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Effects of common germline genetic variation in cell cycle control genes on breast cancer survival: results from a population-based cohort.

Azzato EM, Driver KE, Lesueur F, Shah M, Greenberg D, Easton DF, Teschendorff AE, Caldas C, Caporaso NE, Pharoah PD - Breast Cancer Res. (2008)

Bottom Line: The rare allele of the tagging single nucleotide polymorphism (SNP) rs2479717 is associated with an increased risk of death (hazard ratio = 1.26 per rare allele carried, 95% confidence interval: 1.12 to 1.42; P = 0.0001), which was not attenuated after adjusting for tumour stage, grade, and treatment.This SNP is part of a large linkage disequilibrium block, which contains CCND3, BYSL, TRFP, USP49, C6ofr49, FRS3, and PGC.Further study is required to validate this finding.

View Article: PubMed Central - HTML - PubMed

Affiliation: Department of Oncology, University of Cambridge, Strangeways Research Laboratory, Worts Causeway, Cambridge, UK. ema32@cam.ac.uk

ABSTRACT

Introduction: Somatic alterations have been shown to correlate with breast cancer prognosis and survival, but less is known about the effects of common inherited genetic variation. Of particular interest are genes involved in cell cycle pathways, which regulate cell division.

Methods: We examined associations between common germline genetic variation in 13 genes involved in cell cycle control (CCND1, CCND2, CCND3, CCNE1, CDK2 [p33], CDK4, CDK6, CDKN1A [p21, Cip1], CDKN1B [p27, Kip1], CDKN2A [p16], CDKN2B [p15], CDKN2C [p18], and CDKN2D [p19]) and survival among women diagnosed with invasive breast cancer participating in the SEARCH (Studies of Epidemiology and Risk factors in Cancer Heredity) breast cancer study. DNA from up to 4,470 women was genotyped for 85 polymorphisms that tag the known common polymorphisms (minor allele frequency > 0.05) in the genes. The genotypes of each polymorphism were tested for association with survival using Cox regression analysis.

Results: The rare allele of the tagging single nucleotide polymorphism (SNP) rs2479717 is associated with an increased risk of death (hazard ratio = 1.26 per rare allele carried, 95% confidence interval: 1.12 to 1.42; P = 0.0001), which was not attenuated after adjusting for tumour stage, grade, and treatment. This SNP is part of a large linkage disequilibrium block, which contains CCND3, BYSL, TRFP, USP49, C6ofr49, FRS3, and PGC. We evaluated the association of survival and somatic expression of these genes in breast tumours using expression microarray data from seven published datasets. Elevated expression of the C6orf49 transcript was associated with breast cancer survival, adding biological interest to the finding.

Conclusion: It is possible that CCND3 rs2479717, or another variant it tags, is associated with prognosis after a diagnosis of breast cancer. Further study is required to validate this finding.

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Kaplan-Meier survival function by CCND3 rs2479717 genotype. Kaplan-Meier survival probabilities for women diagnosed with invasive breast cancer in the SEARCH (Studies of Epidemiology and Risk factors in Cancer Heredity) breast cancer study by rs2479717 genotype are shown.
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Figure 1: Kaplan-Meier survival function by CCND3 rs2479717 genotype. Kaplan-Meier survival probabilities for women diagnosed with invasive breast cancer in the SEARCH (Studies of Epidemiology and Risk factors in Cancer Heredity) breast cancer study by rs2479717 genotype are shown.

Mentions: CCND3 rs2479717 remained significant in the joint analysis (HR per rare allele carried = 1.26, 95% confidence interval [CI]: 1.12 to 1.42; P = 0.0001) (Figure 1). Data on tumour grade, TNM stage, and age at diagnosis were available for 80%, 97%, and 100% of the cases, respectively. Only stage and grade remained significantly associated with survival in the multivariate model. Radiotherapy, chemotherapy, and adjuvant hormone therapy treatment data were available for 4,303 (96.3%) cases. Of these, 1,412 (32.8%) underwent chemotherapy, 3,006 (69.9%) were treated with adjuvant hormone therapy, and 3,099 (72.0%) received radiotherapy. Surgical treatment information was available for 4,194 (93.8%) cases; of these, 3,840 (91.6%) underwent surgery. The risk associated with CCND3 rs2479717 was not significantly attenuated after adjusting for tumour stage, grade, radiotherapy, chemotherapy, adjuvant hormone therapy, and surgery (HR per rare allele carried = 1.23, 95% CI: 1.07 to 1.41; P = 0.003). We repeated the analysis in those recruited within 3 years of diagnosis (3,558 individuals), and there were no differences in the results for both the univariate analysis (HR per rare allele carried = 1.28, 95% CI: 1.13 to 1.46; P = 0.0002) and the multivariate model (HR per rare allele carried = 1.23, 95% CI: 1.07 to 1.42; P = 0.004).


Effects of common germline genetic variation in cell cycle control genes on breast cancer survival: results from a population-based cohort.

Azzato EM, Driver KE, Lesueur F, Shah M, Greenberg D, Easton DF, Teschendorff AE, Caldas C, Caporaso NE, Pharoah PD - Breast Cancer Res. (2008)

Kaplan-Meier survival function by CCND3 rs2479717 genotype. Kaplan-Meier survival probabilities for women diagnosed with invasive breast cancer in the SEARCH (Studies of Epidemiology and Risk factors in Cancer Heredity) breast cancer study by rs2479717 genotype are shown.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC2481496&req=5

Figure 1: Kaplan-Meier survival function by CCND3 rs2479717 genotype. Kaplan-Meier survival probabilities for women diagnosed with invasive breast cancer in the SEARCH (Studies of Epidemiology and Risk factors in Cancer Heredity) breast cancer study by rs2479717 genotype are shown.
Mentions: CCND3 rs2479717 remained significant in the joint analysis (HR per rare allele carried = 1.26, 95% confidence interval [CI]: 1.12 to 1.42; P = 0.0001) (Figure 1). Data on tumour grade, TNM stage, and age at diagnosis were available for 80%, 97%, and 100% of the cases, respectively. Only stage and grade remained significantly associated with survival in the multivariate model. Radiotherapy, chemotherapy, and adjuvant hormone therapy treatment data were available for 4,303 (96.3%) cases. Of these, 1,412 (32.8%) underwent chemotherapy, 3,006 (69.9%) were treated with adjuvant hormone therapy, and 3,099 (72.0%) received radiotherapy. Surgical treatment information was available for 4,194 (93.8%) cases; of these, 3,840 (91.6%) underwent surgery. The risk associated with CCND3 rs2479717 was not significantly attenuated after adjusting for tumour stage, grade, radiotherapy, chemotherapy, adjuvant hormone therapy, and surgery (HR per rare allele carried = 1.23, 95% CI: 1.07 to 1.41; P = 0.003). We repeated the analysis in those recruited within 3 years of diagnosis (3,558 individuals), and there were no differences in the results for both the univariate analysis (HR per rare allele carried = 1.28, 95% CI: 1.13 to 1.46; P = 0.0002) and the multivariate model (HR per rare allele carried = 1.23, 95% CI: 1.07 to 1.42; P = 0.004).

Bottom Line: The rare allele of the tagging single nucleotide polymorphism (SNP) rs2479717 is associated with an increased risk of death (hazard ratio = 1.26 per rare allele carried, 95% confidence interval: 1.12 to 1.42; P = 0.0001), which was not attenuated after adjusting for tumour stage, grade, and treatment.This SNP is part of a large linkage disequilibrium block, which contains CCND3, BYSL, TRFP, USP49, C6ofr49, FRS3, and PGC.Further study is required to validate this finding.

View Article: PubMed Central - HTML - PubMed

Affiliation: Department of Oncology, University of Cambridge, Strangeways Research Laboratory, Worts Causeway, Cambridge, UK. ema32@cam.ac.uk

ABSTRACT

Introduction: Somatic alterations have been shown to correlate with breast cancer prognosis and survival, but less is known about the effects of common inherited genetic variation. Of particular interest are genes involved in cell cycle pathways, which regulate cell division.

Methods: We examined associations between common germline genetic variation in 13 genes involved in cell cycle control (CCND1, CCND2, CCND3, CCNE1, CDK2 [p33], CDK4, CDK6, CDKN1A [p21, Cip1], CDKN1B [p27, Kip1], CDKN2A [p16], CDKN2B [p15], CDKN2C [p18], and CDKN2D [p19]) and survival among women diagnosed with invasive breast cancer participating in the SEARCH (Studies of Epidemiology and Risk factors in Cancer Heredity) breast cancer study. DNA from up to 4,470 women was genotyped for 85 polymorphisms that tag the known common polymorphisms (minor allele frequency > 0.05) in the genes. The genotypes of each polymorphism were tested for association with survival using Cox regression analysis.

Results: The rare allele of the tagging single nucleotide polymorphism (SNP) rs2479717 is associated with an increased risk of death (hazard ratio = 1.26 per rare allele carried, 95% confidence interval: 1.12 to 1.42; P = 0.0001), which was not attenuated after adjusting for tumour stage, grade, and treatment. This SNP is part of a large linkage disequilibrium block, which contains CCND3, BYSL, TRFP, USP49, C6ofr49, FRS3, and PGC. We evaluated the association of survival and somatic expression of these genes in breast tumours using expression microarray data from seven published datasets. Elevated expression of the C6orf49 transcript was associated with breast cancer survival, adding biological interest to the finding.

Conclusion: It is possible that CCND3 rs2479717, or another variant it tags, is associated with prognosis after a diagnosis of breast cancer. Further study is required to validate this finding.

Show MeSH
Related in: MedlinePlus