TY - JOUR
T1 - Effect of germ-line genetic variation on breast cancer survival in a population-based study
AU - Goode, Ellen L.
AU - Easton, Douglas F.
AU - Dunning, Alison M.
AU - Kuschel, Bettina
AU - Healey, Catherine S.
AU - Ponder, Bruce A.J.
AU - Pharoah, Paul P.D.
AU - Day, Nicholas E.
AU - Goode, Ellen L.
PY - 2002/6/1
Y1 - 2002/6/1
N2 - Somatic genetic alterations in tumors are known to correlate with survival, but little is known about the prognostic significance of germ-line variation. We assessed the effect of germ-line variation on survival among women with breast cancer participating in a British population-based study. Up to 2430 cases for whom current vital status data were available were screened for BRCA1/2 mutations and genotyped for polymorphisms in 22 DNA repair, hormone metabolism, carcinogen metabolism, and other genes. The effect of genotype on outcome was assessed by Cox regression analysis. The largest effect was observed for the silent polymorphism D501D (t>c) in L1G4, a gene involved in DNA double-strand break repair. The estimated hazard ratio (HR) in cc homozygotes relative to tt homozygotes was 4.0 (95% confidence interval, 2.1-7.7; P = 0.002), and this effect remained after stratification by stage, grade, and tumor type [HR, 4.2 (1.8-9.4); P = 0.01]. Total length of a CYP19 IVS4 (ttta)n repeat was also associated with survival [HR, 0.9 (0.8-1.0); P = 0.01], but this became nonsignificant after stratification by stage, grade, and tumor type. Poorer survival was observed for 10 BRCA1 mutation carriers [HR, 4.1 (1.3-13); P = 0.047]; however, after adjustment for known prognostic factors, the HR estimate decreased to 2.0 and became nonsignificant (P = 0.4). CYP17 (P = 0.05) and TP53 (P = 0.06) polymorphisms showed marginally significant associations in unstratified analyses. No effect on survival was seen for polymorphisms in ATM, BRCA1/2, CHK2, KU70, NBS1, RAD51, RAD52, XRCC3, AR, COMT, NQO1, VDR, ADH3, CYP1A1, GSTP1, TGF-β, or CDH1. Even if confirmed, the prognostic markers identified in this study are unlikely to replace current markers of prognosis such as estrogen receptor status. However, our results demonstrate the potential of the analysis of germ-line variation to provide insight into the biological determinants of response to treatment and prognosis in breast cancer.
AB - Somatic genetic alterations in tumors are known to correlate with survival, but little is known about the prognostic significance of germ-line variation. We assessed the effect of germ-line variation on survival among women with breast cancer participating in a British population-based study. Up to 2430 cases for whom current vital status data were available were screened for BRCA1/2 mutations and genotyped for polymorphisms in 22 DNA repair, hormone metabolism, carcinogen metabolism, and other genes. The effect of genotype on outcome was assessed by Cox regression analysis. The largest effect was observed for the silent polymorphism D501D (t>c) in L1G4, a gene involved in DNA double-strand break repair. The estimated hazard ratio (HR) in cc homozygotes relative to tt homozygotes was 4.0 (95% confidence interval, 2.1-7.7; P = 0.002), and this effect remained after stratification by stage, grade, and tumor type [HR, 4.2 (1.8-9.4); P = 0.01]. Total length of a CYP19 IVS4 (ttta)n repeat was also associated with survival [HR, 0.9 (0.8-1.0); P = 0.01], but this became nonsignificant after stratification by stage, grade, and tumor type. Poorer survival was observed for 10 BRCA1 mutation carriers [HR, 4.1 (1.3-13); P = 0.047]; however, after adjustment for known prognostic factors, the HR estimate decreased to 2.0 and became nonsignificant (P = 0.4). CYP17 (P = 0.05) and TP53 (P = 0.06) polymorphisms showed marginally significant associations in unstratified analyses. No effect on survival was seen for polymorphisms in ATM, BRCA1/2, CHK2, KU70, NBS1, RAD51, RAD52, XRCC3, AR, COMT, NQO1, VDR, ADH3, CYP1A1, GSTP1, TGF-β, or CDH1. Even if confirmed, the prognostic markers identified in this study are unlikely to replace current markers of prognosis such as estrogen receptor status. However, our results demonstrate the potential of the analysis of germ-line variation to provide insight into the biological determinants of response to treatment and prognosis in breast cancer.
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M3 - Article
C2 - 12036913
AN - SCOPUS:0036606622
SN - 0008-5472
VL - 62
SP - 3052
EP - 3057
JO - Cancer Research
JF - Cancer Research
IS - 11
ER -