Genetic Basis of Familial Endometrial Cancer: Is There More to Learn?

As a result of the reduced incidence of uterine cervical carcinoma associated with screening, carcinoma of the uterine endometrium (EC) has become the most common gynecologic cancer in the United States. As for several other solid tumor types, familial clustering of EC is recognized, although the literature on this topic is relatively sparse and has been slow to materialize. For example, in a 1949 doctoral thesis on the role of heredity in EC, Brobeck concluded that “no hereditary tendency to the development of cancer of the endometrium has ever been observed.” Evidence to counter to this view included case reports of siblings with early-onset EC, now a well-established hallmark of genetic predisposition to cancer generally. Early genetic-based evidence for the potential role of heredity in EC included the observation that blood group A was over-represented in EC patients. More recent epidemiologic studies demonstrated increased relative risks of EC and colorectal cancer in relatives of EC patients. Notably, in the study by Gruber et al, the authors concluded that a family history of EC was an independent risk factor for EC alone, and that 5% of ECs may be attributable to a site-specific EC syndrome. A historic precursor to the seminal advance in our understanding of genetic susceptibility to EC occurred in 1913, when Alfred Warthin, a pathologist at the University of Michigan, described an excess of gastric and uterine cancers in the family of his seamstress, who later died of EC. The ever-expanding pedigree of Warthin’s “cancer family G” was systematically studied during the next six decades by Warthin, his colleagues Hauser and Weller, and finally Henry Lynch et al. The recognition of similar kindreds by Lynch et al in 1966 led to the description of a cancer-prone syndrome that included aggregation of colon, gastric, and notably, endometrial cancers, which they termed the “cancer family syndrome.” In 1984, the terms Lynch syndromes I and II were proposed by Boland and Troncale as corresponding to site-specific familial colorectal cancer and the cancer family syndrome, respectively, without antecedent polyposis. Then, during a 7-year period from 1991 to 1997, a series of advances extraordinary in pace and breadth resulted in the establishment of a clinical definition (the Amsterdam criteria) of what is now known as the hereditary nonpolyposis colorectal cancer (HNPCC) syndrome, localization and cloning of the tumor suppressor genes responsible for HNPCC (MSH2, MLH1, and MSH6) all involved in the same pathway of DNA mismatch repair, and characterization at the genetic and biochemical levels of the molecular hallmark of tumors associated with defective mismatch repair, microsatellite instability (MSI). The term HNPCC is now preferable to the historical terms cancer family syndrome and Lynch syndrome(s). Although it remains common to hear health professionals refer to HNPCC as Lynch II, the latter term, although an appropriate tribute to Henry Lynch and his work, propagates confusion and should be avoided because the distinction between Lynch syndromes I and II, as originally proposed, is likely artificial at the genetic level. There is no evidence for a distinct genetic basis for Lynch syndrome I, which likely represents HNPCC with over-representation of colorectal cancers, or in some cases the incomplete or inaccurate ascertainment of family histories. An analogous cancer genetics story evolved over several years after the discovery of the breast and ovarian cancer susceptibility genes, BRCA1 and BRCA2; sitespecific ovarian cancer was soon shown to represent a variant manifestation of the breast and ovarian cancer syndrome, with essentially all such kindreds showing linkage to BRCA1. In contrast, there remains a substantial proportion of site-specific breast cancer families that are apparently not linked to the BRCA1/2 or other known breast cancer susceptibility alleles, and BRCA3 does not appear to be forthcoming. JOURNAL OF CLINICAL ONCOLOGY E D I T O R I A L VOLUME 23 NUMBER 21 JULY 2