Endometrial Cancer and Inheritance
Please use for reference only.
Paul C. Liu, JD, MD and Allan J. Jacobs, MD
Beth Israel Medical Center, New York, New York
Last Modified: November 1, 2001
In 1996, endometrial carcinoma is the most common gynecological cancer and the fourth most frequently diagnosed cancer among American women. In 1991, approximately 33,000 new cases were diagnosed and some 5,500 deaths occurred (1). It is well established that prolonged exposure to unopposed estrogen; obesity; diabetes mellitus; and hypertension are risk factors in the development of endometrial cancer (2-5).
In addition to the traditional risk factors identified above, as early as 1966, Henry Lynch suggested that inheritance of certain genetic factors may also be a risk factor for the development of endometrial cancer (6). Lynch and his colleagues reviewed the charts of 154 patients with histologically documented endometrial cancer who were seen at Creighton University of Nebraska Hospital over a 20-year period. It was noted that 20 of 154 (13%) patients had one or more first degree relatives with endometrial cancer. In one family, three sisters had histologically confirmed endometrial cancer and in two families, a mother and daughter had endometrial cancer. In a separate study, Lynch et al. (7) examined the pedigree of two "cancer families" and noted that in one family of 147 members, there were 43 carcinoma of many different sites including the colon, endometrium and ovary. From this observation, Lynch postulated that development of some cancers may be more likely as a result of inheritance of certain genetic factors. In this manner, Lynch Type II familial cancer syndrome became described. Presently, this syndrome is also known as hereditary nonpolyposis colorectal cancer (HNPCC).
It is unclear if there is a group of endometrial cancer patients who develop endometrial carcinoma as a result of genetic predisposition (inheritance of mutated genes). At this point it seems unlikely that site-specific inherited form of endometrial cancer exists. Instead, it appears that endometrial cancers associated with a genetic prediposition are a component of the HNPCC syndrome. Molecular studies have identified four genes which, when mutated, contribute to development of HNPCC (8-10). However, it is not entirely clear whether there is an inheritable genetic mutation that increases the risk of an individual for the development of endometrial cancer only, separate and distinct from the HNPCC pattern.
In 1992, Sandles et al. (11) performed pedigree analysis of 64 probands with endometrial cancer. The results showed that there were 4 families in which endometrial carcinoma was diagnosed in at least one first degree relative (mother, daughter, sister) of the proband, and none of whom had either colon or ovarian cancer. There were 4 other families in which first degree relatives of the proband had multiple carcinomas of the endometrium, colon, and ovary. From this data, Sandles concluded that there are at least two forms of inheritable endometrial cancer. The first form is an inheritable pattern as described by Lynch Type II familial cancer syndrome or HNPCC and the second form is an inheritable site-specific endometrial cancer, separate and distinct from Lynch II syndrome. Boltenberg et al. (12) in a pedigree analysis of 51 probands with endometrial cancer noted a similar pattern supporting the hypothesis that at least two genetic models may play a role in the development of endometrial cancer: The cancer family syndrome and a separate mutation leading to predisposition of endometrial cancer alone.
It is generally recognized that there are at least two major variants of endometrial cancer; one that tends to be estrogen dependent and one that is estrogen independent. The tumors that are associated with estrogen use usually demonstrate favorable characteristics, including lower grade tumors, earlier stage at diagnosis and fewer instances of myometrial invasion. Although the numbers were small, both Sandles and Boltenberg noted that the endometrial cancer occurring in families tended to be of poorer grade and more anaplastic, the so called "high risk" endometrial cancers, leading to decreased survival. In contrast, others have noted that familial endometrial cancer tended to occur in a younger population and with a more favorable prognosis (13, 14).
Development of cancer is a multi-step process. This has been supported by experimental, clinical and epidemiological observations. In 1971, Knudson in a seminal paper (15) proposed the "two mutation hypothesis". He postulated that retinoblastoma results from an inherited mutation and an acquired mutation, usually from exposure to environmental factors. This cumulative, two mutation hypothesis has become the basis of many subsequent genetic analysis models. From this conceptual framework, it has become apparent that certain individuals are in fact at increased risk of developing cancer by the virtue of already having inherited a mutation from the germ cell line such as the BRCA 1 mutation in breast cancer.
Based on the available data at the present, family history of endometrial cancer in a first degree relative may increase the risk of that individual in the development of endometrial cancer. While it had been postulated that there may be a mutation which is responsible for site-specific endometrial cancer, it is likely that a genetic disposition for the development of endometrial cancer stems from mutations associated with the HNPCC syndrome.
3. Silverberg, S.G., Mullen, D., Faraci, J. et al. Endometrial Carcinoma: Clinical-Pathologic comparison of cases in postmenopausal women receiving and not receiving exogenous estrogen. Cancer 45 : 3018, 1980.
10. Liu, B., Nicolaides, N.C., Markowitz, S., Wilson, J.K.V., Parsons, R.E., Jen, J., Papadopoulos, N., Peltomaki, P., de la Chapelle, A., Hamilton, S.R., Kinzler, K.W., and Vogelstein, B. Mismatch repair gene defects in sporadic colorectal cancers with microsatellite instability. Nat. Genet., 9 : 48-55, 1995.
11. Sandles, L.G., Shulman, L.P., Elias, S., Photopolus, G. J., Smiley, L.M., Posten, W.M., and Simpson, J.L. Endometrial Adenocarcinoma : Genetic Analysis Suggesting Heritable Site-Specific Uterine Cancer, Gynecol Oncol 47, 167-171 (1992).
14. Vasen, H.F.A., Watson, P., Mecklin, J.P., Jass, J.R., Green, J.S., Nomizu, T., Muller, H., Lynch, H.T. Epidemiology of endometrial cancer in hereditary nonpolyposis colorectal cancer Anticancer Res 14 : 1675-1678 (1994).