Familial clustering of endometrial cancer in a well-defined population

Abstract

Objective

Using a genealogical database, we examined risk of endometrial cancer among family members of individuals with endometrial cancer.

Methods

We identified endometrial cancer cases in the Utah Population Database (UPDB), a computerized archive of genealogy data linked to the Utah Cancer Registry. We tested for excess relatedness and estimated relative risks (RR) among first-, second-, and third-degree relatives of endometrial cancer cases and stratified analyses by tumor histology and body mass index (BMI).

Results

We identified 3911 cases; 3546 were Type I cancers and 365 Type II cancers. The RR for all endometrial cancer cases and for cases with type I histology was significantly increased for first-, second-, and third-degree relatives. An almost three-fold risk was observed among first-degree relatives of individuals with Type I cancers and a 2.24-fold risk among second-degree relatives of Type I morbidly obese cases. The magnitude of endometrial cancer risk among relatives appeared to increase with case BMI.

Conclusions

The elevated risks for endometrial cancer among first-, second-, and third-degree relatives support a genetic contribution to predisposition to endometrial cancer. The increased risk appears to be limited to Type I endometrial cancer. We observed increased risks for endometrial cancer among relatives of obese and morbidly obese Type I cases, which may be indicative of a synergistic relationship between underlying genetic propensity and shared environment. This study quantifies risk of developing cancer among relatives of patients with disease and provides the basis for further analysis of high risk pedigrees and gene identification for genetic etiologies of endometrial cancer.

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.