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Originally published as JCO Early Release 10.1200/JCO.2005.01.902 on April 18 2005 © 2005 American Society of Clinical Oncology.
Genetic Basis of Familial Endometrial Cancer: Is There More to Learn?Memorial Sloan-Kettering Cancer Center, New York, NY 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, Brøbeck concluded that "no hereditary tendency to the development of cancer of the endometrium has ever been observed."1 Evidence to counter to this view included case reports of siblings with early-onset EC,2,3 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.4 More recent epidemiologic studies demonstrated increased relative risks of EC5,6 and colorectal cancer6 in relatives of EC patients. Notably, in the study by Gruber et al,6 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.7 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,8 and finally Henry Lynch et al.9 The recognition of similar kindreds by Lynch et al10 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 Troncale11 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).12-14 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; site-specific 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 BRCA1.15 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.16,17 A similar problem as it pertains to familial EC also is not resolved. For several years, many in the cancer genetics community, including myself, have considered HNPCC to be the only manifestation of hereditary predisposition to EC, at least in the context of an autosomal dominant allele acting with high penetrance. Available data indicate that EC is the most commonly occurring extracolonic tumor in HNPCC, with lifetime risk estimates ranging from 40% to 60% in female mutation carriers.18-20 Indeed, the original Amsterdam criteria were revised in 1999 to include EC among the diagnostic criteria.21 Challenging this view, however, are several reports suggesting the existence of a heritable site-specific form of EC.22-25 Careful examination of the pedigrees presented in these reports commonly reveals the occurrence of colon or ovarian cancers (HNPCC-associated tumors), or small pedigrees, such as a mother and daughter or two sisters among six or fewer total family members. In these occurrrences, ruling out HNPCC based simply on pedigree structure is problematic. One report indicated that in female carriers of MSH6 mutations, EC was the most common malignancy, raising the possibility that this variant manifestation of HNPCC could account for apparent site-specific EC families.26 This observation has not been confirmed, however. In this issue of the Journal of Clinical Oncology, Ollikainen et al27 make a valiant effort to address the difficult question of whether familial, site-specific EC may reflect a genetic basis distinct from that underlying HNPCC, thus representing a truly separate clinical syndrome. A strength of this article is the study of a large (n = 519) consecutive series of EC patients from a single institution, with very thorough family history documentation for all first-degree relatives of each patient case. After elimination of nine families with HNPCC based on the Amsterdam criteria I or II followed by confirmation of germline mutations in MSH2 or MLH1, another 23 probands (from 22 families) met the liberal criterion for classification as site-specific EC, which consisted of diagnosis of EC in at least one first-degree relative of the proband. Archival fixed and embedded tumor and normal tissue specimens from 34 EC patients from these 22 families were obtained for analysis. At this point, the optimal strategy for identifying those additional patient cases attributable to HNPCC is debatable. An extensive commentary accompanying the revised Bethesda Guidelines, which are designed to identify individuals at risk for HNPCC and recommend criteria for MSI testing, highlights the complexity and inherent imperfections related to sensitivity and specificity of this process.28 Germline mutation analyses of the mismatch repair genes MSH2, MLH1, and MSH6 by direct sequencing together with a technique to detect large genomic deletions is the most direct method, but is impractical in most research and clinical settings. Thus, the surrogate screening techniques of MSI testing using the panel of markers recommended by the National Cancer Institute, and the classification of tumors as MSI high (MSI-H), MSI low (MSI-L), or MSI stable (MSS),28,29 or immunohistochemical (IHC) analysis of mismatch repair gene expression in tumors, followed by mutation analyses in those patients with MSI or loss of gene expression, is suggested as the optimal approach.28 Indeed, these indirect screening procedures provide additional data that often lend a measure of reliability to the mutation analyses. Ollikainen et al27 chose to implement a two-phased molecular strategy in which 33 of the familial EC tissue specimens were first subjected to IHC analyses for expression of MSH2, MLH1, and MSH6, along with testing for MSI, somatic methylation of the MLH1 promoter (which accounts for MSI observed in 15% to 20% of all sporadic cases of EC), and loss of heterozygosity at markers adjacent to the mismatch repair genes. Phase two consisted of complete mutational analyses of MSH2, MLH1, or MSH6 in those tumors with loss of expression of the respective gene(s). Although prudence would dictate mutation analyses in patients displaying MSI as well, all of the tumors affected by MSI-H in this study also displayed loss of expression of one or another mismatch repair gene, and were already included in the mutational analysis. Those tumors that were MSI-L with normal IHC results were not subjected to mutational analyses, which may have led to an underestimation of mutations, as illustrated below. Furthermore, it is impossible to assess the sensitivity of IHC analysis when those patients with normal expression results were not subjected to sequence analysis. The end result of this exercise is that two of the 23 (8.7%) families studied were found to harbor a mismatch repair gene mutation, one in MSH6 and one in MSH2. Of the remaining 21 families, there were three in which one patient with EC displayed loss of expression of a mismatch repair gene and MSI-H. However, in the first such family, the second affected member displayed MSI-L and MLH1 methylation (a probable sporadic EC); in the second family only one member was tested; and in the third family, the second affected member had normal IHC results and an MSS tumor. Thus, all three familial clusters of EC must be interpreted as uninformative with respect to their attribution to HNPCC. Of the remaining 18 families, six displayed aberrant IHC results in either the only member whose tumor was tested (four families) or discordant results in two or more members whose tumors were tested (two families), with all EC patients displaying either MSS or MSI-L. Although it is reasonable to speculate that these families are unlikely to be associated with HNPCC, it is important to recall that the family in which a germline MSH6 mutation was identified had three affected members, one with a MSI-L tumor and two with MSS tumors, even though MSH6 expression was lacking in all three patients. This leaves 12 families with no evidence of somatic or germline defects in the mismatch repair pathway. Although Ollikainen is technically correct in stating that "only a small fraction of families with site-specific EC is explained by germline mutations in mismatch repair genes" (two of 23), the fact remains that only about half of the families in this study have EC patients with no evidence of defective mismatch repair. This does not diminish the fact that a significant proportion of familial clusters of EC identified in this study remain unaccounted for by known molecular genetic mechanisms. Possible explanations for this observation include the chance association of two or more EC patients in the same family, the existence of an unidentified, highly penetrant, site-specific EC susceptibility gene (dominant or recessive) that could account for pedigrees such as that shown in Figure 2 of the article, the existence of one or more polymorphic alleles (each of which confers a moderately increased relative risk of EC) that may act alone or in combination (as in, for example, De Vivo et al,30 Sasaki et al,31 and Berstein32), resulting in modest familial clustering such as that observed in most of the pedigrees described27 or some combination of the above. I propose that the weight of available evidence supports the following conclusions. First, some familial clustering of EC, especially in the context of two patients only, represents a stochastic association. Second, a highly penetrant EC susceptibility gene, other than those responsible for HNPCC, is unlikely to exist, and if it does, it is extremely rare. Otherwise, more large site-specific EC pedigrees would certainly have been described, and a gene or genetic locus would have been identified by now using standard genetic linkage approaches. Finally, if a familial site-specific EC syndrome exists, it results from inherited susceptibility rendered by one or several polymorphic alleles, each acting with relatively low penetrance. Such a model would be consistent with the occasional site-specific clustering of EC in families. This model is aptly applied to a number of other solid tumors as well, and has been discussed in detail elsewhere.33,34 The challenge is now to identify the low-penetrance genetic or polygenic basis of moderately increased EC risk to refine prevention strategies beyond those currently in place for HNPCC. Author's Disclosures of Potential Conflicts of Interest The author indicated no potential conflicts of interest. REFERENCES 1. Brøbeck O: Heredity in carcinoma uteri [doctoral thesis]. University of Copenhagen, Copenhagen, Denmark, 1949 2. Purdie AW: Carcinoma corporis uteri in 2 sisters aged 34 and 32 years. J Obstet Gynaecol Br Emp 52:575-579, 1945
3. Porter JE: Cancer of corpus uteri in premenopausal siblings. Obstet Gynecol 28:675-679, 1966 4. Bergsjö P, Kolstad P: The ABO blood groups and cancer of the female genital tract. Acta Obstet Gynecol Scand 41:397-404, 1962 5. Schildkraut JM, Risch N, Thompson WD: Evaluating genetic association among ovarian, breast, and endometrial cancer: Evidence for a breast/ovarian cancer relationship. Am J Hum Genet 45:521-529, 1989[Medline] 6. Gruber SB, Thompson WD: A population-based study of endometrial cancer and familial risk in younger women. Cancer Epidemiol Biomarkers Prev 5:411-417, 1996[Abstract] 7. Warthin AS: Heredity with reference to carcinoma as shown by the study of the cases examined in the pathological laboratory of the University of Michigan, 1895-1913. Arch Intern Med 12:546-555, 1913 8. Hauser IJ, Weller CV: A further report on the cancer family of Warthin. Am J Cancer 27:434-444, 1936 9. Lynch HT, Krush AJ: Cancer family G revisited: 1895-1970. Cancer 27:1505-1511, 1971[CrossRef][Medline] 10. Lynch HT, Shaw MW, Magnuson CW, et al: Hereditary factors in cancer: Study of two large midwestern kindreds. Arch Intern Med 117:206-212, 1966[CrossRef][Medline] 11. Boland CR, Troncale FJ: Familial colonic cancer without antecedent polyposis. Ann Intern Med 100:700-701, 1984
12. Peltomäki P: Role of DNA mismatch repair defects in the pathogenesis of human cancer. J Clin Oncol 21:1174-1179, 2003
13. Lynch HT, de la Chapelle A: Hereditary colorectal cancer. N Engl J Med 348:919-932, 2003 14. Lynch HT, Lynch JF: Lynch syndrome: History and current status. Dis Markers 20:181-198, 2004[Medline] 15. Steichen-Gersdorf E, Gallion HH, Ford D, et al: Familial site-specific ovarian cancer is linked to BRCA1 on 17q12-21. Am J Hum Genet 55:870-875, 1994[Medline] 16. Easton DF: How many more breast cancer predisposition genes are there? Breast Cancer Res 1:14-17, 1999[CrossRef][Medline] 17. Peto J: Breast cancer susceptibility: A new look at an old model. Cancer Cell 1:411-412, 2002[CrossRef][Medline] 18. Vasen HF, Wijnen JT, Menko FH, et al: Cancer risk in families with hereditary nonpolyposis colorectal cancer diagnosed by mutation analysis. Gastroenterology 110:1020-1027, 1996[CrossRef][Medline]
19. Dunlop MG, Farrington SM, Carothers AD, et al: Cancer risk associated with germline DNA mismatch repair gene mutations. Hum Mol Genet 6:105-110, 1997 20. Aarnio M, Sankila R, Pukkala E, et al: Cancer risk in mutation carriers of DNA-mismatch-repair genes. Int J Cancer 81:214-218, 1999[CrossRef][Medline] 21. Vasen HF, Watson P, Mecklin JP, et al: New clinical criteria for hereditary nonpolyposis colorectal cancer (HNPCC, Lynch syndrome) proposed by the International Collaborative Group on HNPCC. Gastroenterology 116:1453-1456, 1999[CrossRef][Medline] 22. Lynch HT, Krush AJ, Larsen AL, et al: Endometrial carcinoma: Multiple primary malignancies, constitutional factors, and heredity. Am J Med Sci 36:381-390, 1966 23. Boltenberg A, Furgyik S, Kullander S: Familial cancer aggregation in cases of adenocarcinoma corporis uteri. Acta Obstet Gynecol Scand 69:249-258, 1990[Medline] 24. Sandles LG, Shulman LP, Elias S, et al: Endometrial adenocarcinoma: Genetic analysis suggesting heritable site-specific uterine cancer. Gynecol Oncol 47:167-171, 1992[CrossRef][Medline] 25. Lynch HT, Lynch J, Conway T, et al: Familial aggregation of carcinoma of the endometrium. Am J Obstet Gynecol 171:24-27, 1994[Medline] 26. Wijnen J, de Leeuw W, Vasen H, et al: Familial endometrial cancer in female carriers of MSH6 germline mutations. Nat Genet 23:142-144, 1999[CrossRef][Medline] 27. Ollikainen M, Abdel-Rahman WM, Moisio A-L, et al: Molecular analysis of familial endometrial carcinoma: A manifestation of hereditary nonpolyposis colorectal cancer or a separate syndrome? J Clin Oncol 23:4609-4616, 2005
28. Umar A, Boland CR, Terdiman JP, et al: Revised Bethesda Guidelines for hereditary nonpolyposis colorectal cancer (Lynch syndrome) and microsatellite instability. J Natl Cancer Inst 96:261-268, 2004
29. Boland CR, Thibodeau SN, Hamilton SR, et al: A National Cancer Institute Workshop on Microsatellite Instability for Cancer Detection and Familial Predisposition: Development of international criteria for the determination of microsatellite instability in colorectal cancer. Cancer Res 58:5248-5257, 1998
30. De Vivo I, Huggins GS, Hankinson SE, et al: A functional polymorphism in the promoter of the progesterone receptor gene associated with endometrial cancer risk. Proc Natl Acad Sci U S A 99:12263-12268, 2002
31. Sasaki M, Tanaka Y, Kaneuchi M, et al: CYP1B1 gene polymorphisms have higher risk for endometrial cancer, and positive correlations with estrogen receptor alpha and estrogen receptor beta expressions. Cancer Res 63:3913-3918, 2003 32. Berstein LM, Imyanitov EN, Kovalevskij AJ, et al: CYP17 and CYP19 genetic polymorphisms in endometrial cancer: Association with intratumoral aromatase activity. Cancer Lett 207:191-196, 2004[CrossRef][Medline] 33. Houlston RS, Peto J: The search for low-penetrance cancer susceptibility alleles. Oncogene 23:6471-6476, 2004[CrossRef][Medline] 34. de la Chapelle A: Genetic predisposition to colorectal cancer. Nat Rev Cancer 4:769-780, 2004[CrossRef][Medline] Related Article
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Copyright © 2005 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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