The BRCA1 3'-UTR: 5711+421T/T_5711+1286T/T genotype is a possible breast and ovarian cancer risk factor.
BACKGROUND
A significant proportion of familial and early-onset breast and ovarian cancers occur in individuals without coding mutations of BRCA1 and BRCA2.


OBJECTIVE
We identified genetic variation at 3'-untranslated region (UTR) of BRCA1 in familial and early-onset breast and ovarian cancer patients both with and without BRCA1/2 mutation in the coding regions (BRCA1/2 pos and BRCA1/2 neg), and verified the possible cancer risk factor of the specific 3'-UTR variation using functional analysis.


METHODS
BRCA1 SNP analysis was screened in 46 patients and 103 unaffected Thais by heteroduplex analysis and DNA sequencing. After chi-square test for the potential cancer association of the specific 3'-UTR genotypes, the functional tests were conducted using several strategies of the luciferase gene expression model.


RESULTS
We document the existence of two 3'-UTR polymorphic sites, the 5711+421(G or T) and the 5711+1286(C or T). Frequency of homozygous genotype 5711+421T/T_5711+1286T/T (or T/T-T/T) in the group of BRCA1/2 neg cancer patients was triple of that seen in unaffected persons and showed a significant cancer association (p = 0.007). Functional analysis of these polymorphic sites using luciferase experiments showed an obvious significant reduction in activity associated with the T allele at both sites.


CONCLUSIONS
These results suggest that the inheritance of specific 3'-UTR polymorphisms may predispose individuals to early-onset or familial breast or ovarian cancer.
Pongsavee
Malinee
M
Faculty of Medical Technology, Mahidol University, Salaya, Thailand.
Yamkamon
Vichanan
V
Dakeng
Sumana
S
O-charoenrat
Pornchai
P
Smith
Duncan R
DR
Saunders
Grady F
GF
Patmasiriwat
Pimpicha
P
D020413:3' Untranslated Regions / Q000235:genetics*; D000328:Adult; D000368:Aged; D000483:Alleles; D019313:BRCA1 Protein / Q000235:genetics*; D001943:Breast Neoplasms / Q000235:genetics*; D016022:Case-Control Studies; D005260:Female; D005787:Gene Frequency; D019398:Genes, BRCA1; D017930:Genes, Reporter; D014644:Genetic Variation; D005838:Genotype; D020180:Heteroduplex Analysis; D006579:Heterozygote; D006720:Homozygote; D006801:Humans; D008156:Luciferases / Q000378:metabolism; D008875:Middle Aged; D016297:Mutagenesis, Site-Directed; D010051:Ovarian Neoplasms / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide; D012307:Risk Factors; D017422:Sequence Analysis, DNA; D013785:Thailand; D014162:Transfection
D020413:3' Untranslated Regions; D019313:BRCA1 Protein; D008156:Luciferases