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Study Establishes Basis for Genomic Classification of Endometrial Cancers

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Key Points

  • Approximately 25% of high-grade endometrioid tumors showed frequent mutations in TP53, as well as extensive copy number alterations—both of which are key molecular characteristics associated with serous tumors.
  • Researchers found genomic similarities between endometrial serous carcinoma and basal-like breast cancer, and endometrioid tumors and colorectal tumors.
  • The new findings may provide a roadmap for future clinical trials for endometrial cancer.

A comprehensive genomic analysis of nearly 400 endometrial tumors suggests that certain molecular characteristics, such as the frequency of mutations, could complement current pathology methods and help distinguish between principal types of endometrial tumors, as well as provide insights into potential treatment strategies.  In addition, the study, led by investigators in The Cancer Genome Atlas (TCGA) Research Network, revealed four novel tumor subtypes, while also identifying genomic similarities between endometrial and other types of cancers, including breast, ovarian, and colorectal cancers.

These findings represent the most comprehensive characterization of the molecular alterations in endometrial cancers available to date. They were published May 2, 2013, in the journal Nature.

Endometrial Cancers

Clinically, endometrial cancers fall into two categories: endometrioid (type I) and serous (type II) tumors. Type I is correlated with excess estrogen, obesity, and a favorable prognosis, and tumors are often treated with radiation therapy given in addition to or after primary treatment. Type II endometrial cancer is more common in older women and generally has a less favorable outcome; tumors are generally treated with chemotherapy.

Distinguishing between different types of endometrial cancers is currently based on histology, but categorizing endometrial cancer tissues is often difficult, and specialists frequently disagree on the classification of individual cases.

Study Details

In this study, investigators showed that approximately 25% of tumors that pathologists classified as high-grade endometrioid showed frequent mutations in TP53, a tumor suppressor gene, as well as extensive copy number alterations. Both are key molecular characteristics associated with serous tumors, along with a small number of DNA methylation changes. Most endometrioid tumors, by contrast, have few copy number alterations or mutations in TP53, though there are frequent mutations in other well known cancer-associated genes, including PTEN, another tumor suppressor gene, and KRAS, a gene involved in regulating cell division.

These data suggest that some high-grade endometrioid tumors have developed a strikingly similar pattern of alterations to serous tumors, and may benefit from a similar course of treatment.

Roadmap for Future Clinical Trials

“This study highlights the fact that some tumors with the same characterization by pathologists may have very different molecular features. That’s where these findings will be directly implemented in additional research, and also in the context of clinical trials,” said Douglas A. Levine, MD, Head of the Gynecology Research Laboratory at Memorial Sloan-Kettering Cancer Center, New York, and a co-leader in the study.

According to the authors, the new findings provide a roadmap for future clinical trials for endometrial cancer.  “Each tumor subtype might warrant dedicated clinical trials because of the marked genomic differences between them that are indicative of different drivers of cancer,” said study co-leader Elaine Mardis, PhD, Co-Director of the Genome Institute at Washington University School of Medicine, St. Louis.  “Developing therapies for each subtype independent of the other may improve outcomes, as has been shown in breast cancer.”

Other Genomic Similarities

Investigators also found genomic similarities between endometrial cancers and other tumor types.  Previous TCGA research showed that high-grade serous ovarian carcinoma and a basal-like breast cancer share many genomic features. In this study, the scientists found that endometrial serous carcinoma also has some of these same genomic characteristics. The cancers share a high frequency of mutations in TP53 (between 84% and 96%) and a low frequency in PTEN, with only 1% to 2% mutated. Surprisingly, the researchers also found many shared characteristics between endometrioid tumors and colorectal tumors. Both cancer types demonstrate a high frequency of microsatellite instability, where the repair mechanism for DNA is broken, and mutations in POLE, a gene responsible for producing a protein involved in DNA replication and repair. These genomic changes led to high mutation rates in both tumor types.

“Finding genomic similarities among types of breast, ovarian, endometrial and colorectal tumors once again reveals that cancer, although very complex, may have themes extending beyond tissue type that can be exploited for therapeutic benefit,” said Eric D. Green, MD, PhD, NHGRI Director. “These similar genomic features demonstrate hitherto unknown commonalities among these cancers.

The content in this post has not been reviewed by the American Society of Clinical Oncology, Inc. (ASCO®) and does not necessarily reflect the ideas and opinions of ASCO®.


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