A NEW GENOME-DRIVEN CLASSIFICATION OF ENDOMETRIAL CANCER

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

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

On the contrary, type II EC is a more life-threatening form and not associated with estrogen exposure. Clinically, this type of EC is marked by an aggressive clinical course, and has a tendency for early spread and poor prognosis. Endometroid (type I) tumors are treated with adjuvant radiotherapy, whereas serous (type II) tumors are treated with chemotherapy. Even though EC is one of the most common pelvic gynecologic malignancies in the world, to date no targeted therapies are available to treat patients.

Therefore, in order to formulate an efficient treatment plan, detailed genomic characterization of primary and metastatic endometrial cancers are required. Several studies have reported numerous genetic changes associated with endometrial cancer. Type I endometrial carcinomas involve mutations in PTEN, KRAS, FGFR2, PIK3CA and β-catenin, as well as defects in DNA mismatch repair. Type II endometrial carcinomas frequently show aneuploidy and TP53, PIK3CA, and PPP2R1A gene mutations. Using whole exome DNA sequencing on 13 primary serous EC patients, a study by Bell and colleagues (2012) identified high frequency somatic mutations in CHD4, FBXW7, and SPOP genes (associated with chromatin-remodeling and ubiquitin ligase complex). These mutations may play a significant role as driver mutations (gene mutations implicated in cancer initiation and progression) in serous EC.

To better understand the molecular alterations associated with endometrial cancer, a recent study was performed by The Cancer Genome Atlas Research Network (TCGA) using integrated genomic and proteomic analysis appearing in a recent issue of Nature journal (May 2nd, 2013).

Using a multiplatform analysis approach on 373 endometrial carcinomas including low-grade endometroid, high-grade endometroid, and serous carcinomas this study provided key molecular insight into the classification of endometrial cancer. This new study classified endometrial cancer into four new categories:

* The POLE group contained 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 showed a high mutation rate, as well as few copy number alterations, and reduced expression of DNA mismatch repair gene MLH1

* The copy-number low group showed increased expression of progesterone receptor and DNA repair protein RAD50

* The copy-number high group composed of mostly serous tumors and serous-like endometroid tumors and exhibited increased transcriptional activity of cell cycle related genes (MYC, CCNE1, PIK3CA, CDKN2A etc.) and a mutation in tumor suppressor gene TP53.

In addition, this study also observed compelling similarities in the molecular phenotype between 25% of high-grade endometroid tumors and uterine serous carcinoma, suggesting that this genome-based molecular characterization may benefit these patients. Overall, this new molecular characterization might facilitate the discovery of effective, targeted treatments as well as may affect post-surgical adjuvant treatment 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.

About Arup Chakraborty

Arup Chakraborty is postdoctoral research fellow at the National Cancer Institute, Bethesda, MD. He earned a doctoral degree from Texas Tech University, and his primary research interest is in the field of clinical cancer mainly in mechanisms of resistance to molecularly targeted therapies