Elsevier

Gynecologic Oncology

Volume 114, Issue 2, August 2009, Pages 260-264
Gynecologic Oncology

Polymorphisms in TCEAL7 and risk of epithelial ovarian cancer

https://doi.org/10.1016/j.ygyno.2009.03.038Get rights and content

Abstract

Objective

We have previously shown that TCEAL7 (transcription elongation factor A (SII)-like 7) is epigenetically down-regulated in the majority of epithelial ovarian cancers. We now examine the hypothesis that inherited alterations in TCEAL7 play a role in the etiology of ovarian cancer.

Methods

A two-site case-control study of 930 cases of ovarian cancer and 1037 controls, frequency-matched on residence, age and race, was conducted. Six informative SNPs (tagSNPs and putative-functional SNPs) were genotyped. Logistic regression was used to adjust for potential confounders and determine if inherited variation at this locus was associated with risk of ovarian cancer in general and among cases with invasive disease and serous histology. Gene-level principal component and haplotype analyses were also conducted.

Results

None of the SNPs or haplotypes studied were significantly associated with ovarian cancer risk overall. However, among the 440 invasive serous cases, the minor alleles for three correlated SNPs were significantly associated with reduced risk (p-values < 0.05), summarized gene-level variation was weakly associated with reduced risk (p-value = 0.05), and the predominant haplotype was less common among cases than controls (0.36 v 0.40, p-value = 0.05), consistent with single-SNP results.

Conclusion

TCEAL7 polymorphisms may play a role in the development of invasive serous ovarian cancers. Follow-up molecular and replication studies are warranted.

Introduction

There are over 205,000 new cases and 125,000 deaths annually from ovarian cancer worldwide [1]; overall five-year survival is around 35%, primarily because 70% of cases are diagnosed in late stages. Elucidating the risks for ovarian cancer may help in early diagnosis and consequently reduce mortality from this disease. Family history is associated with an approximate two-fold increased risk for ovarian cancer, even after accounting for known genetic syndromes due to BRCA1, BRCA2, MLH1, MSH2, and other genes [2], suggesting the existence of additional risk alleles. Although genome-wide association studies (GWAS) are underway to identify newly-associated single-nucleotide polymorphisms (SNPs), the candidate gene approach is a useful complementary mechanism that has been successfully applied in other cancers [3].

Several candidate genes have emerged from accumulating evidence of differential expression or epigenetic silencing in tumors. One down-regulated gene is transcription elongation factor A (SII)-like 7 (TCEAL7) on the X chromosome which encodes a cell death regulatory protein inactivated by methylation [4], [5]. Down-regulation of TCEAL7 has been associated with increased NF-κB activity, higher levels of pro-proliferative genes cyclin D1 and c-Myc, and also pro-angiogenic genes IL-6, IL-8, and VEGF [6]. TCEAL7 shares amino acid sequence homology with several other pro-apoptotic proteins [7] and is lost in over 90% of primary ovarian tumors and 100% of cell lines tested compared to adjacent genes on the X chromosome [4]. Furthermore, in immortalized human ovarian epithelial cells, TCEAL7 down-regulation promotes anchorage-independent cell growth, and results suggest that TCEAL7 may limit Myc activity leading to restriction of ovarian epithelial cell transformation [6].

As TCEAL7 is thought to play a role in these critical cancer-related processes, we sought to assess whether inherited variation in this gene was associated with risk of epithelial ovarian cancer. We used a traditional case-control design at two study centers to examine a set of informative TCEAL7 SNPs and here report results of association-testing with the hope that novel risk alleles may help inform on disease biology and risk prediction.

Section snippets

Study participants

Participants were recruited into two ongoing case-control studies at Mayo Clinic in Rochester, MN and at Duke University in Durham, NC. At Mayo Clinic, cases were women over age 20 years with histologically-confirmed epithelial ovarian cancer living in the Upper Midwest and enrolled within 1 year of diagnosis. Controls without ovarian cancer and who had at least one intact ovary were recruited from among those seen for general medical examinations and frequency-matched to cases on age and

Results

Participants showed the expected distributions of demographic, risk factor, and clinical characteristics. Table 1 includes the distributions of each study population by demographic and lifestyle factors, and Table 2 summarizes histology, stage, and tumor behavior among both case groups. Generally, compared to controls (N = 1037), cases (N = 930) were more likely to be overweight and have a family history of ovarian cancer, and they were less likely to have used oral contraceptives or given birth.

Discussion

In a two-study analysis of ovarian cancer cases and controls, we found evidence that correlated SNPs within TCEAL7 (including rs5987515, rs5987724, rs5945971, and rs5945680) differed in frequency among serous invasive ovarian cancer cases and controls. Because proto-oncogenes and tumor suppressor genes are involved in normal cellular proliferation, our hypothesis was that inherited alterations in these genes could initiate tumorigenesis as well as tumor progression. Several oncogenes have been

Conflict of interest statement

The authors declare that there are no conflicts of interest.

Acknowledgments

We thank Ms. Elaine Elliott for study management, Ms. Karin Goodman and Ms. Ashley Pitzer for subject recruitment, Dr. Mark Liebow for coordination of control recruitment, and Ms. Kristin White for assistance with table preparation. Financial support was provided by R01 CA88868, R01 CA122443, Fraternal Order of Eagles, and Minnesota Ovarian Cancer Alliance.

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