FaCD Online Syndrome Fact Sheet

Last updated: 22 Aug 2008

Name: Endometrial Cancer, Familial Clustering of

Mode of Inheritance: multifact?/ AD?

Genes

CYP1A1, mapped to 15q22-q24
TP53, mapped to 17p13.1

Tumor features

breast cancer
colorectal cancer
endometrial cancer
thyroid cancer

Comment

The proportion of endometrial carcinoma based on a strong genetic predisposition has been estimated at less than 1 to 6 %[1-4]. The risk of endometrial cancer has been found to be positively associated with a family history of this cancer[5]. Women with a first degree relative with endometrial cancer were shown to have a relative risk (RR) of 1.5-2.8 of developing this tumor type[1;3;6;7], although in a study of data from the Utah Population Database, first-degree relatives of women with endometrial cancer failed to show a significant excess of this tumor type[8]. Women with endometrial cancer and a family history of this tumor are relatively young at the time of diagnosis[4]. Studying specifically women with endometrial cancer diagnosed under 55, Dupuis et al.[9] observed an RR of 17.5 for first-degree relatives to develop endometrial cancer at any age and an RR of 37 for those under 55. An increased risk of endometrial cancer was also found in first-degree relatives of breast cancer [10] and colorectal cancer patients[3]. The occurrence in a proband of double primary cancers of the endometrium and colorectum strongly increases the risk in first-degree relatives to develop endometrial cancer under age 55 (RR 7-28) or at any age (RR 3-10), colorectal cancer under age 55 (11-22) or at any age (RR 3-6) and pancreatic cancer under age 55 (RR 3-29) or at any age (RR 1-6) as calculated by Pal et al.[11] (finding those double primary tumors is suggestive of Lynch syndrome[12]).

Olson et al.[13] found no evidence that a family history of cancer (of any type) contributed to the risk of postmenopausal endometrial cancer. Bermejo et al[21] calculated endometrial cancer risks after excluding families that fulfilled the Bethesda criteria (see Lynch syndrome) thereby excluding probabably most of the Lynch syndrome families in this group. Risks were increased for individuals whose parents had been diagnosed with endometrial or thyroid gland cancers. Lynch syndrome should be in the genetic differential diagnosis of endometrial cancer patients who developed other tumors from the Lynch syndrome-associated tumor spectrum, as discussed above, those with a family history of those tumors and those with early onset disease[22,23].br>
Polymorphisms of the TP53, CYP1A1 and methylenetetrahydrofolate reductase (MTHFR) genes were shown to be associated with an enhanced endometrial cancer risk[14;15]. Some authors have suggested the existence of hereditary site-specific endometrial cancer based on striking cases of familial clustering of this tumor[16-18]. Possibly these cases are variants of Lynch syndrome[19;20].

References

[1] Parazzini F, Lavecchia C, Moroni S, Chatenoud L, Ricci E. Family history and the risk of endometrial cancer. Int J Cancer 1994; 59:460-462.
[2] Suomi R, Hakalaalapietila T, Leminen A, Mecklin JP, Lehtovirta P. Hereditary aspects of endometrial adenocarcinoma. Int J Cancer 1995; 62:132-137.
[3] Gruber SB, Thomson WD, the Cancer and Steroid Hormone Study Group. A population-based study of endometrial cancer and familial risk in younger women. Cancer Epidemiol Biomarkers Prev 5, 411-417. 1996.
[4] Fornasarig M, Campagnutta E, Talamini R, Franceschi S, Boz G, Scarabelli C, Andreaus CM, Scozzari G, Valentini M. Risk factors for endometrial cancer according to familial susceptibility. Int J Cancer 77[1], 29-32. 1998.
[5] Slattery ML, Mori M, Gao R, Kerber RA. Impact of family history of colon cancer on development of multiple primaries after diagnosis of colon cancer. Dis Colon Rectum 1995; 38:1053-1058.
[6] 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 1989; 45:521-529.
[7] Nelson CL, Sellers TA, Rich SS, Potter JD, Mcgovern PG, Kushi LH. Familial clustering of colon, breast, uterine, and ovarian cancers as assessed by family history. Genet Epidemiol 1993; 10(4):235-244.
[8] Goldgar DE, Easton DF, Cannon Albright LA, Skolnick MH. Systematic population-based assessment of cancer risk in first- degree relatives of cancer probands. J Natl Cancer Inst 1994; 86(21):1600-1608.
[9] Dupuis L, Lerner B, Mecsas-Faxon S, Berlin B, Foulkes WD. The incidence of cancer in first degree relatives of women diagnosed with endometrial cancer under age 55. Am J Hum Genet 63[4], A67. 1998. Ref Type: Abstract
[10] Peto J, Easton DF, Matthews FE, Ford D, Swerdlow AJ. Cancer mortality in relatives of women with breast cancer: the OPCS Study. Office of Population Censuses and Surveys. Int J Cancer 1996; 65(3):275-283.
[11] Pal T, Flanders T, Mitchell-Lehman M, MacMillan A, Brunet JS, Narod SA, Foulkes WD. Genetic implications of double primary cancers of the colorectal and endometrium. J Med Genet 1998; 35:978-984.
[12] Millar AL, Pal T, Madlensky L, Sherman C, Temple L, Mitri A, Cheng H, Marcus V, Gallinger S, Redston M, Bapat B, Narod S. Mismatch repair gene defects contribute to the genetic basis of double primary cancers of the colorectum and endometrium. Hum Mol Genet 8[5], 823-829. 1999.
[13] Olson JE, Sellers TA, Anderson KE, Folsom AR. Does a family history of cancer increase the risk for postmenopausal endometrial carcinoma? Cancer 85[11], 2444-2449. 1999.
[14] Esteller M, Garcia A, Martinez-Palones JM, Xercavins J, Reventos J. Susceptibility to endometrial cancer: Influence of allelism at p53, glutathione S-transferase (GSTM1 and GSTT1) and cytochrome P- 450 (CYP1A1) loci. Br J Cancer 75[9], 1385-1388. 1997.
[15] Esteller M, Garcia A, Martinez-Palones JM, Xercavins J, Reventos J. Germ line polymorphisms in cytochrome-P450 1A1 (C4887 CYP1A1) and methylenetetrahydrofolate reductase (MTHFR) genes and endometrial cancer susceptibility. Carcinogenesis 18[12], 2307-2311. 1997.
[16] Sandles LG, Shulman LP, Elias S, Photopulos GJ, Smiley LM, Posten WM, Simpson JL. Endometrial adenocarcinoma: genetic analysis suggesting heritable site-specific uterine cancer. Gynecol Oncol 1992; 47:167-171.
[17] Boltenberg A, Furgyik S, Kullander S. Familial cancer aggregation in cases of adenocarcinoma corporis uteri. Acta Obstet Gynecol Scand 1990; 69:249-258.
[18] Shulman LP, Photopulos GJ, Simpson JL, Smiley LM, Sandles LG, Elias S. Adenocarcinoma of the endometrium: family cancer studies demonstrating heritable site-specific endometrial cancer. Am J Hum Genet 1992; 51:A50.
[19] Lynch HT, Lynch J, Conway T, Watson P, Coleman RL. Familial aggregation of carcinoma of the endometrium. Am J Obstet Gynecol 1994; 171:24-27.
[20] Menko FH, Verheijen RHM, Everhardt E, Louwe LA, Wijnen JT, Band SC, Felt-Bersma JF, Vasen HFA, Meera Khan P. Endometrial cancer in four sisters: report of a kindred with presumed cancer family syndrome. Gynecol Oncol 1994; 54:171-174.
[21] Lorenzo Bermejo J, Büchner FL, Hemminki K. Familial risk of endometrial cancer after exclusion of families that fulfilled Amsterdam, Japanese or Bethesda criteria for HNPCC. Annals of oncology 2004; 15(4):598-604.
[22] Matthews KS, Estes JM, Conner MG, Manne U, Whitworth JM, Huh WK, Alvarez RD, Straughn JM, Barnes MN, Rocconi RP. Lynch syndrome in women less than 50 years of age with endometrial cancer. Obstetrics and gynecology 2008; 111(5):1161-6.
[23] Hampel H, Frankel W, Panescu J, Lockman J, Sotamaa K, Fix D, Comeras I, La Jeunesse J, Nakagawa H, Westman JA, Prior TW, Clendenning M, Penzone P, Lombardi J, Dunn P, Cohn DE, Copeland L, Eaton L, Fowler J, Lewandowski G, Vaccarello L, Bell J, Reid G, de la Chapelle A. Screening for Lynch syndrome (hereditary nonpolyposis colorectal cancer) among endometrial cancer patients. Cancer research 2006; 66(15):7810-7.