A NEW GENOME-DRIVEN CLASSIFICATION OF ENDOMETRIAL CANCER

Endometrial Cancer: Two Types, Different Outcomes

Endometrial cancer (EC) is the seventh most commonly diagnosed cancer among women worldwide, with 189,000 new cases and 45,000 deaths each year. In the United States, it’s the fourth most commonly diagnosed cancer among women. According to the National Cancer Institute (NCI), approximately 50,000 women were diagnosed with endometrial cancer in 2013, with more than an estimated 8,000 deaths from the disease.

Endometrial cancers fall into two types: endometrioid (type I) and serous (type II). Type I EC is the less severe form. Risk factors include obesity, anovulation, nulliparity, and exogenous estrogen exposure. This type commonly expresses both estrogen and progesterone receptors, and is more often a low-grade tumor with a favorable prognosis.

Type II EC, on the other hand, is more life-threatening and isn’t associated with estrogen exposure. It follows an aggressive clinical course, with a tendency to spread early and a poor prognosis. Endometrioid (type I) tumors are treated with adjuvant radiotherapy, while serous (type II) tumors are treated with chemotherapy. Even though EC is one of the most common pelvic gynecologic malignancies worldwide, no targeted therapies are available to treat patients yet.

Why Genomic Classification Matters

To design an effective treatment plan, researchers need detailed genomic characterization of primary and metastatic endometrial cancers. Several studies have reported numerous genetic changes linked to endometrial cancer.

Known Genetic Drivers

Type I endometrial carcinomas involve mutations in PTEN, KRAS, FGFR2, PIK3CA, and β-catenin, along with defects in DNA mismatch repair. Type II endometrial carcinomas frequently show aneuploidy and mutations in TP53, PIK3CA, and PPP2R1A genes. Using whole exome DNA sequencing on 13 primary serous EC patients, a 2012 study by Bell and colleagues identified high-frequency somatic mutations in CHD4, FBXW7, and SPOP genes, which are associated with chromatin-remodeling and the ubiquitin ligase complex. These mutations may act as driver mutations — gene mutations implicated in cancer initiation and progression — in serous EC.

A New Genomic Classification from TCGA

To better understand the molecular changes behind endometrial cancer, The Cancer Genome Atlas Research Network (TCGA) ran a recent study using integrated genomic and proteomic analysis, published in Nature in May 2013.

Using a multiplatform analysis approach on 373 endometrial carcinomas — including low-grade endometrioid, high-grade endometrioid, and serous carcinomas — this study provided key molecular insight into classifying endometrial cancer. It sorted endometrial cancer into four new categories:

• The POLE group, with ultrahigh mutation rates in the POLE gene (involved in cellular metabolism) and frequent activation of the WNT/CTNNB1 signaling pathway.
• The hypermutated microsatellite instability group, with a high mutation rate, few copy number alterations, and reduced expression of the DNA mismatch repair gene MLH1.
• The copy-number low group, with increased expression of progesterone receptor and DNA repair protein RAD50.
• The copy-number high group, made up mostly of serous tumors and serous-like endometrioid tumors, with increased transcriptional activity of cell cycle-related genes (MYC, CCNE1, PIK3CA, CDKN2A, etc.) and a mutation in the tumor suppressor gene TP53.

What This Means for Treatment

The study also found compelling molecular similarities between 25% of high-grade endometrioid tumors and uterine serous carcinoma — suggesting that this genome-based classification could benefit these patients. Overall, this new molecular characterization may help researchers discover effective, targeted treatments, and could also influence post-surgical adjuvant treatment decisions for women with endometrial cancer.

References

Bansal N, Yendluri V, Wenham RM (2009) The molecular biology of endometrial cancers and the implications for pathogenesis, classification, and targeted therapies. Cancer Control 16: 8-13.

Hecht JL, Mutter GL (2006) Molecular and pathologic aspects of endometrial carcinogenesis. J Clin Oncol 24: 4783-4791.

Kandoth C, Schultz N, Cherniack AD, Akbani R, Liu Y, Shen H, Robertson AG, Pashtan I, Shen R, Benz CC, Yau C, Laird PW, Ding L, Zhang W, Mills GB, Kucherlapati R, Mardis ER, Levine DA, Network CGAR (2013) Integrated genomic characterization of endometrial carcinoma. Nature 497: 67-73.

Kuhn E, Wu RC, Guan B, Wu G, Zhang J, Wang Y, Song L, Yuan X, Wei L, Roden RB, Kuo KT, Nakayama K, Clarke B, Shaw P, Olvera N, Kurman RJ, Levine DA, Wang TL, Shih IM (2012) Identification of molecular pathway aberrations in uterine serous carcinoma by genome-wide analyses. J Natl Cancer Inst 104: 1503-1513.

Le Gallo M, O’Hara AJ, Rudd ML, Urick ME, Hansen NF, O’Neil NJ, Price JC, Zhang S, England BM, Godwin AK, Sgroi DC, Hieter P, Mullikin JC, Merino MJ, Bell DW, Program NISCNCS (2012) Exome sequencing of serous endometrial tumors identifies recurrent somatic mutations in chromatin-remodeling and ubiquitin ligase complex genes. Nat Genet 44: 1310-1315.