Scientists identify genetic subtypes of endometrial cancer, a step forward toward individualized treatments
Los Angeles - MAY 1, 2013 – A collaborative, multicenter team of researchers has discovered that endometrial cancer is more complex than previously thought with at least four distinct molecular subtypes. This finding represents an important step forward toward individualized treatments and will allow scientists and physicians to more accurately classify tumor subtypes to direct and improve therapeutic responses.
The study, published in the May 2 print edition of Nature, gathered data from 373 endometrial carcinoma patients across the U.S. as part of The Cancer Genome Atlas (TCGA) project. By utilizing sophisticated molecular analytic techniques, researchers developed a comprehensive strategy to compare and identify the genomic makeup of the patients’ tumors, including DNA structures and copy number alterations, which uniquely classify each patient.
"The Cancer Genome Atlas analyses allow us to better understand the molecular distinctions and similarities between different cancers and now include endometrial cancer along with ovarian, breast, lung and other cancers. Collaborative efforts like TCGA will ultimately allow us to provide more precise treatments that are based on the intrinsic molecular characteristics of the individual cancer, rather than just on its site of origin," said Beth Y. Karlan, MD, director of the Women's Cancer Program at the Cedars-Sinai Samuel Oschin Comprehensive Cancer Institute and director of the Division of Gynecologic Oncology in the Department of Obstetrics and Gynecology. Karlan, the Cedars-Sinai Board of Governors Chair in Gynecologic Oncology, is one of the researchers who participated in the nationwide study.
Endometrial cancer occurs in the lining of the uterus and is the most common pelvic malignancy among women in the U.S., accounting for nearly 50,000 diagnosed cases in 2013. Often referred to as uterine cancer, the disease typically is more common in women who have been through menopause, but also is seen in younger women as well. While mortality statistics for other cancers have improved over the past decade, the death rates for uterine cancer have continued to increase.
The Cedars-Sinai Women’s Cancer Program, led by Karlan, is participating in the TCGA effort to look at various molecular subtypes of endometrial cancer compared with other cancers such as those of the colon and ovary. This work is beginning to identify genetic changes that reveal key information about an individual cancer diagnosis, such as the ability to distinguish early-stage from late-stage tumors, and patterns of genomic changes connected to tumor recurrence.
"The integrated genomic analyses of these endometrial cancers provide insight into disease biology and diagnostic classifications that could have immediate therapeutic applications," said Steven Piantadosi, MD, PhD, director of the Cedars-Sinai Samuel Oschin Comprehensive Cancer Institute and the Phase One Foundation Chair. "Not only does this study hold promise for the diagnostic process, but it may distinguish how a woman would respond to a particular therapy or treatment and her long-term survival potential."
Using sophisticated analytic techniques, such as sequencing of DNA, RNA and proteins in tumor samples, researchers discovered what they call an "ultra-mutated" subtype in 10 percent of tumors that appears to be related to problems with DNA replication and repair. As cells constantly undergo threat from DNA damaging agents, like tobacco smoke and radiation, DNA repair enzymes monitor chromosomes for damage and mutation. The absence of a cell’s ability to instigate DNA repair may lead to cancer. Researchers also believe copy number alterations, alterations that result in cells having an abnormal number of copies of one or more DNA sections, offer important clues to the origins and development of cancer and potential therapeutic targets.
Marc Troup Goodman, PhD, MPH, director of Cancer Prevention and Genetics at the Samuel Oschin Comprehensive Cancer Institute, also participated in the study. Goodman, an expert on the links between diet, metabolism, genetics and cancer, said the study indicated that some therapies worked better than others on some types of endometrial cancer.
"Women with endometrial tumors and extensive copy number alterations had significantly poorer survival rates compared to women with fewer of these cellular defects, suggesting that genomic-based classification may lead to improved management of these patients," Goodman said. "For patients with copy number altered endometrial cancer, radiation therapy may not be the best treatment. Clinicians should consider treating copy number altered endometrioid patients with chemotherapy, rather than adjuvant radiotherapy."
The Cancer Genome Atlas (TCGA) is a comprehensive organization aimed at accelerating the understanding of the molecular basis of cancer through an application of genome analysis technologies, including large-scale genome sequencing. This multi-institutional study is funded in large part by the National Institutes of Health (NIH) and the National Genome Research Institute. Both Karlan and Goodman serve on the Steering Committee of the Endometrial Cancer Genome Atlas.
Citation: Nature, "Integrated Genomic Characterization of Endometrial Carcinoma," May 1, 2013 (online) and May 2, 2013 (print).
National Institutes of Health (NIH) grants include: 5U24CA14799-04, 5U24CA14835-04, 5U24CA14840-04, 5U24CA142843-04, 5U24CA143845-04, 5U24CA143848-04, 5U24CA143858-04, 5U24CA14866-04, 5U24CA143867-04, 5U24CA143882-04, 5U24CA143883-04, 5U24CA144025-04, U54HG003067, U54HG003079 and U54HG003273.