Evaluation of 19 susceptibility loci of breast cancer in women of African ancestry

Multiple breast cancer susceptibility loci have been identified in genome-wide association studies (GWAS) in populations of European and Asian ancestry using array chips optimized for populations of European ancestry. It is important to examine whether these loci are associated with breast cancer risk in women of African ancestry. We evaluated 25 single nucleotide polymorphisms (SNPs) at 19 loci in a pooled case-control study of breast cancer, which included 1509 cases and 1383 controls. Cases and controls were enrolled in Nigeria, Barbados and the USA; all women were of African ancestry. We found significant associations for three SNPs, which were in the same direction and of similar magnitude as those reported in previous fine-mapping studies in women of African ancestry. The allelic odds ratios were 1.24 [95% confidence interval (CI): 1.04-1.47; P = 0.018] for the rs2981578-G allele (10q26/FGFR2), 1.34 (95% CI: 1.10-1.63; P = 0.0035) for the rs9397435-G allele (6q25) and 1.12 (95% CI: 1.00-1.25; P = 0.04) for the rs3104793-C allele (16q12). Although a significant association was observed for an additional index SNP (rs3817198), it was in the opposite direction to prior GWAS studies. In conclusion, this study highlights the complexity of applying current GWAS findings across racial/ethnic groups, as none of GWAS-identified index SNPs could be replicated in women of African ancestry. Further fine-mapping studies in women of African ancestry will be needed to reveal additional and causal variants for breast cancer.     

A haplotype-based case-control study of BRCA1 and sporadic breast cancer risk

Rare, highly penetrant germ line mutations in BRCA1 strongly predispose women to a familial form of breast and ovarian cancer. Whether common variants (either coding or noncoding) at this locus contribute to the more common form of the disease is not yet known. We tested common variation across the BRCA1 locus in African American, Native Hawaiian, Japanese, Latino, and White women in the Multiethnic Cohort Study. Specifically, 28 single nucleotide polymorphisms (SNPs) spanning the BRCA1 gene were used to define patterns of common variation in these populations. The majority of SNPs were in strong linkage disequilibrium with one another, indicating that our survey captured most of the common inherited variation across this gene. Nine tagging SNPs, including five missense SNPs, were selected to predict the common BRCA1 variants and haplotypes among the non-African American groups (five additional SNPs were required for African Americans) and genotyped in a breast cancer case-control study nested in the Multiethnic Cohort Study (cases, n = 1,715; controls, n = 2,502). We found no evidence for significant associations between common variation in BRCA1 and risk of breast cancer. Given the large size of our study population and detailed analysis of the locus, this result indicates either that common variants in BRCA1 do not substantially influence sporadic breast cancer risk, or that unmeasured heterogeneity in the breast cancer phenotype or unmeasured interactions with genetic or environmental exposures obscure our ability to detect any influence that may be present.     

Common genetic variation at PTEN and risk of sporadic breast and prostate cancer.

PTEN frequently shows loss of heterozygosity in breast and prostate cancers, and mutations in this gene are responsible for Cowden disease, a rare Mendelian syndrome that includes breast cancer as part of its phenotype. Thus, PTEN serves as a candidate susceptibility gene for both breast and prostate cancer risk. Whether common inherited variation (either coding or noncoding) at the PTEN locus contribute to nonfamilial, sporadic breast and prostate cancer risk is not known. In this study, we employed a linkage disequilibrium-based approach to test for association between common genetic variation at the PTEN locus and breast and prostate cancer risk in African-American, Native Hawaiian, Japanese, Latina, and White men and women in the Multiethnic Cohort Study. We genotyped 17 common single nucleotide polymorphisms (SNP; >/=5% frequency in at least one ethnic group) spanning the PTEN gene to define the common alleles in these populations. These SNPs were in strong linkage disequilibrium, indicating that our survey captured most of the common sequence variation across this locus. Eight tagging SNPs were selected to predict the common PTEN haplotypes (>/=0.05 frequency) in these populations (two additional tagging SNPs were required for African Americans). These SNPs were evaluated in a breast cancer case-control study (cases, n = 1,615; controls, n = 1,962) and prostate cancer case-control study (cases, n = 2,320; controls, n = 2,290) nested within the Multiethnic Cohort Study. Multiple testing was explicitly accounted for by applying a permutation-based framework. We found no strong association with any common haplotype in relation to breast or prostate cancer risk. In summary, our results show that common variants in PTEN do not substantially influence risk of these two common cancers.     

Common variations in TERT-CLPTM1L locus are reproducibly associated with the risk of nasopharyngeal carcinoma in Chinese populations

Associations between single nucleotide polymorphisms (SNPs) at 5p15 (TERT-CLPTM1L) and multiple cancer types have been reported. We examined whether polymorphisms in the TERT-CLPTM1L locus were related to the risk of developing nasopharyngeal carcinoma (NPC) among Chinese populations. In the first stage, 26 tag SNPs were genotyped in a Guangxi population (855 patients and 1036 controls). In the second stage, the SNPs, which showed significant association, were further genotyped in a Guangdong population (997 patients and 972 controls). Functional analyses were conducted to verify the biological relevance of the associated polymorphism. In the 1st stage, four SNPs (rs2736098, rs2735845, rs402710, and rs401681) were significantly associated with the risk of developing NPC. After the 2nd stage validation, rs2735845 and rs401681 were independently associated with the risk of developing NPC in the additive model (rs2735845, OR = 1.19, 95% CI = 1.04–1.37, P = 0.011; rs401681, OR = 0.85, 95% CI = 0.74–0.99, P = 0.034). Furthermore, we observed higher CLPTM1L messenger RNA levels in fetal mesenchymal stem cells from the rs2735845 G allele carriers compared with that from non-carriers. In addition, using an immunohistochemistry assay, we observed higher TERT and CLPTM1L levels in NPC tissues compared with that in non-cancerous nasopharyngeal tissues. Our findings suggest that polymorphisms in the TERT-CLPTM1L locus may play a role in mediating the susceptibility to NPC in Chinese populations.     

Genetic variants in one‐carbon metabolism genes and breast cancer risk in European American and African American women

Folate‐mediated one‐carbon metabolism plays critical roles in DNA synthesis, repair and DNA methylation. The impact of single nucleotide polymorphisms (SNPs) in folate‐metabolizing enzymes has been investigated in risk of breast cancer among European or Asian populations, but not among women of African ancestry. We conducted a comprehensive analysis of SNPs in eleven genes involved in one‐carbon metabolism and risk of breast cancer in 1,275 European‐American (EA) and 1,299 African‐American (AA) women who participated in the Women's Circle of Health Study. Allele frequencies varied significantly between EA and AA populations. A number of these SNPs, specifically in genes including MTR, MTRR, SHMT1, TYMS and SLC19A1, were associated with overall breast cancer risk, as well as risk by estrogen receptor (ER) status, in either EA or AA women. Associations appeared to be modified by dietary folate intake. Although single‐SNP associations were not statistically significant after correcting for multiple comparisons, polygenetic score analyses revealed significant associations with breast cancer risk. Per unit increase of the risk score was associated with a modest 19 to 50% increase in risk of breast cancer overall, ER positive or ER negative cancer (all p < 0.0005) in EAs or AAs. In summary, our data suggest that one‐carbon metabolizing gene polymorphisms could play a role in breast cancer and that may differ between EA and AA women.     

Genetic variants on chromosome 5p12 are associated with risk of breast cancer in African American women: the Black Women’s Health Study

Two single nucleotide polymorphisms (SNPs), rs4415084, and rs10941679 on chromosome 5p12 were associated with risk of breast cancer in a recent genome-wide association study (GWAS) of women of European ancestry. Both SNPs are located in a large high-LD region and the causal variant(s) are still unknown. We conducted a nested case–control study in a cohort of African American women to replicate and narrow the region carrying the causal variant(s). We evaluated 14 tagging SNPs in a 98 kb LD block surrounding the index SNPs in 886 breast cancer cases and 1,089 controls from the Black Women’s Health Study. We used the Cochran–Armitage trend test to assess association with breast cancer risk. Odds ratios were derived from logistic regression analyses adjusted for potential confounders including percent European admixture. We confirmed the reported association of rs4415084 SNP with overall risk of breast cancer (P = 0.06), and, as in the original study, observed a stronger association with estrogen receptor positive tumors (P = 0.03). We identified four other SNPs (rs6451770, rs12515012, rs13156930, and rs16901937) associated with risk of breast cancer at the nominal alpha value of 0.05; all of them were located in a 59 kb HapMap YRI LD block. After correction for multiple testing, the association with SNP rs16901937 remained significant (P permutated = 0.038). The G allele was associated with a 21% increased risk of breast cancer overall and with a 32% increase in tumors positive for both estrogen and progesterone receptors. The present results from an African ancestry (AA) population confirm the presence of breast cancer susceptibility genetic variants in the chromosome 5p12 region. We successfully used the shorter range of LD in our AA sample to refine the localization of the putative causal variant.     

Adiponectin pathway polymorphisms and risk of breast cancer in African Americans and Hispanics in the Women’s Health Initiative

Adiponectin, a protein secreted by the adipose tissue, is an endogenous insulin sensitizer with circulating levels that are decreased in obese and diabetic subjects. Recently, circulating levels of adiponectin have been correlated with breast cancer risk. Our previous work showed that polymorphisms of the adiponectin pathway are associated with breast cancer risk. We conducted the first study of adiponectin pathways in African Americans and Hispanics in the Women’s Health Initiative SNP Health Association Resource cohort of 3,642 self-identified Hispanic women and 8,515 self-identified African American women who provided consent for DNA analysis. Single nucleotide polymorphisms (SNPs) from three genes were included in this analysis: ADIPOQ, ADIPOR1, and ADIPOR2. The genome-wide human SNP array 6.0 (909,622 SNPs) (www.affymetrix.com) was used. We found that rs1501299, a functional SNP of ADIPOQ that we previously reported was associated with breast cancer risk in a mostly Caucasian population, was also significantly associated with breast cancer incidence (HR for the GG/TG genotype: 1.23; 95 % CI 1.059–1.43) in African American women. We did not find any other SNPs in these genes to be associated with breast cancer incidence. This is the first study assessing the role of adiponectin pathway SNPs in breast cancer risk in African Americans and Hispanics. RS1501299 is significantly associated with breast cancer risk in African American women. As the rates of obesity and diabetes increase in African Americans and Hispanics, adiponectin and its functional SNPs may aid in breast cancer risk assessment.     

High prevalence of BRCA1 and BRCA2 mutations in unselected Nigerian breast cancer patients

Inherited mutations in the BRCA1 and BRCA2 genes are the strongest genetic predictors of breast cancer and are the primary causes of familial breast/ovarian cancer syndrome. The frequency, spectrum and penetrance of mutant BRCA1/BRCA2 alleles have been determined for several populations, but little information is available for populations of African ancestry, who suffer a disproportionate burden of early onset breast cancer. We have performed complete sequence analysis of all BRCA1 and BRCA2 exons and intron-exon boundaries for 434 Nigerian breast cancer patients from the University College Hospital in Ibadan, Nigeria. In contrast to previous suggestions that BRCA1/BRCA2 mutation frequencies are low or undetectable in African American populations, we find that Nigerian breast cancer patients have an exceptionally high frequency of BRCA1 and BRCA2 mutations (7.1 and 3.9%, respectively). Sixteen different BRCA1 mutations were detected, seven of which have never been reported previously, while thirteen different BRCA2 mutations were seen, six of which were previously unreported. Thus, our data support enrichment for genetic risk factors in this relatively young cohort. To improve breast cancer outcomes, we suggest that family-based models of risk assessment and genetic counseling coupled with interventions to reduce breast cancer risk should be broadly disseminated in Nigeria and other underserved and understudied populations.     

Novel genetic markers of breast cancer survival identified by a genome-wide association study

Only two genome-wide association studies (GWAS) have been conducted to date to identify potential markers for total mortality after diagnosis of breast cancer. Here, we report the identification of two single-nucleotide polymorphisms (SNP) associated with total mortality from a two-stage GWAS conducted among 6,110 Shanghai-resident Chinese women with tumor-node-metastasis (TNM) stage I to IV breast cancer. The discovery stage included 1,950 patients and evaluated 613,031 common SNPs. The top 49 associations were evaluated in an independent replication stage of 4,160 Shanghai patients with breast cancer. A consistent and highly significant association with total mortality was documented for SNPs rs3784099 and rs9934948. SNP rs3784099, located in the RAD51L1 gene, was associated with total morality in both the discovery stage (P = 1.44 × 10(-8)) and replication stage (P = 0.06; P-combined = 1.17 × 10(-7)). Adjusted HRs for total mortality were 1.41 [95% confidence interval (CI), 1.18-1.68] for the AG genotype and 2.64 (95% CI, 1.74-4.03) for the AA genotype, when compared with the GG genotype. The variant C allele of rs9934948, located on chromosome 16, was associated with a similarly elevated risk of total mortality (P-combined = 5.75 × 10(-6)). We also observed this association among 1,145 patients with breast cancer of European ancestry from the Nurses' Health Study (NHS; P = 0.006); the association was highly significant in a combined analysis of NHS and Chinese data (P = 1.39 × 10(-7)). Similar associations were observed for these two SNPs with breast cancer-specific mortality. This study provides strong evidence suggesting that the RAD51L1 gene and a chromosome 16 locus influence breast cancer prognosis.     

Genetic variation at the CYP19A1 locus predicts circulating estrogen levels but not breast cancer risk in postmenopausal women

The CYP19A1 gene encodes the enzyme aromatase, which is responsible for the final step in the biosynthesis of estrogens. In this study, we used a systematic two-step approach that included gene resequencing and a haplotype-based analysis to comprehensively survey common genetic variation across the CYP19A1 locus in relation to circulating postmenopausal steroid hormone levels and breast cancer risk. This study was conducted among 5,356 invasive breast cancer cases and 7,129 controls comprised primarily of White women of European descent drawn from five large prospective cohorts within the National Cancer Institute Breast and Prostate Cancer Cohort Consortium. A high-density single-nucleotide polymorphism (SNP) map of 103 common SNPs (> or =5% frequency) was used to identify the linkage disequilibrium and haplotype patterns across the CYP19A1 locus, and 19 haplotype-tagging SNPs were selected to provide high predictability of the common haplotype patterns. We found haplotype-tagging SNPs and common haplotypes spanning the coding and proximal 5' region of CYP19A1 to be significantly associated with a 10% to 20% increase in endogenous estrogen levels in postmenopausal women [effect per copy of the two-SNP haplotype rs749292-rs727479 (A-A) versus noncarriers; P = 4.4 x 10(-15)]. No significant associations were observed, however, with these SNPs or common haplotypes and breast cancer risk. Thus, although genetic variation in CYP19A1 produces measurable differences in estrogen levels among postmenopausal women, the magnitude of the change was insufficient to contribute detectably to breast cancer.     

Risk factors for breast cancer in East Asian women relative to women in the West

The incidence of breast cancer in women of East Asian ancestry (Chinese, Japanese and Korean) is lower than in women of European ancestry but is currently rising. This review explores potential reasons for this inter-ethnic difference in incidence by profiling breast cancer risk factors reported for East Asian and Western women. Factors such as endogenous hormone exposure, lifestyle choices, diet and genetic predisposition are associated with breast cancer risk in both East Asian and Western women. However, the relative exposure to these risk factors may vary according to a woman's geographical ancestry and culture. For example, age at menarche and menopause, parity, breast-feeding history, low fat and high soy consumption as well as the prevalence of high risk genetic alleles may vary with a woman's geographical ancestry and/or culture. Differences in exposure to these risk factors in East Asian and Western women are consistent with the inter-ethnic differences in breast cancer incidence observed. Understanding the underlying factors contributing to differences in the profile of breast cancer across populations is important when considering screening and prevention programs for East Asian women resident in the East or the West.     

FGF receptor genes and breast cancer susceptibility: results from the Breast Cancer Association Consortium

Background:

Breast cancer is one of the most common malignancies in women. Genome-wide association studies have identified FGFR2 as a breast cancer susceptibility gene. Common variation in other fibroblast growth factor (FGF) receptors might also modify risk. We tested this hypothesis by studying genotyped single-nucleotide polymorphisms (SNPs) and imputed SNPs in FGFR1, FGFR3, FGFR4 and FGFRL1 in the Breast Cancer Association Consortium.

Methods:

Data were combined from 49 studies, including 53 835 cases and 50 156 controls, of which 89 050 (46 450 cases and 42 600 controls) were of European ancestry, 12 893 (6269 cases and 6624 controls) of Asian and 2048 (1116 cases and 932 controls) of African ancestry. Associations with risk of breast cancer, overall and by disease sub-type, were assessed using unconditional logistic regression.

Results:

Little evidence of association with breast cancer risk was observed for SNPs in the FGF receptor genes. The strongest evidence in European women was for rs743682 in FGFR3; the estimated per-allele odds ratio was 1.05 (95% confidence interval=1.02–1.09, P=0.0020), which is substantially lower than that observed for SNPs in FGFR2.

Conclusion:

Our results suggest that common variants in the other FGF receptors are not associated with risk of breast cancer to the degree observed for FGFR2.     

Cytokine and cytokine receptor genes of the adaptive immune response are differentially associated with breast cancer risk in American women of African and European ancestry

Disparities in breast cancer biology are evident between American women of African ancestry (AA) and European ancestry (EA) and may be due, in part, to differences in immune function. To assess the potential role of constitutional host immunity on breast carcinogenesis, we tested associations between breast cancer risk and 47 single nucleotide polymorphisms (SNPs) in 26 cytokine‐related genes of the adaptive immune system using 650 EA (n = 335 cases) and 864 AA (n = 458 cases) women from the Women's Circle of Health Study (WCHS). With additional participant accrual to the WCHS, promising SNPs from the initial analysis were evaluated in a larger sample size (1,307 EAs and 1,365 AAs). Multivariate logistic regression found SNPs in genes important for T helper type 1 (Th1) immunity (IFNGR2 rs1059293, IL15RA rs2296135, LTA rs1041981), Th2 immunity (IL4R rs1801275), and T regulatory cell‐mediated immunosuppression (TGFB1 rs1800469) associated with breast cancer risk, mainly among AAs. The combined effect of these five SNPs was highly significant among AAs (P‐trend = 0.0005). When stratified by estrogen receptor (ER) status, LTA rs1041981 was associated with ER‐positive breast cancers among EAs and marginally among AAs. Only among AA women, IL15 rs10833 and IL15RA rs2296135 were associated with ER‐positive tumors, and IL12RB1 rs375947, IL15 rs10833 and TGFB1 rs1800469 were associated with ER‐negative tumors. Our study systematically identified genetic variants in the adaptive immune response pathway associated with breast cancer risk, which appears to differ by ancestry groups, menopausal status and ER status.     

Risk factors for breast cancer in East Asian women relative to women in the West

The incidence of breast cancer in women of East Asian ancestry (Chinese, Japanese and Korean) is lower than in women of European ancestry but is currently rising. This review explores potential reasons for this inter‐ethnic difference in incidence by profiling breast cancer risk factors reported for East Asian and Western women. Factors such as endogenous hormone exposure, lifestyle choices, diet and genetic predisposition are associated with breast cancer risk in both East Asian and Western women. However, the relative exposure to these risk factors may vary according to a woman's geographical ancestry and culture. For example, age at menarche and menopause, parity, breast‐feeding history, low fat and high soy consumption as well as the prevalence of high risk genetic alleles may vary with a woman's geographical ancestry and/or culture. Differences in exposure to these risk factors in East Asian and Western women are consistent with the inter‐ethnic differences in breast cancer incidence observed. Understanding the underlying factors contributing to differences in the profile of breast cancer across populations is important when considering screening and prevention programs for East Asian women resident in the East or the West.     

Genetic variation in the vitamin D related pathway and breast cancer risk in women of African ancestry in the root consortium

The vitamin D related pathway has been evaluated in carcinogenesis but its genetic contribution remains poorly understood. We examined single‐nucleotide polymorphisms (SNPs) in the vitamin D related pathway genes using data from a genome‐wide association study (GWAS) of breast cancer in the African Diaspora that included 3,686 participants (1,657 cases). Pathway‐ and gene‐level analyses were conducted using the adaptive rank truncated product test. Odds ratios (OR) and 95% confidence intervals (CI) were estimated at SNP‐level. After stringent Bonferroni corrections, we observed no significant association between variants in the vitamin D pathway and breast cancer risk at the pathway‐, gene‐, or SNP‐level. In addition, no association was found for either the reported signals from GWASs of vitamin D related traits, or the SNPs within vitamin D receptor (VDR) binding regions. Furthermore, a decrease in genetically predicted 25(OH)D levels by Mendelian randomization was not associated with breast cancer (p = 0.23). However, an association for breast cancer with the pigment synthesis/metabolism pathway almost approached significance (pathway‐level p = 0.08), driven primarily by a nonsense SNP rs41302073 in TYRP1, with an OR of 1.54 (95% CI = 1.24–1.91, p_adj = 0.007). In conclusion, we found no evidence to support an association between vitamin D status and breast cancer risk in women of African ancestry, suggesting that vitamin D is unlikely to have significant effect on breast carcinogenesis. Interestingly, TYRP1 might be related to breast cancer through a non‐vitamin D relevant mechanism but further studies are needed.     

Variants in the vitamin D pathway, serum levels of vitamin D, and estrogen receptor negative breast cancer among African-American women: a case-control study

Introduction

American women of African ancestry (AA) are more likely than European Americans (EA) to have estrogen receptor (ER)-negative breast cancer. 25-hydroxyvitamin D (25OHD) is low in AAs, and was associated with ER-negative tumors in EAs. We hypothesized that racial differences in 25OHD levels, as well as in inherited genetic variations, may contribute, in part, to the differences in tumor characteristics.

Methods

In a case (n = 928)-control (n = 843) study of breast cancer in AA and EA women, we measured serum 25OHD levels in controls and tested associations between risk and tag single nucleotide polymorphisms (SNPs) in VDR, CYP24A1 and CYP27B1, particularly by ER status.

Results

More AAs had severe vitamin D deficiency (< 10 ng/ml) than EAs (34.3% vs 5.9%), with lowest levels among those with the highest African ancestry. Associations for SNPs differed by race. Among AAs, VDR SNP rs2239186, associated with higher serum levels of 25OHD, decreased risk after correction for multiple testing (OR = 0.53, 95% CI = 0.31-0.79, p by permutation = 0.03), but had no effect in EAs. The majority of associations were for ER-negative breast cancer, with seven differential associations between AA and EA women for CYP24A1 (p for interaction < 0.10). SNP rs27622941 was associated with a > twofold increased risk of ER-negative breast cancer among AAs (OR = 2.62, 95% CI = 1.38-4.98), but had no effect in EAs. rs2209314 decreased risk among EAs (OR = 0.38, 95% CI = 0.20-0.73), with no associations in AAs. The increased risk of ER-negative breast cancer in AAs compared to EAs was reduced and became non-significant (OR = 1.20, 95% CI = 0.80-1.79) after adjusting for these two CYP24A1 SNPs.

Conclusions

These data suggest that genetic variants in the vitamin D pathway may be related to the higher prevalence of ER-negative breast cancer in AA women.     

HSD17B1 gene polymorphisms and risk of endometrial and breast cancer.

Estrogen exposure influences breast and endometrial cancer risk. The HSD17B1 gene produces an enzyme that catalyzes the conversion of estrone to estradiol. We hypothesized that genetic variations in HSD17B1 gene may alter endogenous estrogen levels and, thus, influence endometrial and breast cancer risk. We validated and genotyped polymorphisms in the HSD17B1 gene and assessed whether these single nucleotide polymorphisms (SNPs), or the imputed haplotypes, were associated with endometrial and breast cancer risk. We also assessed whether a priori risk factors modified the associations between HSD17B1 genotype and cancer risk, and whether HSD17B1 genotypes were associated with plasma estrogen levels among postmenopausal women not using hormone replacement therapy. Ten SNPs of HSD17B1 gene were validated in 30 women from the Nurses' Health Study. Using the expectation maximization algorithm, three common (>5% frequency) haplotypes accounted for 97% of the chromosomes at this locus, and seven SNPs were in complete linkage disequilibrium. We identified and genotyped two haplotype-tagging SNPs (+1004C/T and +1322C/A), and genotyped an additional SNP [+1954A/G (Ser312Gly)] in nested case-control studies of endometrial cancer (cases = 222, controls = 666) and breast cancer (cases = 1007, controls = 1441) in the prospective Nurses' Health Study. Although no overall association by SNP or haplotype analysis was observed with endometrial or breast cancer risk, the +1954A/A genotype was associated with higher estradiol levels in lean women (P = 0.01) and interaction between the +1954 genotype with body mass index in postmenopausal breast cancer (P = 0.05) was suggested. These findings suggest that the HSD17B1 may be associated with circulating estradiol levels and interact with body mass index in postmenopausal breast cancer.     

Incremental impact of breast cancer SNP panel on risk classification in a screening population of white and African American women

Breast cancer risk prediction remains imperfect, particularly among non-white populations. This study examines the impact of including single-nucleotide polymorphism (SNP) alleles in risk prediction for white and African American women undergoing screening mammogram. Using a prospective cohort study, standard risk information and buccal swabs were collected at the time of screening mammography. A 12 SNP panel was performed by deCODE genetics. Five-year and lifetime risks incorporating SNPs were calculated by multiplying estimated Breast Cancer Risk Assessment Tool (BCRAT) risk by the total genetic risk ratio. Concordance between the BCRAT and the combined model (BCRAT + SNPs) in identifying high-risk women was measured using the kappa statistic. SNP data were available for 810 women (39 % African American, 55 % white). The mean BCRAT 5-year risk was 1.71 % for whites and 1.18 % for African Americans. Mean genetic risk ratios were 1.09 in whites and 1.29 in African Americans. Among whites, three SNPs had higher frequencies, and among African Americans, seven SNPs had higher and four had lower high-risk allele frequencies than previously reported. Agreement between the BCRAT and the combined model was relatively low for identifying high-risk women (5-year κ = 0.54, lifetime κ = 0.36). Addition of SNPs had the greatest effect among African Americans, with 12.4 % identified as having high-5-year risk by BCRAT, but 33 % by the combined model. A greater proportion of African Americans were reclassified as having high-5-year risk than whites using the combined model (21 vs. 10 %). The addition of SNPs to the BCRAT reclassifies the high-risk status of some women undergoing screening mammography, particularly African Americans. Further research is needed to determine the clinical validity and utility of the SNP panel for use in breast cancer risk prediction, particularly among African Americans for whom these risk alleles have generally not been validated.