Br J Cancer. Jan 29, 2008; 98(2): 282–288.
Progesterone receptor variation and risk of ovarian cancer is limited to the invasive endometrioid subtype: results from the ovarian cancer association consortium pooled analysis
1Department of Preventive Medicine, Keck School of Medicine, University of Southern California Norris Comprehensive Cancer Center, 1441 Eastlake Avenue, Room 4415A, Los Angeles, CA 90089, USA
2Translational Research Laboratories, Windeyer Institute, University College London, 46 Cleveland Street, London W1T 4JF, UK
3Department of Genetics, Yale University School of Medicine, 333 Cedar Street, SHM I-321, New Haven, CT 06510, USA
4The Queensland Institute of Medical Research, Post Office Royal Brisbane Hospital, Herston, Brisbane QLD 4029, Australia
5Center for Cancer Research, National Cancer Institute, National Institutes of Health, MSC 4605, 8717 Grovemont Circle, Gaithersburg, MD 20892-4605, USA
6Obstetrics and Gynecology Epidemiology Center, Brigham and Women's Hospital, 221 Longwood, Boston, MA 02115, USA
7Department of Cancer Genetics, Roswell Park Cancer Institute, Buffalo, NY 14263, USA
8Magee-Womens Research Institute, University of Pittsburgh, 204 Craft Avenue, Pittsburgh, PA 15213, USA
9Department of Health Sciences Research, Mayo Clinic College of Medicine, 200 First Street SW, Rochester, MN 55905, USA
10Division of Cancer Genetics and Epidemiology, National Cancer Institute, National Institutes of Health, 6120 Executive Boulevard, Room 5014, Rockville, MD 20852-7234, USA
11Department of Virus, Hormones and Cancer, Institute of Cancer Epidemiology, Danish Cancer Society, Rigshospitalet Strandboulevarden 49, Copenhagen DK-2100, Denmark
12Department of Cancer Epidemiology and Prevention, Cancer Center and M Sklodowska-Curie Institute of Oncology, Roentgena 5, Warszawa 02-781, Poland
13Division of Epidemiology and Biostatistics, Department of Health Research and Policy, Stanford University School of Medicine, Stanford, CA 94305, USA
14Department of Epidemiology and University of Pittsburgh Cancer Institute, Pittsburgh, PA, USA
15Department of Epidemiology and Public Health, Yale University School of Medicine, 60 College Street, PO Box 208034, New Haven, CT 06520-8034, USA
16Division of Cancer Prevention & Control, H Lee Moffitt Cancer Center, 12902 Magnolia Drive, Tampa, FL 33612, USA
17CR-UK Department of Oncology, Strangeways Research Laboratory, University of Cambridge, Worts Causeway, Cambridge CB1 8RN, UK
18Department of Pathology, University of Arizona Medical College, 1501 North Campbell Avenue, Tucson, AZ 85724, USA
19Division of Preventive Medicine, The Duke Comprehensive Cancer Center, Durham, NC 27710, USA
Received September 24, 2007; Revised November 20, 2007; Accepted November 27, 2007.
Since the publication of the first paper examining the relationship between the PROGINS and ovarian cancer risk more than 10 years ago, there has been substantial interest in the role of the PGR in risk of this disease. We have evaluated three SNPs, +331C/T (rs10895068), PROGINS (rs1042838), and a 3′ variant (rs608995), in the PGR in a pooled ovarian cancer dataset from 12 groups around the world and have found no overall role for this gene in disease risk.
The pooled analysis does provide statistically significant evidence of an association between the PROGINS and risk of invasive endometrioid ovarian cancer. The restriction of an association to this subtype only provides an explanation for the equivocal nature of the published results on the PROGINS and ovarian cancer risk, given that the proportion of endometrioid ovarian cancer cases likely varied by published study and typically accounts for no more than 15–20% of cases.
We also found suggestive evidence of an association between endometrioid ovarian cancer and the +331C/T variant (OR=0.80, 95% CI 0.62–1.04, P
=0.100). As suggested by Berchuck et al (2004)
, combining endometrioid and clear cell histologies in which the effect is similar, resulted in a borderline statistically significant association (n
=1088 cases, OR=0.81, 95% CI 0.65–1.01, P
Pearce et al (2005
) had previously suggested that rs608995 may explain the PROGINS-ovarian cancer association, however, in this larger dataset in which the effect was restricted to endometrioid cases, this was not supported. When examining the joint effects of the PROGINS and rs608995, the OR for endometrioid ovarian cancer associated with the rs608995 minor allele was 0.79 (95% CI 0.59–1.07, P
=0.12) in the absence of the PROGINS allele. This suggests that the PROGINS allele or a marker in linkage disequilibrium with the PROGINS is responsible for the association and not the rs608995 variant.
Both the +331 variant and the PROGINS have been studied with regard to their functional effect. The T allele of the +331 favours an increase in the transcription of PR-B relative to PR-A (De Vivo et al, 2002
); PR-B acts as a classic steroid receptor whereas PR-A acts as a repressor of both PR-B and other steroid receptors. PR-A therefore may lessen overall progesterone responsiveness through its repressive effect. Any variation which increases PR-B relative to PR-A may reduce risk of ovarian cancer by increasing exposure to the beneficial effects of progesterone. In a small study of 107 ovarian cancer cases, decreased risk of death was observed among cases positive for PRB (labelling index>10) relative to cases negative for PRB (P
=0.037). However, this finding was amongst all cell types (Akahira et al, 2000
). There is also a suggestion that the PROGINS allele as defined by the V660L exon five variant (as examined in the present study) decreases overall response to progesterone which would be consistent with an increased risk of disease associated with this variant (Romano et al, 2007
In this collaborative effort, there were 4788 ovarian cancer cases, of which 766 (16.0%) were endometrioid tumours. With the samples sizes available in this current OCAC study, we had 80% power to detect odds ratios of 0.83 and 1.12 for the +331, and PROGINS variants, respectively for all cases using a log additive genetic model and a two-sided α of 0.05. Among endometrioid subtypes, we had 80% power to detect odds ratios of 0.67 and 1.25 for the +331 and PROGINS variants, respectively using a log additive genetic model and a two-sided α of 0.05. Although the power in the current OCAC study is still quite limited, it underscores the importance of collaborative efforts, as the largest individual OCAC study had only 124 endometrioid ovarian cancers. Thus the power of subgroups analyses is clear and will be enhanced in the future with continued patient accrual to existing studies and additional investigators contributing to OCAC studies.
Alternatively, the findings of an association with the +331C/T and PROGINS, variants with the endometrioid histology may simply be due to chance. By assigning priors of 0.05, 0.10, and 0.15, the resulting false positive report probabilities (Wacholder et al, 2004
) are approximately 0.78, 0.62, and 0.52 for the +331C/T variant and 0.61, 0.42, and 0.32 for the PROGINS, respectively. Thus they may represent false positive findings.
Our analysis is the largest report describing the association between ovarian cancer risk and variants in the PGR. However, there remain several limitations to the study. For example, it is possible that environmental modifiers, such as oral contraceptive use, may be important in refining the PGR ovarian cancer risk associations and such analyses are planned in the future. There are also weaknesses of this study. Firstly, there are variable participation rates for cases between studies (). If any or all of the variants analysed is related to survival, then the low participation rates among cases might be expected to influence the results. Efforts to evaluate this include the analyses of data stratified by FIGO stage and time from diagnosis to blood collection. None of the results differed significantly when conducting these analyses. Second, as is the nature of collaborative projects, each study had a different level of pathology review and random misclassification cannot be ruled out, which would bias results towards the null in histologic-specific analyses suggesting that our results may be attenuated. Lastly, while we evaluated the best PGR candidate variants suggested by the literature, it remains possible that other, as yet unidentified variants at the locus, influence ovarian cancer risk.
Also, we observed significant heterogeneity of effect for the PROGINS allele and risk of ovarian cancer overall. Evaluation of the heterogeneity by removing one study at a time revealed that the NECC study population had a significantly different odds ratio (OR=0.75, heterogeneity P=0.011) from the other 10 OCAC studies. We investigated possible explanations for the heterogeneity we observed in the NECC study, but the reason could not be elucidated. Genotyping error is the most likely reason for experimental bias towards the null. Therefore, we regenotyped the PROGINS allele in the NECC case–control study. The results were 98% concordant with the original genotyping data, ruling this out as an explanation. Also, standard epidemiological risk and protective factors are observed with the NECC study suggesting no coding errors in the data with respect to case–control status. Further stratification of White race by Jewish ancestry was done and the results were consistent across Jewish and non-Jewish Whites (data not shown). The age distribution and participation rates are consistent with the other OCAC studies (). This heterogeneity may simply be due to chance.
Heterogeneity was also present with the +331 variant and endometrioid ovarian cancer, however no single study accounted for this heterogeneity. The minor allele frequency of this SNP is approximately 5% and the fluctuations in the data may simply represent chance; further follow-up is needed.
If these are true results and variation at the PGR locus is associated with endometrioid ovarian cancer only, then it has implications for the identification of moderate risk genes for ovarian cancer. In the past, ovarian cancer has frequently been treated as a single-disease entity for genetic association studies, mainly because studies have been too small to perform subtype analyses that are substantially powered. However, there is a large body of evidence that indicates different germline and somatic genetic factors contribute to different histological subtypes of ovarian cancer. For example, BRCA1 mutation carriers appear to predispose to serous ovarian cancers (Pal et al, 2005
); mutations in the PTEN tumour suppressor gene are more associated with endometrioid ovarian cancers (Obata et al, 1998
); and K-ras mutations are more common in mucinous tumours than in either serous of endometrioid subtypes (Gemignani et al, 2003
In conclusion, in the present analysis, we were able to exclude an overall effect of these variants in the PGR with risk of ovarian cancer. However, our evidence suggests histology-specific effects, demonstrating the necessity of data pooling to examine subgroup effects for this cancer. Although the PROGINS is unlikely to represent appreciable susceptibility risk factor, given the restriction of the association to endometrioid histology, the magnitude of the observed odds ratio, and the modest allele frequency of this variant, further analysis of this gene with regard to the endometrioid subtype is warranted to provide insight into the mechanisms underlying disease aetiology.