Familial clustering of endometrial cancer in a well-defined population
Research Highlights
► Family study of endometrial cancer quantifies risk in relatives. ► Relatives have two-fold risk of endometrial cancer. ► Family study provides basis for identifying rare cancer syndromes.
Introduction
Endometrial cancer is the most common gynecologic malignancy among U.S. women, with 40,100 new cases and 7470 deaths in the United States 2008 [1]. There are several known risk factors for the disease, including obesity, estrogen replacement therapy, and low parity. These risk factors relate to unopposed estrogen stimulation of the endometrium and are common and multifactorial, limiting their clinical usefulness for screening and prevention.
Specific genetic bases of endometrial cancer have been studied. The Hereditary Nonpolyposis Colorectal Cancer Syndrome (HNPCC) is a genetic syndrome, inherited in an autosomal dominant manner, associated with multiple malignancies due to defects in mismatch repair genes. HNPCC is most strongly associated with colon and endometrial cancer. The lifetime risk of endometrial cancer among women with HNPCC is 50%–60%, whereas that of the general population is 2%–3% [2]. Therefore, identification of the syndrome, knowledge of its genetic basis, and potential screening methods are clinically useful in the care of individuals known to have a family history of malignancy.
Other potential genetic etiologies have been investigated using DNA analysis to examine potential mutations with likely physiologic relationships to development of endometrial malignancies. Genes with mutations that are associated with endometrial cancer with unknown magnitude and clinical significance include the sex hormone binding globulin gene [3]; Fas gene promoter [4]; p53 gene [4]; mitochondrial gene polymorphisms [5]; the methylenetetrahydrofolate reductase gene [6]; the methylguanine DNA methyltransferase gene [7]; the androgen receptor gene [8]; CYP19 [9] and CYP17 gene mutations [10], [11]; ATM, CHEK2, ERBB2 haplotypes [12]; the MDM2 gene mutation [13] and the catechol-O-methyltransferase gene [14].
Candidate genes that have been studied and have not been found to have an association with endometrial cancer include the progesterone receptor gene [15]; BRCA1 and BRCA2 mutations [16]; PIK3CA and PTEN mutations [17], [18]; epidermal growth factor and human epidermal growth factor receptor 2 genes [19], [20]; and vascular endothelial growth factor and angiopoietin-2 genes [20].
The possibility of a genetic contribution to endometrial cancer, in addition to HNPCC, exists; however, the ability of existing small case–control studies to identify the specific genes or variants responsible is limited. The majority of the studies mentioned above examined specific genes and are case–control studies, often with small numbers of study subjects. It may be difficult to isolate a heritable genetic mutation with these methods, as most inherited cancer syndromes are expected to be responsible for only a small percentage of the total cancer cases that occur. For example, HNPCC causes only 2%–3% of all colon cancers [21]. However, individuals who carry this mutation have a lifetime risk of developing colon cancer of 80% [22]. In small case–control studies the significance of this mutation might be missed due to the small percentage of at-large cases that carry the mutation. We have analyzed genetic relationships among endometrial cases in a population-based resource to test hypotheses of a genetic contribution to predisposition to endometrial cancer.
Section snippets
Data and methods
Historically, the study of familial diseases often began by examining clusters of a certain disease within single families. This approach was effective for identifying simple dominant or recessive patterns of inheritance for some cancers; however, this approach is limited for more complex or multifactorial etiologies. To examine diseases with multiple genetic etiologies, gene-by-environment interactions or variable penetrance, a population-based description of familial clustering would be more
Discussion
Studies of families with colon and endometrial cancer were useful in identifying the HNPCC genes, mostly among the Dutch population. The UPDB has been used to investigate familial diseases including diabetes [26], coronary heart disease [27], and rectal cancer [28], among others. Once high risk pedigrees were studied, gene mapping studies have led to important discoveries for various diseases including breast cancer [29], prostate cancer [30], and melanoma [31], among others. This approach has
Conflicts of interest statement
The authors declare that there are no conflicts of interest.
References (31)
- et al.
Germline polymorphism of p53 codon 72 in gynecological cancer
Gynecol. Oncol.
(2006) - et al.
Association between a functional single nucleotide polymorphism in the MDM2 gene and sporadic endometrial cancer risk
Gynecol. Oncol.
(2007) - et al.
The risk of endometrial cancer in women with BRCA1 and BRCA2 mutations. A prospective study
Gynecol. Oncol.
(2007) - et al.
Evaluation of germline PTEN mutations in endometrial cancer patients
Gynecol. Oncol.
(2005) - et al.
Management of extracolonic tumors in patients with Lynch syndrome
Lancet Oncol.
(2009) - et al.
Identification of excess clustering of coronary heart diseases among extended pedigrees in a genealogical population database
Am. Heart J.
(2006) - et al.
A familial component to human rectal cancer, independent of colon cancer risk
Clin. Gastroenterol. Hepatol.
(2007) - American Cancer Society, Cancer Facts & Figures 2008, American Cancer Society:...
- et al.
The hereditary nonpolyposis colorectal cancer syndrome: genetics and clinical implications
Ann. Intern. Med.
(2003) - et al.
Association of endometrial cancer risk with a functional polymorphism (Asp(327)Asn) in the sex hormone-binding globulin gene
Cancer
(2007)
Mitochondrial polymorphisms as risk factors for endometrial cancer in southwest China
Int. J. Gynecol. Cancer
Dietary folate intake, MTHFR genetic polymorphisms, and the risk of endometrial cancer among Chinese women
Cancer Epidemiol. Biomark. Prev.
Polymorphisms in O6-methylguanine DNA methyltransferase and endometrial cancer risk
Carcinogenesis
Androgen receptor polymorphisms and endometrial cancer risk
Int. J. Cancer
CYP19 (aromatase) haplotypes and endometrial cancer risk
Int. J. Cancer
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