Clarifying the PROGINS Allele Association in Ovarian and Breast Cancer Risk: A Haplotype-Based Analysis

Pearce, Celeste Leigh; Hirschhorn, Joel N.; Wu, Anna H.; Burtt, Noél P.; Stram, Daniel O.; Young, S Stanley; Kolonel, Laurence N.; Henderson, Brian E.; Altshuler, David; Pike, Malcolm C.

doi:10.1093/jnci/dji007

Cited by 59 publications

(52 citation statements)

References 42 publications

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“…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 ¼ 1088 cases, OR ¼ 0.81, 95% CI 0.65 -1.01, P ¼ 0.058). 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 ¼ 0.12) in the absence of the PROGINS allele.…”

Section: Discussioncontrasting

confidence: 80%

“…The participating groups for this PGR study are the Australian Cancer Study, (Merritt et al, 2008) the Australian Ovarian Cancer Study (Merritt et al, 2008), the Connecticut Ovary Study (CONN) (Risch et al, 2006), the Family Registry for Ovarian Cancer Study (Auranen et al, 2005;Song et al, 2006), the Hormones and Ovarian Cancer Prediction Study, the Danish Malignant Ovarian Cancer Study (MALOVA) (Auranen et al, 2005;Song et al, 2006), the Mayo Clinic Ovarian Cancer Case -Control Study (Sellers et al, 2005), the North Carolina Ovarian Cancer Study (Berchuck et al, 2004), the New England-based Case -Control Study (NECC) (Terry et al, 2005), the Polish Ovarian Cancer Study (POCS) (García-Closas et al, 2007), the UK SEARCH Ovarian Cancer Study (SEARCH) (Auranen et al, 2005;Song et al, 2006) and the USC/Los Angeles County Case -Control Studies of Ovarian Cancer (USC) (Pearce et al, 2005). Details of these studies have been published previously (Gayther et al, 2007); Table 1 shows the basic information for each study.…”

Section: Study Populationsmentioning

confidence: 99%

“…The PROGINS (or variants in which it is in perfect linkage disequilibrium) has been studied by many groups in relation to ovarian cancer risk. The results are, however, equivocal Manolitsas et al, 1997;Lancaster et al, 1998Lancaster et al, , 2003Spurdle et al, 2001;Tong et al, 2001;Agoulnik et al, 2004;Pearce et al, 2005;Terry et al, 2005;Romano et al, 2006). Pearce et al (2005), suggested that a variant 3 0 of the PGR (rs608995), in partial linkage disequilibrium with the PROGINS, might be a better marker of ovarian cancer risk, but this has not been confirmed by other investigators.…”

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confidence: 97%

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Progesterone receptor variation and risk of ovarian cancer is limited to the invasive endometrioid subtype: results from the ovarian cancer association consortium pooled analysis

Pearce

Gayther

et al. 2008

Br J Cancer

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There is evidence that progesterone plays a role in the aetiology of invasive epithelial ovarian cancer. Therefore, genes involved in pathways that regulate progesterone may be candidates for susceptibility to this disease. Previous studies have suggested that genetic variants in the progesterone receptor gene (PGR) may be associated with ovarian cancer risk, although results have been inconsistent. We have established an international consortium to pool resources and data from many ovarian cancer case -control studies in an effort to identify variants that influence risk. In this study, three PGR single nucleotide polymorphisms (SNPs), for which previous data have suggested they affect ovarian cancer risk, were examined. These were þ 331 C/T (rs10895068), PROGINS (rs1042838), and a 3 0 variant (rs608995). A total of 4788 ovarian cancer cases and 7614 controls from 12 case -control studies were included in this analysis. Unconditional logistic regression was used to model the association between each SNP and ovarian cancer risk and twosided P-values are reported. Overall, risk of ovarian cancer was not associated with any of the three variants studied. However, in histopathological subtype analyses, we found a statistically significant association between risk of endometrioid ovarian cancer and the PROGINS allele (n ¼ 651, OR ¼ 1.17, 95% CI ¼ 1.01 -1.36, P ¼ 0.036). We also observed borderline evidence of an association between risk of endometrioid ovarian cancer and the þ 331C/T variant (n ¼ 725 cases; OR ¼ 0.80, 95% CI 0.62 -1.04, P ¼ 0.100). These data suggest that while these three variants in the PGR are not associated with ovarian cancer overall, the PROGINS variant may play a modest role in risk of endometrioid ovarian cancer.

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Section: Discussioncontrasting

confidence: 80%

Section: Study Populationsmentioning

confidence: 99%

mentioning

confidence: 97%

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Progesterone receptor variation and risk of ovarian cancer is limited to the invasive endometrioid subtype: results from the ovarian cancer association consortium pooled analysis

Pearce

Gayther

et al. 2008

Br J Cancer

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“…All study individuals were nonHispanic Whites. Details for several of these studies have been published before (Dicioccio et al, 2004;Pearce et al, 2005;Song et al, 2006Song et al, , 2007Gayther et al, 2007;Rossing et al, 2007) and are summarised in Table 1. Local ethics committee approval was given for the collections and genotyping in all individuals.…”

Section: Study Individualsmentioning

confidence: 99%

Tagging single-nucleotide polymorphisms in candidate oncogenes and susceptibility to ovarian cancer

et al. 2009

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Low -moderate risk alleles that are relatively common in the population may explain a significant proportion of the excess familial risk of ovarian cancer (OC) not attributed to highly penetrant genes. In this study, we evaluated the risks of OC associated with common germline variants in five oncogenes (BRAF, ERBB2, KRAS, NMI and PIK3CA) known to be involved in OC development. Thirty-four tagging SNPs in these genes were genotyped in B1800 invasive OC cases and 3000 controls from population-based studies in Denmark, the United Kingdom and the United States. We found no evidence of disease association for SNPs in BRAF, KRAS, ERBB2 and PIK3CA when OC was considered as a single disease phenotype; but after stratification by histological subtype, we found borderline evidence of association for SNPs in KRAS and BRAF with mucinous OC and in ERBB2 and PIK3CA with endometrioid OC. For NMI, we identified a SNP (rs11683487) that was associated with a decreased risk of OC (unadjusted P dominant ¼ 0.004). We then genotyped rs11683487 in another 1097 cases and 1792 controls from an additional three case -control studies from the United States. The combined odds ratio was 0.89 (95% confidence interval (CI): 0.80 -0.99) and remained statistically significant (P dominant ¼ 0.032). We also identified two haplotypes in ERBB2 associated with an increased OC risk (P global ¼ 0.034) and a haplotype in BRAF that had a protective effect (P global ¼ 0.005). In conclusion, these data provide borderline evidence of association for common allelic variation in the NMI with risk of epithelial OC.

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“…Some of these have been found very recently, however, in the published data the presence of rs1042838 with both an Alu insertion in intron 7 of PGR and a silent SNP (rs1042839) on exon 5, has been referred to collectively as the PROGINS allele. 21 There are reports in the literature that the PROGINS allele may be associated with increased risk of ovarian cancer [22][23][24][25][26] and decreased risk of breast cancer. 21,27 Our results do not support the latter association with breast cancer, at least in the Spanish population.…”

Section: Genotype Distributionmentioning

confidence: 99%

Estrogen and progesterone receptor gene polymorphisms and sporadic breast cancer risk: A Spanish case‐control study

Fernández

Milne

Barroso

et al. 2006

Intl Journal of Cancer

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Estrogens, and to a lesser extent progesterones, influence the proliferation, differentiation and physiology of breast tissue as well as the development and progression of breast cancer. Genetic variants in the steroid hormone receptor genes ESR1 and PGR (belonging to the nuclear receptor superfamily) could therefore modify sporadic breast cancer susceptibility. Two studies have shown a protective effect associated with variants in ESR1 in 2 distinct populations. We studied 4 single nucleotide polymorphisms (SNPs) in ESR1 and 4 in PGR in 550 consecutive and unrelated sporadic Spanish breast cancer patients and 564 healthy Spanish controls. We observed a dominant protective effect for the S10S variant in ESR1, with an estimated odds ratio (OR) of 0.75 (95% CI 5 0.58-0.97; p 5 0.03) although functional studies did not show changes in the RNA stability. A small subset of individuals carried a haplotype combination that corroborates this protection. No other SNP considered in either gene was found to be associated with sporadic breast cancer. Our results obtained in a European population confirm the protective role of the S10S variant in ESR1, previously reported in an Asian and a European-American population. ' 2006 Wiley-Liss, Inc.

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Clarifying the PROGINS Allele Association in Ovarian and Breast Cancer Risk: A Haplotype-Based Analysis

Cited by 59 publications

References 42 publications

Progesterone receptor variation and risk of ovarian cancer is limited to the invasive endometrioid subtype: results from the ovarian cancer association consortium pooled analysis

Progesterone receptor variation and risk of ovarian cancer is limited to the invasive endometrioid subtype: results from the ovarian cancer association consortium pooled analysis

Tagging single-nucleotide polymorphisms in candidate oncogenes and susceptibility to ovarian cancer

Estrogen and progesterone receptor gene polymorphisms and sporadic breast cancer risk: A Spanish case‐control study

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