The BRCA2 372 HH genotype is associated with risk of breast cancer in Australian women under age 60 years.
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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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.Human Genetics 05/2006; 119(4):376-88. DOI:10.1007/s00439-006-0135-z · 4.52 Impact Factor
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ABSTRACT: Breast cancer is a major health problem in Indonesia, especially among young women. Early onset breast cancer has been known as one of the indicators harboring germline BRCA1/2 mutation. Giving the fact that different BRCA1/2 mutations were found in different ethnic populations and no publications on BRCA1/2 mutation detection in the Indonesian population are available, identifying the Indonesian mutations is important for better risk assessment of Indonesian women who are susceptible to the BRCA1/2 related hereditary cancers. However, the large size of the BRCA1 and BRCA2, and the scattered distribution of mutations complicate the task of mutation detection and make rapid screening for mutations a major technical challenge. In chapter 2, we describe an intelligent pooled DGGE method to screen for BRCA1/2 mutations. This method seems to be the ideal approach for screening naﶥ populations for mutations and was able to detect single base differences using non-toxic and relatively simple and inexpensive procedures. A larger group of early onset breast cancer patients and their family members from three Indonesian cities were screened for BRCA1/2 mutations in chapter 3. A relatively high percentage of early onset Indonesian breast cancer patients were observed to carry a germline mutation in either BRCA1 or BRCA2, which comprises of several novel pathogenic and a variety of novel “unclassified variant” mutations that could be specific for the Indonesian population. Comparison of the three different Indonesian regions for BRCA1/2 mutations pointed to geographic differences. To distinguish between BRCA and non-BRCA carriers among these young women, we investigated in chapter 5 their histopathological and immuno-histochemical characteristics. Within the early onset group (< 40 years), family history of breast and or ovarian cancer, CK5/6 and EGFR expression, p53 accumulation and high proliferation features increased the chance of a germline BRCA1/2 mutation. This finding is potentially useful to optimize selection of early onset breast cancer patients for BRCA1/2 mutation testing. The Multiplex Ligation dependent Probe Amplification (MLPA) PCR technique was validated as an attractive alternative to FISH for amplification testing of HER-2/neu (chapter 4) as well as for multiplex testing of amplification of twenty-seven oncogenes (chapter 7). Tumors with frequent amplification (>2 genes) were more often poorly differentiated and at advanced stage compared to those with infrequent amplification (0-2 genes). This finding is important because it links gene amplification with well established pathological prognostic and predictive features of breast cancer. In chapter 6, we used the methylation specific MS-MLPA technique to do a comprehensive analysis of promoter methylation status of 22 tumor suppressor genes in invasive breast cancer, which revealed remarkable differences in methylation frequency for various genes. Promoter methylation of multiple genes was correlated to poor differentiation and HER-2/neu amplification. Although earlier studies have shown genetic differences between early and late onset breast cancer patients, such differences were not apparent with regard to promoter methylation of the tumor suppressor genes or amplification of the oncogenes analyzed in our Indonesian breast cancer population.
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ABSTRACT: Male breast cancer (MBC) is a rare disease and little is known about its aetiology. Germ-line mutations of BRCA2 and, at lower frequency, of BRCA1 are implicated in a relatively small proportion of MBC cases. Common polymorphic variants in BRCA1 and BRCA2 genes may represent breast cancer (BC) susceptibility alleles and could be associated with a modestly increased risk of MBC at population level. Considering the relevant role of BRCA2 in MBC, we investigated whether the BRCA2 N372H variant, representing the only common non-synonymous polymorphism in BRCA2, might modulate the risk of BC in male populations. A case-control study was performed comparing a population-based series of 99 MBC cases, characterized for BRCA1 and BRCA2 mutations, with 261 male population controls, all residing in Tuscany, Central Italy. All MBC cases and controls were genotyped for the BRCA2 N372H allele by TaqMan allelic discrimination assays. To evaluate the genotype specific risk of the BRCA2 N372H variant, MBC carriers of germ-line BRCA1/2 mutations were excluded from the analyses. No association emerged in univariate and age-adjusted analyses. Age-specific analyses suggested an increased risk for the HH homozygous genotype in subjects younger than 60 years. A statistically significant interaction emerged between this genotype and age (p = 0.032). When analyses were restricted to MBC cases enrolled in the first 4 years following diagnosis, a recessive model showed a significantly increased risk of MBC in HH subjects younger than 60 years (OR = 5.63; 95% CI = 1.70;18.61). Overall, our findings, although based on a relatively small series, suggest that the BRCA2 HH homozygous genotype might be positively associated with an increased risk of MBC in men younger than 60 years.BMC Cancer 02/2007; 7:170. DOI:10.1186/1471-2407-7-170 · 3.32 Impact Factor