Functional polymorphisms in the BRCA1 promoter influence transcription and are associated with decreased risk for breast cancer in Chinese women

Chan, Keith; Liu, W; Long, Jirong; Yip, Shea Ping; Chan, Sy; Shu, XO; Chua, Delia; Cheung, Annie N.Y.; Ching, Jianhong; Cai, Hui; Au, Gordon K.H.; Chan, Michael; Foo, Wen‐Chi; Ngan, Hextan Ys; Yt, Gao; Ngan, Emily; Garcia-Barcelo, MM; Wang, Zheng; Khoo, Ui‐Soon

doi:10.1136/jmg.2007.057174

Cited by 27 publications

(26 citation statements)

References 29 publications

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“…Accumulating evidence also demonstrated that not only reduced DNA repair capacity due to polymorphisms in the coding region, but also decreased expression of DNA repair genes resulting from genetic polymorphisms in the regulatory region was associated with increased risk of human cancers [37][38][39][40][41]. The XRCC1 gene, which maps to chromosome 19q13.2 and consists of 17 exons, encodes a scaffold protein that interacts with most of the core components participated in the BER pathway.…”

Section: Discussionmentioning

confidence: 97%

A functional −77T>C polymorphism in XRCC1 is associated with risk of breast cancer

Yuan

Liu

et al. 2010

Breast Cancer Res Treat

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X-ray repair cross-complementing 1 (XRCC1) plays a critical role in base excision repair and genetic variations of XRCC1 may be associated with cancer susceptibility. We tested this hypothesis by examining the contribution of polymorphism in the regulatory region of XRCC1 -77T>C to risk of breast cancer in 995 patients and 1,004 controls. We found this polymorphism was associated with an increased risk of breast cancer, with an OR of 1.25 (95% CI, 1.00-1.56) for the -77TC genotype and 2.55 (95% CI, 1.11-5.86) for the -77CC genotype compared with the -77TT genotype. Haplotype analysis combining the -77T>C with three well-studied non-synonymous polymorphisms (Arg194Trp, Arg280His, and Arg399Gln) showed that only the -77C-containing haplotype was associated with the risk. Moreover, the C allele had more than 3-fold decreased luciferase expression compared with the T allele in breast cancer cell line MCF-7 (P < 0.001). A meta-analysis of seven publications with a total 2,888 cancer cases and 3,177 controls demonstrated that -77C was significantly associated with cancer risk, with an OR of 1.34 (95% CI, 1.18-1.51) for the TC genotype and 1.53 (95% CI, 1.14-2.07) for the CC genotype compared with the TT genotype. In conclusion, these findings indicated that XRCC1 -77T>C polymorphism may be a genetic determinant for developing breast cancer.

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Section: Discussionmentioning

confidence: 97%

A functional −77T>C polymorphism in XRCC1 is associated with risk of breast cancer

Yuan

Liu

et al. 2010

Breast Cancer Res Treat

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“…In all these cases, the incorporation of the now 30+ common breast cancer susceptibility alleles into comprehensive risk prediction models will be of great value in allowing women and their providers to make informed management decisions. In addition, it would be interesting to specifically explore if BRCA1 haplotypes altering promoter activity,34 35 or potentially altering 3′ untranslated region (UTR) microRNA binding,36 influence the level of function of R1699Q in vivo, and explain in part the variable presentation of families.…”

Section: Discussionmentioning

confidence: 99%

BRCA1 R1699Q variant displaying ambiguous functional abrogation confers intermediate breast and ovarian cancer risk

et al. 2012

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Background Clinical classification of rare sequence changes identified in the breast cancer susceptibility genes BRCA1 and BRCA2 is essential for appropriate genetic counselling of individuals carrying these variants. We previously showed that variant BRCA1 c.5096G>A p. Arg1699Gln in the BRCA1 transcriptional transactivation domain demonstrated equivocal results from a series of functional assays, and proposed that this variant may confer low to moderate risk of cancer. Methods Measures of genetic risk (report of family history, segregation) were assessed for 68 BRCA1 c.5096G>A p.Arg1699Gln (R1699Q) families recruited through family cancer clinics, comparing results with 34 families carrying the previously classified pathogenic BRCA1 c.5095C>T p.Arg1699Trp (R1699W) mutation at the same residue, and to 243 breast cancer families with no BRCA1 pathogenic mutation (BRCA-X). Results Comparison of BRCA1 carrier prediction scores of probands using the BOADICEA risk prediction tool revealed that BRCA1 c.5096G>A p.Arg1699Gln variant carriers had family histories that were less ‘BRCA1-like’ than BRCA1 c.5095C>T p.Arg1699Trp mutation carriers (p<0.00001), but more ‘BRCA1-like’ than BRCA-X families (p=0.0004). Further, modified segregation analysis of the subset of 30 families with additional genotyping showed that BRCA1 c.5096G >A p. Arg1699Gln had reduced penetrance compared with the average truncating BRCA1 mutation penetrance (p=0.0002), with estimated cumulative risks to age 70 of breast or ovarian cancer of 24%. Conclusions Our results provide substantial evidence that the BRCA1 c.5096G>A p.Arg1699Gln (R1699Q) variant, demonstrating ambiguous functional deficiency across multiple assays, is associated with intermediate risk of breast and ovarian cancer, highlighting challenges for risk modelling and clinical management of patients of this and other potential moderate-risk variants.

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“…In 2009, Chan et al found that rs799906, located in the promoter region of BRCA1 gene, could increase promoter activity through altering the binding affinity of transcriptional factor. This study also concluded that rs799906 decreased breast cancer risk (OR = 0.72, 95%CI = 0.53-0.97, P = 0.032) by genotyping 380 cases and 390 controls recruited in Hong Kong [37]. Therefore, maybe rs799906 is the real causal variant.…”

Section: Commentmentioning

confidence: 84%

Association of genetic polymorphisms in AURKA, BRCA1, CCNE1 and CDK2 with the risk of endometrial carcinoma and clinicopathological parameters among Chinese Han women

Zheng

Song

Chen

et al. 2015

European Journal of Obstetrics & Gynecology and Reproductiv

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Functional polymorphisms in the BRCA1 promoter influence transcription and are associated with decreased risk for breast cancer in Chinese women

Abstract: Background-The BRCA1 gene is an important breast cancer susceptibility gene. Promoter polymorphisms can alter the binding affinity of transcription factors, changing transcriptional activity and may affect susceptibility to disease.

Cited by 27 publications

References 29 publications

A functional −77T>C polymorphism in XRCC1 is associated with risk of breast cancer

A functional −77T>C polymorphism in XRCC1 is associated with risk of breast cancer

BRCA1 R1699Q variant displaying ambiguous functional abrogation confers intermediate breast and ovarian cancer risk

Association of genetic polymorphisms in AURKA, BRCA1, CCNE1 and CDK2 with the risk of endometrial carcinoma and clinicopathological parameters among Chinese Han women

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