Box 1 | Familial endometrial cancer

From the following article:

Molecular mechanisms of oestrogen and SERMs in endometrial carcinogenesis

Yongfeng Shang

Nature Reviews Cancer 6, 360-368 (May 2006)


Even though most cases are sporadic, about 10% of endometrial carcinomas have a hereditary basis. Many of these cases are associated with hereditary non-polyposis colorectal cancer (HNPCC), a dominantly inherited syndrome with germline mutations in one of the DNA-mismatch repair (MMR) genes that can lead to microsatellite instability4. HNPCC is characterized by early development of cancer in the colon as well as in the endometrium, stomach, small intestine and ovary. Women with HNPCC have a tenfold higher lifetime risk of endometrial cancer compared with the general population, and that risk (42%) is even higher than that for colorectal carcinoma (30%)5. Hereditary endometrial cancer is more likely to occur at a younger age than the sporadic form. Also, it is characterized by a high stage and grade, cribriform growth pattern, mucinous differentiation and necrosis6.

MMR gene mutations are generally not found in sporadic type I endometrial carcinomas but, instead, MMR genes might be inactivated or silenced in some of these cancers by epigenetic mechanisms such as promoter hypermethylation149. The normal function of MMR genes and their association with endometrial cancer are illustrated below. DNA replication leads to occasional errors that are repaired by the MMR proteins MSH2 (mutS homologue 2), MSH3, MSH6, MLH1 (mutL homologue 1), PMS1 (postmeitoic segregation increased 1) and PMS2. Familial defects in the genes that encode these proteins leads to instability of various microsatellites, which can cause endometrial cancer.

Molecular mechanisms of oestrogen and SERMs in endometrial carcinogenesis