnosis, and mechanisms of disease, without preference for a specific analytic method. High priority is given to studies on human disease and relevant experimental models using cellular, molecular, animal, biological, chemical, and immunological approaches in conjunction with morphology.
The leading global forum for reporting quality original research on cellular and molecular mechanisms of disease, The American Journal of Pathology is the most highly cited journal in Pathology – over 38,000 cites in 2011 – with an Impact Factor of 4.890 according to 2011 Journal Citation Reports®, Thomson Reuters.
Elsevier is a world-leading provider of scientific, technical and medical information products and services. The company works in partnership with the global science and health communities to publish more than 2,000 journals, including The Lancet and Cell, and close to 20,000 book titles, including major reference works from Mosby and Saunders. Elsevier’s online solutions include ScienceDirect, Scopus , Reaxys, ClinicalKey and Mosby’s Nursing Suite, which enhance the productivity of science and health professionals, and the SciVal suite and MEDai’s Pinpoint Review, which help research and health care institutions deliver better outcomes more cost-effectively.
A global business headquartered in Amsterdam, Elsevier employs 7,000 people worldwide. The company is part of Reed Elsevier Group PLC, a world-leading publisher and information provider, which is jointly owned by Reed Elsevier PLC and Reed Elsevier NV. The ticker symbols are REN (Euronext Amsterdam), REL (London Stock Exchange), RUK and ENL (New York Stock Exchange).
Elsevier is a global information analytics company that helps institutions and professionals progress science, advance healthcare and improve performance for the benefit of humanity. Elsevier provides digital solutions and tools in the areas of strategic research management, R&D performance, clinical decision support, and professional education; including ScienceDirect, Scopus, ClinicalKey and Sherpath. Elsevier publishes over 2,500 digitized journals, including The Lancet and Cell, more than 35,000 e-book titles and many iconic reference works, including Gray's Anatomy. Elsevier is part of RELX Group, a global provider of information and analytics for professionals and business customers across industries. www.elsevier.com