Polyglutamine repeat length in the AIB1 gene modifies breast cancer susceptibility in BRCA1 carriers.
Variation in the penetrance estimates for BRCA1 and BRCA2 mutation carriers suggests that other factors may modify cancer risk from specific mutations. One possible mechanism is an epigenetic effect of polymorphisms in other genes. Genes involved in hormonal signal transduction are possible candidates. The AIB1 gene, an estrogen receptor (ER) coactivator, is frequently amplified in breast and ovarian tumors. Variation of a CAG repeat length has been reported within this gene that encodes a polyglutamine repeat in the C-terminus of the protein. Three hundred eleven BRCA1/2 mutation carriers (257 were of Ashkenazi origin) were genotyped for the AIB1 polyglutamine repeat. Relative risks (RR) were estimated using a maximum likelihood approach. The estimated breast cancer (BC) RR per average repeat length adjusted for population type (Ashkenazi vs. non-Ashkenazi) was 1.15 (95% CI = 1.02-1.30; p = 0.01) for BRCA1/2 carriers, and 1.25 (95% CI = 1.09-1.42; p = 0.001) when analysis was restricted to BRCA1 carriers. RR of BC was 1.17 (95% CI = 0.91-1.74), for individuals with 2 alleles >/=29 polyglutamine repeats and 0.78 (95% CI = 0.50-1.16) for those with at least 1 allele of </=26 repeats, compared to individuals with the common genotypes 28;28, 28;29 or 28;30. The corresponding BC RR in BRCA1 mutation carriers was 0.55 (95% CI = 0.34-0.90) and 1.29 (95% CI = 0.85-1.96) in those with </=26 and >/=29 repeats respectively (p = 0.025). These results indicate significant association of the risk for BC in carriers of BRCA1 mutations with the polyglutamine chain of the AIB1 gene. Longer repeat length correlates with elevated risk, whereas in carriers of a shorter AIB1 allele BC risk was reduced. The AIB1 polyglutamine length did not affect BC risk among BRCA2 mutation carriers.
Kadouri
Luna
L
Sharett Institute of Oncology, Hebrew University-Hadassah Medical Center, Jerusalem, Israel. luna@hadassah.org.il
Kote-Jarai
Zsofia
Z
Easton
Douglas F
DF
Hubert
Ayala
A
Hamoudi
Rifat
R
Glaser
Benjamin
B
Abeliovich
Dvorah
D
Peretz
Tamar
T
Eeles
Rosalind A
RA
D000328:Adult; D000483:Alleles; D001943:Breast Neoplasms / Q000235:genetics*; D005260:Female; D019398:Genes, BRCA1; D024522:Genes, BRCA2; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D018095:Germ-Line Mutation; D006579:Heterozygote; D006801:Humans; D007585:Jews; D056921:Nuclear Receptor Coactivator 3; D019683:Penetrance; D010455:Peptides / Q000235:genetics*; D011110:Polymorphism, Genetic; D012091:Repetitive Sequences, Nucleic Acid / Q000235:genetics*; D014157:Transcription Factors / Q000235:genetics*
D010455:Peptides; D014157:Transcription Factors; C097188:polyglutamine; D056921:Nuclear Receptor Coactivator 3