Effect of germ-line genetic variation on breast cancer survival in a population-based study.
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 LIG4, 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-beta, 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.
Goode
Ellen L
EL
Cancer Research United Kingdom Genetic Epidemiology Group, Strangeways Research Laboratories, University of Cambridge, Wort's Causeway, Cambridge CB1 8RN, United Kingdom.
Dunning
Alison M
AM
Kuschel
Bettina
B
Healey
Catherine S
CS
Day
Nicholas E
NE
Ponder
Bruce A J
BA
Easton
Douglas F
DF
Pharoah
Paul P D
PP
D000368:Aged; D019313:BRCA1 Protein / Q000235:genetics / Q000378:metabolism; D024682:BRCA2 Protein / Q000235:genetics / Q000378:metabolism; D001943:Breast Neoplasms / Q000201:enzymology / Q000235:genetics* / Q000378:metabolism; D002273:Carcinogens / Q000378:metabolism; D004260:DNA Repair / Q000235:genetics; D005260:Female; D019398:Genes, BRCA1; D024522:Genes, BRCA2; D014644:Genetic Variation; D005838:Genotype; D018095:Germ-Line Mutation; D006728:Hormones / Q000378:metabolism; D006801:Humans; D008875:Middle Aged; D011110:Polymorphism, Genetic; D011379:Prognosis; D015996:Survival Rate
D019313:BRCA1 Protein; D024682:BRCA2 Protein; D002273:Carcinogens; D006728:Hormones