One of the earliest studies of hereditary EC (77-78) involved 154 consecutive patients, all of whom were histologically confirmed. They were seen over a 20-year period (1946-1965). Obesity was the most frequently occurring constitutional factor in this series of patients with EC, being present in 123 (80%) of the 154 patients. Obesity was extreme in many of the patients, with several weighing more than 300 pounds and two of those weighing more than 400 pounds. Hypertension was present in 65% and diabetes mellitus was present in 43% of these patients.

Twenty-six patients (16%) had first-degree relatives with EC. The finding of 16% of the probands whose first-degree relatives had EC is conservative. Rigorous documentation, either through personal examination of tissues or evaluation of pathology reports, or highly reliable information from physicians were the criteria, which are required for family members to be included with a diagnosis of EC. In one of the families, three sisters had EC histologically confirmed. Two of the families had a mother and daughter with histologically confirmed EC. In two of the families, sisters had histologically confirmed EC. The average age of EC in multicase families was 50 years, contrasted with an average age of 63 years in probands of the EC series overall.

Multiple primary cancers were found in 17 patients (11%), and five of these individuals had three primary malignant neoplasms. When one of the cancers was EC, carcinoma of the colon was the most frequently associated extra-EC primary malignant neoplasm. This finding was in striking contrast to the probands of the overall EC series in which no patients with multiple primary cancers had carcinoma of the colon as their associated extra-EC primary malignancy.

Previous studies of EC had been primarily concerned with selective evaluation of patients for the related incidences of obesity, diabetes mellitus, endometrial hyperpla-sia, hypertension, cardiovascular disease, parity, and other constitutional associations (79,80) as well as a study of hereditary factors (14,81,82). The 11% incidence of multiple primary malignancies in the series was not significantly different from that of Moertel and associates (83) who found an incidence of 9.9% of multiple primary malignancies in their study of 807 patients with EC. These investigators found carcinoma of the breast to be the primary cancer most frequently associated with EC. They found CRC as a separate primary site in 14% of their EC patients. Therefore, it was of interest that none of the probands in the EC series showed carcinoma of the colon as a separate primary site; yet, this was the most frequent site for a second primary in patients with EC in "cancer families," which demonstrated early ages of onset and multiple cancers. These studies were an early indication that EC in some cases is a heritable disease (84).

Besides the inheritance of adverse germline mutations of MMR genes, other hereditary predispositions to EC could result from genetic defects of the endocrine system, such as Stein-Leventhal syndrome leading to anovulation and excess unopposed estrogen stimulation of the endometrium (85). Any inherited defect in the hypothalamic-pituitary-ovarian axis or defective thyroid or adrenal function could result in anovulation and unopposed estrogenic milieu leading to endometrial hyperplasia. It is speculated that such endocrinopathies could predispose to type I EC by serving as cofactors in women who are more susceptible to malignant transformation because they also carry defective MMR genes.

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