A tetranucleotide repeat polymorphism in CYP19 and breast cancer risk.
The CYP19 gene codes for aromatase, a key steroidogenic enzyme involved in the conversion of androgens to estrogens. A tetranucleotide (TTTA) repeat polymorphism is present in intron 4 of CYP19; 2 out of 4 breast cancer case-control studies have reported a greater frequency of 2 specific alleles among affected women. We evaluated associations between CYP19 repeat alleles and breast cancer risk in a case-control study nested within the Nurses' Health Study cohort (incident cases: n=462; controls: n=618). We observed seven different CYP19 alleles (TTTA(7-13)). Compared to controls, cases had a statistically significant greater frequency of the 10 (TTTA)(10) repeat allele (10 allele: 2.3% vs. 0.7%, p = 0.005) and a nonsignificant increase in the frequency of the 12 (TTTA)(12) allele (12 allele: 3.1% vs. 2.1%, p = 0.11). A higher frequency of the 10 allele was observed in more advanced cancer cases defined as four or more involved nodes or distant metastasis [4+ nodes: 5/36 (13.9%) vs. 0-3 nodes: 13/330 (3.9%), p = 0.02]. Among controls, we found women with the 7 repeat allele to have decreased levels of estrone sulfate (-16.4%, p = 0.02), estrone (-6.1%, p = 0.22) and estradiol (-9.9%, p = 0.10), and a lower estrone/androstenedione ratio (E1/A) (-10.5%, p = 0.08) compared to non-carriers. A higher E1/A ratio and elevated estrogen levels were observed among carriers of the 8 repeat allele; E1/A ratio (+21.0%, p = 0.003), estrone (+7.5%, p = 0.16) and estradiol (+10.8%, p = 0.08). However, we observed no evidence of an association between these alleles and breast cancer risk. We were unable to make inferences regarding the effect of the 10 allele on hormone levels due to the small number of allele carriers in the subgroup with hormone levels. As this repeat polymorphism is not close to the splice sites in intron 4, linkage disequilibrium with other functional polymorphisms in CYP19 may explain the findings of an increased association between breast cancer and the 10 allele variant of CYP19. We did not detect any sequence variants in the regulatory region or in the adipose-specific exon I.4. The lack of an established effect on CYP19 function associated with the 10 allele means that these findings should be interpreted with caution.
Haiman
C A
CA
Department of Epidemiology, Harvard School of Public Health, Boston, Massachusetts, USA. nhchr@gauss.bwh.harvard.edu
Hankinson
S E
SE
Spiegelman
D
D
De Vivo
I
I
Colditz
G A
GA
Willett
W C
WC
Speizer
F E
FE
Hunter
D J
DJ
D000483:Alleles; D001141:Aromatase / Q000235:genetics*; D001943:Breast Neoplasms / Q000235:genetics* / Q000378:metabolism; D016022:Case-Control Studies; D004958:Estradiol / Q000096:biosynthesis; D004970:Estrone / Q000031:analogs & derivatives / Q000096:biosynthesis; D005260:Female; D005838:Genotype; D006801:Humans; D007438:Introns; D015810:Linkage Disequilibrium; D008593:Menopause; D018895:Microsatellite Repeats; D015233:Models, Statistical; D011110:Polymorphism, Genetic; D012306:Risk; D017422:Sequence Analysis, DNA; D014158:Transcription, Genetic
D004970:Estrone; D004958:Estradiol; D001141:Aromatase; C017296:estrone sulfate