New study sheds new light on the progression and invasiveness of ductal breast cancer

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 , 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, (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 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 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 , 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 . 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.

Explore further: How early breast tumors become deadly: A small group of molecules might hold the answer

More information: "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. dx.doi.org/10.1016/j.ajpath.2012.07.012 . It appears in The American Journal of Pathology, Volume 181, Issue 5 (November 2012)

Related Stories

How early breast tumors become deadly: A small group of molecules might hold the answer

February 7, 2012
Researchers have discovered a restricted pattern of molecules that differentiate early-stage breast tumors from invasive, life-threatening cancer. They also found a similar molecular signature that correlated with the aggressiveness ...

New test predicts risk for recurrence for patients with DCIS

December 7, 2011
In a significant advance for patients with ductal carcinoma in situ, researchers have developed and prospectively validated a multigene test to identify the risk for recurrence of breast cancer.

Digital mammography improves population-based breast cancer screening

October 2, 2012
New research from the Netherlands shows that the switch from screen film mammography (SFM) to digital mammography (DM) in large, population-based breast cancer screening programs improves the detection of life-threatening ...

Recommended for you

Shooting the achilles heel of nervous system cancers

July 20, 2017
Virtually all cancer treatments used today also damage normal cells, causing the toxic side effects associated with cancer treatment. A cooperative research team led by researchers at Dartmouth's Norris Cotton Cancer Center ...

Molecular changes with age in normal breast tissue are linked to cancer-related changes

July 20, 2017
Several known factors are associated with a higher risk of breast cancer including increasing age, being overweight after menopause, alcohol intake, and family history. However, the underlying biologic mechanisms through ...

Immune-cell numbers predict response to combination immunotherapy in melanoma

July 20, 2017
Whether a melanoma patient will better respond to a single immunotherapy drug or two in combination depends on the abundance of certain white blood cells within their tumors, according to a new study conducted by UC San Francisco ...

Discovery could lead to better results for patients undergoing radiation

July 19, 2017
More than half of cancer patients undergo radiotherapy, in which high doses of radiation are aimed at diseased tissue to kill cancer cells. But due to a phenomenon known as radiation-induced bystander effect (RIBE), in which ...

Definitive genomic study reveals alterations driving most medulloblastoma brain tumors

July 19, 2017
The most comprehensive analysis yet of medulloblastoma has identified genomic changes responsible for more than 75 percent of the brain tumors, including two new suspected cancer genes that were found exclusively in the least ...

Novel CRISPR-Cas9 screening enables discovery of new targets to aid cancer immunotherapy

July 19, 2017
A novel screening method developed by a team at Dana-Farber/Boston Children's Cancer and Blood Disorders Center—using CRISPR-Cas9 genome editing technology to test the function of thousands of tumor genes in mice—has ...

0 comments

Please sign in to add a comment. Registration is free, and takes less than a minute. Read more

Click here to reset your password.
Sign in to get notified via email when new comments are made.