SNOMEDCT: 254878006; DO: 1380;
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
Gene/Locus |
Gene/Locus MIM number |
|---|---|---|---|---|---|---|
| 2p16.3 | {Endometrial cancer, familial} | 608089 | Autosomal dominant; Somatic mutation | 3 | MSH6 | 600678 |
| 5q14.1 | Endometrial carcinoma, somatic | 608089 | 3 | MSH3 | 600887 | |
| 14q24.3 | {Endometrial cancer, susceptibility to} | 608089 | Autosomal dominant; Somatic mutation | 3 | MLH3 | 604395 |
| 16q22.1 | Endometrial carcinoma, somatic | 608089 | 3 | CDH1 | 192090 |
A number sign (#) is used with this entry because of evidence that mutations in various genes are responsible for susceptibility to endometrial cancer.
Approximately 20% of endometrial cancers demonstrate microsatellite instability (MSI) (Simpkins et al., 1999), a reflection of mutations in mismatch repair genes. The mismatch repair genes that have been identified as having a role in endometrial cancer include MSH2 (609309), MSH3 (600887), MSH6 (600678), MLH1 (120436), and MLH3 (604395).
In some families, endometrial cancer is associated with colorectal cancer in the same individual or individuals with hereditary nonpolyposis colorectal cancer type 1 (HNPCC1) or HNPCC2, also known as Lynch syndrome (120435). 'Lynch syndrome II' refers to extracolonic cancers, including endometrial cancers.
Mutation in the PTEN1 gene (601728) and somatic mutations in the CDH1 (192090) and FGFR2 (176943) genes have also been demonstrated in endometrial cancers.
Liu et al. (2003) found an association between the common 16189T-C transition within the D loop region of the mitochondrial chromosome and endometrial cancer; the mutation had previously been found to be associated with type II diabetes (125853) (Poulton et al., 1998) and dilated cardiomyopathy (Khogali et al., 2001).
Barnetson et al. (2007) reported a patient with endometrial adenocarcinoma and sebaceous carcinoma of the face who was compound heterozygous for 2 common mutations in the MUTYH gene (Y165C; 604933.0001 and G382D; 604933.0002). Colonic adenomas were not reported, but a paternal aunt reportedly had colorectal cancer in her thirties. Barnetson et al. (2007) noted that the phenotype associated with biallelic MUTYH mutations may include extracolonic manifestations, including endometrial cancer and sebaceous carcinoma, as seen in other inherited colorectal cancer syndromes such as Muir-Torre syndrome (158320) and Lynch syndrome (120435).
Pollock et al. (2007) identified 11 different somatic FGFR2 mutations (see, e.g., 176943.0010 and 176943.0015) in 3 (30%) of 10 endometrial cancer cell lines and in 19 (10%) of 187 primary endometrial carcinomas. The majority of the mutations were identical to germline activating mutations that cause skeletal dysplasias. There was no apparent correlation between FGFR2 mutation and overall survival.
Dutt et al. (2008) found somatic FGFR2 mutations in 15 (12.3%) of 122 primary endometrial carcinomas, as well as in 2 of 42 lung squamous cell carcinomas and in 2 of 46 cervical carcinomas. Many of the mutations were identical to those associated with congenital craniofacial developmental disorders. Ectopic expression of the mutations in mouse fibroblasts demonstrated constitutive activation and oncogenicity, and inhibition of FGFR2 kinase activity in endometrial cell lines bearing such FGFR2 mutations inhibited transformation and survival.
Le Gallo et al. (2012) used whole-exome sequencing to comprehensively search for somatic mutations in 13 primary serous endometrial tumors, and subsequently resequenced 18 genes that were mutated in more than 1 tumor and/or were components of an enriched functional grouping from 40 additional serous tumors. Le Gallo et al. (2012) identified high frequencies of somatic mutations in CHD4 (603277) (17%), EP300 (602700) (8%), ARID1A (603024) (6%), TSPYL2 (300564) (6%), FBXW7 (606278) (29%), SPOP (602650) (8%), MAP3K4 (602425) (6%), and ABCC9 (601439) (6%). Overall, 36.5% of serous tumors had a mutated chromatin-remodeling gene, and 35% had a mutated ubiquitin ligase complex gene, implicating frequent mutational disruption of these processes in the molecular pathogenesis of one of the deadliest forms of endometrial cancer.
The Cancer Genome Atlas Research Network (2013) performed an integrated genomic, transcriptomic, and proteomic characterization of 373 endometrial carcinomas using array- and sequencing-based technologies. Uterine serous tumors and approximately 25% of high-grade endometrioid tumors had extensive copy number alterations, few DNA methylation changes, low estrogen receptor (see 133430)/progesterone receptor (607311) levels, and frequent TP53 (191170) mutations. Most endometrioid tumors had few copy number alterations or TP53 mutations, but frequent mutations in PTEN (601728), CTNNB1 (116806), PIK3CA (171834), ARID1A, and KRAS (190070) and novel mutations in the SWI/SNF chromatin remodeling complex gene ARID5B (608538). A subset of endometrioid tumors had a markedly increased transversion mutation frequency and hotspot mutations in POLE (174762). The Cancer Genome Atlas Research Network (2013) concluded that their results classified endometrial cancers into 4 categories: POLE ultramutated, microsatellite instability hypermutated, copy number-low, and copy number-high. Uterine serous carcinomas share genomic features with ovarian serous and basal-like breast carcinomas. The Cancer Genome Atlas Research Network (2013) demonstrated that the genomic features of endometrial carcinomas permit a reclassification that may affect postsurgical adjuvant treatment for women with aggressive tumors.
Moore et al. (2020) used whole-genome sequencing to show that normal human endometrial cells are clonal cell populations with total mutation burdens that increase at about 29 base substitutions per year and that are many-fold lower than those of endometrial cancers. Normal endometrial glands frequently carry driver mutations in cancer genes, the burden of which increases with age and decreases with parity. Cell clones with drivers often originate during the first decades of life and subsequently progressively colonize the epithelial lining of the endometrium. Moore et al. (2020) concluded that their results showed that mutational landscapes differ markedly between normal tissues, perhaps shaped by differences in their structure and physiology, and indicated that the procession of neoplastic change that leads to endometrial cancer is initiated early in life.
Barnetson, R. A., Devlin, L., Miller, J., Farrington, S. M., Slater, S., Drake, A. C., Campbell, H., Dunlop, M. G., Porteous, M. E. Germline mutation prevalence in the base excision repair gene, MYH, in patients with endometrial cancer. Clin. Genet. 72: 551-555, 2007. [PubMed: 17956577] [Full Text: https://doi.org/10.1111/j.1399-0004.2007.00900.x]
Cancer Genome Atlas Research Network. Integrated genomic characterization of endometrial carcinoma. Nature 497: 67-73, 2013. Note: Erratum: Nature 500: 242 only, 2013. [PubMed: 23636398] [Full Text: https://doi.org/10.1038/nature12113]
Dutt, A., Salvesen, H. B., Chen, T.-H., Ramos, A. H., Onofrio, R. C., Hatton, C., Nicoletti, R., Winckler, W., Grewal, R., Hanna, M., Wyhs, N., Ziaugra, L., and 13 others. Drug-sensitive FGFR2 mutations in endometrial carcinoma. Proc. Nat. Acad. Sci. 105: 8713-8717, 2008. [PubMed: 18552176] [Full Text: https://doi.org/10.1073/pnas.0803379105]
Khogali, S. S., Mayosi, B. M., Beattie, J. M., McKenna, W. J., Watkins, H., Poulton, J. A common mitochondrial DNA variant associated with susceptibility to dilated cardiomyopathy in two different populations. Lancet 357: 1265-1267, 2001. [PubMed: 11418155] [Full Text: https://doi.org/10.1016/S0140-6736(00)04422-6]
Le Gallo, M., O'Hara, A. J., Rudd, M. L., Urick, M. E., Hansen, N. F., O'Neil, N. J., Price, J. C., Zhang, S., England, B. M., Godwin, A. K., Sgroi, D. C., NIH Intramural Sequencing Center (NISC) Comparative Sequencing Program, Hieter, P., Mullikan, J. C., Merino, M. J., Bell, D. W. Exome sequencing of serous endometrial tumors identifies recurrent somatic mutations in chromatin-remodeling and ubiquitin ligase complex genes. Nature Genet. 44: 1310-1315, 2012. [PubMed: 23104009] [Full Text: https://doi.org/10.1038/ng.2455]
Liu, V. W. S., Wang, Y., Yang, H.-J., Tsang, P. C. K., Ng, T.-Y., Wong, L.-C., Nagley, P., Ngan, H. Y. S. Mitochondrial DNA variant 16189T-to-C is associated with susceptibility to endometrial cancer. (Letter) Hum. Mutat. 22: 173-174, 2003. [PubMed: 12872259] [Full Text: https://doi.org/10.1002/humu.10244]
Moore, L., Leongamornlert, D., Coorens, T. H. H., Sanders, M. A., Ellis, P., Dentro, S. C., Dawson, K. J., Butler, T., Rahbari, R., Mitchell, T. J., Maura, F., Nangalia, J., and 13 others. The mutational landscape of normal human endometrial epithelium. Nature 580: 640-646, 2020. [PubMed: 32350471] [Full Text: https://doi.org/10.1038/s41586-020-2214-z]
Pollock, P. M., Gartside, M. G., Dejeza, L. C., Powell, M. A., Mallon, M. A., Cancer Genome Project, Davies, H., Mohammadi, M., Futreal, P. A., Stratton, M. R., Trent, J. M., Goodfellow, P. J. Frequent activating FGFR2 mutations in endometrial carcinomas parallel germline mutations associated with craniosynostosis and skeletal dysplasia syndromes. Oncogene 26: 7158-7162, 2007. [PubMed: 17525745] [Full Text: https://doi.org/10.1038/sj.onc.1210529]
Poulton, J., Scott-Brown, M., Cooper, A., Marchington, D. R., Phillips, D. I. W. A common mitochondrial DNA variant is associated with insulin resistance in adult life. Diabetologia 41: 54-58, 1998. [PubMed: 9498630] [Full Text: https://doi.org/10.1007/s001250050866]
Simpkins, S. B., Bocker, T., Swisher, E. M., Mutch, D. G., Gersell, D. J., Kovatich, A. J., Palazzo, J. P., Fishel, R., Goodfellow, P. J. MLH1 promoter methylation and gene silencing is the primary cause of microsatellite instability in sporadic endometrial cancers. Hum. Molec. Genet. 8: 661-666, 1999. [PubMed: 10072435] [Full Text: https://doi.org/10.1093/hmg/8.4.661]