Article

The BRCA2 372 HH genotype is associated with risk of breast cancer in Australian women under age 60 years

Oncology Division, Joint Experimental Oncology Programme, The Queensland Institute of Medical Research and The University of Queensland, Brisbane, 4029 Australia.
Cancer Epidemiology Biomarkers & Prevention (Impact Factor: 4.32). 05/2002; 11(4):413-6.
Source: PubMed

ABSTRACT The BRCA2 N372H nonconservative amino acid substitution polymorphism appears to affect fetal survival in a sex-dependent manner, and the HH genotype was found to be associated with a 1.3-fold risk of breast cancer from pooling five case-control studies of Northern European women. We investigated whether the BRCA2 N372H polymorphism was associated with breast cancer in Australian women using a population-based case-control design. The BRCA2 372 genotype was determined in 1397 cases under the age of 60 years at diagnosis of a first primary breast cancer and in 775 population-sampled controls frequency matched for age. Case-control analyses and comparisons of genotype distributions were conducted using logistic regression. All of the statistical tests were two-tailed. The HH genotype was independent of age and family history of breast cancer within cases and controls, and was more common in cases (9.2% versus 6.5%). It was associated with an increased risk of breast cancer, 1.47-fold unadjusted (95% confidence interval, 1.05-2.07; P = 0.02), and 1.42-fold (95% confidence interval, 1.00-2.02; P = 0.05) after adjusting for measured risk factors. This effect was still evident after excluding women with any non-Caucasian ancestry or the 33 cases known to have inherited a mutation in BRCA1 or BRCA2, and would explain approximately 3% of breast cancer. The BRCA2 N372H polymorphism appears to be associated with a modest recessively inherited risk of breast cancer in Australian women. This result is consistent with the findings for Northern European women.

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    • "Arabian populations have not been extensively studied; consequently knowledge of the prevalence and spectrum of BRCA1 and BRCA2 mutations in these populations is sparse. It has been estimated that about 1/3 to 2/3 of familial breast cancer are attributable to polymorphism in BRCA1, and about 10% of cases are attributable to polymorphism in BRCA2 (Gayther et al., 1995; Spurdle et al., 2002; Reedy et al., 2002). Epidemiological data from Caucasian populations indicate that BRCA1 polymorphism account for 2-5% of all breast cancers and as much as 12% of early onset cases (Ford et al., 1998). "
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    • "Homozygous carriers of the BRCA2 N372H polymorphism were first reported to have a 30% increase in breast cancer risk in a pooled analysis from five case-control studies conducted among Northern European Caucasian populations (3,459 cases in total) (Healey et al. 2000). This finding was later confirmed in an Australian population (1,397 cases) (Spurdle et al. 2002), but not in two reports from USA (one with 1,715 cases of different ethnicities (Freedman et al. 2004) one with 1,313 Caucasian cases (Cox et al. 2005)), nor in the combined analyses from the current USA and Polish studies. Summary estimates from a meta-analysis of studies in Caucasian populations, suggested the presence of a weak association, which was evident only for studies conducted in Europe, but not for studies conducted in USA (P for heterogeneity between USA and European studies=0.01). "
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    ABSTRACT: The double-strand break DNA repair pathway has been implicated in breast carcinogenesis. We evaluated the association between 19 polymorphisms in seven genes in this pathway (XRCC2, XRCC3, BRCA2, ZNF350, BRIP1, XRCC4, LIG4) and breast cancer risk in two population-based studies in USA (3,368 cases and 2,880 controls) and Poland (1,995 cases and 2,296 controls). These data suggested weak associations with breast cancer risk for XRCC3 T241M and IVS7-14A>G (pooled odds ratio (95% confidence interval): 1.18 (1.04-1.34) and 0.85 (0.73-0.98) for homozygous variant vs wild-type genotypes, respectively), and for an uncommon variant in ZNF350 S472P (1.24 (1.05-1.48)), with no evidence for study heterogeneity. The remaining variants examined had no significant relationships to breast cancer risk. Meta-analyses of studies in Caucasian populations, including ours, provided some support for a weak association for homozygous variants for XRCC3 T241M (1.16 (1.04-1.30); total of 10,979 cases and 10,423 controls) and BRCA2 N372H (1.13 (1.10-1.28); total of 13,032 cases and 13,314 controls), and no support for XRCC2 R188H (1.06 (0.59-1.91); total of 8,394 cases and 8,404 controls). In conclusion, the genetic variants evaluated are unlikely to have a substantial overall association with breast cancer risk; however, weak associations are possible for XRCC3 (T241M and IVS7-14A>G), BRCA2 N372H, and ZNF350 S472P. Evaluation of potential underlying gene-gene interactions or associations in population subgroups will require even larger sample sizes.
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