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  • American Association for Cancer Research (AACR)  (13)
  • 1
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    Abstract 4613: Cross-ancestry genome-wide association study identifies six new loci for breast cancer in women of African and european ancestry
    American Association for Cancer Research (AACR) ; 2020
    In:  Cancer Research Vol. 80, No. 16_Supplement ( 2020-08-15), p. 4613-4613
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 80, No. 16_Supplement ( 2020-08-15), p. 4613-4613
    Abstract: Background: Over 180 genetic variants have been identified as risk loci for breast cancer. However, most loci were discovered using European ancestry populations. As some common susceptibility loci are shared across populations, we aim to discover new risk loci for breast cancer using a cross-ancestry genome-wide association study (GWAS) approach. Methods: Data from five GWAS studies in women of African ancestry with a combined sample size of 9241 cases and 10192 controls were used to generate pooled breast cancer risk estimates in a fixed effect meta-analysis, and this served as the discovery dataset. Summary statistics from the GWAS conducted in European ancestry populations (Breast Cancer Association Consortium, 122977 cases and 105974 controls) served as the validation dataset. The variants that were associated with breast cancer risk at P & lt; 0.01 in the GWAS of African ancestry were meta-analyzed with the GWAS in European ancestry. A locus was considered novel if the lead index variant was genome-wide significant (5 × 10−8) in the cross-ancestry meta-analysis and & gt;500kb away from known breast cancer risk loci. Conditional on the lead index variants, we searched for additional signals in each locus using multivariable logistic regression. Analyses were done separately for ER-positive, ER-negative and overall breast cancer risk. Results: We discovered four novel loci for overall breast cancer risk (1p13.3, 5q31.1, 15q24, and 15q26.3) and two novel loci for ER-negative breast cancer (1q41 and 7q11.23) at the genome-wide significance level of P & lt; 5 × 10−8. Three index single nucleotide polymorphism (SNPs) lie within introns of genes (KCNK2, C5orf56, and SIN3A) and the other index SNPs are located in intergenic regions (close to GSTM4 and AMPD2, CASTOR2, and the antisense DNA RP11-168G16.2). The direction of the associations was consistent between the GWASs of African and European descendants. At the 15q24 locus, we found an additional SNP (in the intron of the SCAMP2 gene) to be independently associated with overall breast cancer risk. Conclusions: We have identified six new risk loci that may contribute to better prediction of breast cancer risk in African ancestry populations and provide new insights into mechanisms of breast cancer carcinogenesis. Replication of these loci in multiple populations and functional studies can help to identify causal variants. Citation Format: Babatunde Adedokun, Zhaohui Du, Guimin Gao, Thomas Ahearn, Kathryn L. Lunetta, Gary Zirpoli, Jonine Figueroa, Esther M. John, Leslie Bernstein, Wei Zheng, Jennifer J. Hu, Regina G. Ziegler, Sarah Nyante, Elisa V. Bandera, Sue A. Ingles, Michael F. Press, Sandra L. Deming, Jorge L. Rodriguez-Gil, Song Yao, Temidayo O. Ogundiran, Oladosu Ojengbede, William Blot, Melissa Troester, Katherine L. Nathanson, Anselm Hennis, Barbara Nemesure, Stefan Ambs, Lara E. Sucheston-Campbell, Jeannette T. Bensen, Stephen J. Chanock, Andrew F. Olshan, Christine B. Ambrosone, David V. Conti, Olufunmilayo I. Olopade, Montserrat Garcia-Closas, Julie R. Palmer, Christopher A. Haiman, Dezheng Huo. Cross-ancestry genome-wide association study identifies six new loci for breast cancer in women of African and european ancestry [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 4613.
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    URL: Article
    DOI: 10.1158/1538-7445.AM2020-4613
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    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2020
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  • 2
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    Characterizing Genetic Susceptibility to Breast Cancer in Women of African Ancestry
    American Association for Cancer Research (AACR) ; 2017
    In:  Cancer Epidemiology, Biomarkers & Prevention Vol. 26, No. 7 ( 2017-07-01), p. 1016-1026
    Details
    In: Cancer Epidemiology, Biomarkers & Prevention, American Association for Cancer Research (AACR), Vol. 26, No. 7 ( 2017-07-01), p. 1016-1026
    Abstract: Background: Genome-wide association studies have identified approximately 100 common genetic variants associated with breast cancer risk, the majority of which were discovered in women of European ancestry. Because of different patterns of linkage disequilibrium, many of these genetic markers may not represent signals in populations of African ancestry. Methods: We tested 74 breast cancer risk variants and conducted fine-mapping of these susceptibility regions in 6,522 breast cancer cases and 7,643 controls of African ancestry from three genetic consortia (AABC, AMBER, and ROOT). Results: Fifty-four of the 74 variants (73%) were found to have ORs that were directionally consistent with those previously reported, of which 12 were nominally statistically significant (P & lt; 0.05). Through fine-mapping, in six regions (3p24, 12p11, 14q13, 16q12/FTO, 16q23, 19p13), we observed seven markers that better represent the underlying risk variant for overall breast cancer or breast cancer subtypes, whereas in another two regions (11q13, 16q12/TOX3), we identified suggestive evidence of signals that are independent of the reported index variant. Overlapping chromatin features and regulatory elements suggest that many of the risk alleles lie in regions with biological functionality. Conclusions: Through fine-mapping of known susceptibility regions, we have revealed alleles that better characterize breast cancer risk in women of African ancestry. Impact: The risk alleles identified represent genetic markers for modeling and stratifying breast cancer risk in women of African ancestry. Cancer Epidemiol Biomarkers Prev; 26(7); 1016–26. ©2017 AACR.
    Type of Medium: Online Resource
    ISSN: 1055-9965 , 1538-7755
    URL: Article
    DOI: 10.1158/1055-9965.EPI-16-0567
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2017
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  • 3
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    Abstract 2320: Evaluating a polygenic risk score for breast cancer in women of African ancestry
    American Association for Cancer Research (AACR) ; 2020
    In:  Cancer Research Vol. 80, No. 16_Supplement ( 2020-08-15), p. 2320-2320
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 80, No. 16_Supplement ( 2020-08-15), p. 2320-2320
    Abstract: Background: A polygenic risk score (PRS) for breast cancer including 313 common variants developed by the Breast Cancer Association Consortium (BCAC) has been demonstrated to identify women who are at high risk of developing breast cancer [odds ratio (OR 95%CI) = 1.61 (1.57-1.65) per SD] in women of European ancestry. In the present study, we examined the performance of the 313-variant PRS and a PRS including 179 variants reaching genome-wide significance in previous genome-wide association studies (GWAS), in women of African ancestry. Methods: We assembled genotype data for women of African ancestry from 28 breast cancer studies, including a total of 9,241 cases and 10,193 controls. We constructed the 179-variant and 313-variant PRSs with relative risk weights for each variant estimated in women of European ancestry in BCAC. The associations between the two PRSs and overall, ER+ and ER- breast cancer risk were estimated using logistic regression adjusting for age, study site and principal components. Discriminatory accuracy of the PRSs was evaluated using the receiver operating characteristic curve (AUROC). We then recalibrated the 179-variant PRS by replacing index variants with variants in each region that better captured risk in women of African ancestry and used relative risk weights estimated in women of African ancestry. We also assessed PRS performance by age ( & lt;55 versus ≥ 55 years). Results: Both the 179 and 313- variant PRSs were significantly associated with overall, ER+ and ER- breast cancer risk, with odds ratios (OR) per standard deviation of 1.21~1.37 and AUROCs ranging from 0.57 to 0.59. The 179-variant PRS outperformed in ER- cancer [1.31(1.24,1.37) per SD] while the 313-SNP PRS was better for overall [1.27(1.23,1.31) per SD] and ER+ cancer [1.37(1.32,1.43) per SD]. For overall breast cancer, compared to women with average risk (40th-60th PRS percentiles), women in the top decile of PRS had a 1.54 (95% CI: 1.38, 1.72)-fold increased risk. The performance of the recalibrated 179-variant PRS was not improved (average AUROC=0.56). The PRS ORs did not differ significantly across age strata (P-value for age interaction = 0.63). Conclusion: Our study shows that both 179 and 313 variant PRS stratify breast cancer risk in women of African ancestry, with attenuated performance compared to that reported in European and in Latina populations. Future work is needed to improve breast cancer risk stratification for women of African ancestry. Citation Format: Zhaohui Du, Guimin Gao, Babatunde Adedokun, Thomas Ahearn, Kathryn L. Lunetta, Gary Zirpoli, Melissa Troester, Edward A. Ruiz-Narváez, Stephen Haddad, Jonine Figueroa, Esther M. John, Leslie Bernstein, Wei Zheng, Jennifer J. Hu, Regina G. Ziegler, Sarah Nyante, Elisa V. Bandera, Sue A. Ingles, Michael F. Press, Sandra L. Deming, Jorge L. Rodriguez-Gil, Song Yao, Temidayo O. Ogundiran, Oladosu A. Ojengbede, William Blot, Katherine L. Nathanson, Anselm Hennis, Barbara Nemesure, Stefan Ambs, Lara E. Sucheston-Campbell, Jeannette T. Bensen, Stephen J. Chanock, Andrew F. Olshan, Christine B. Ambrosone, David V. Conti, Olufunmilayo I. Olopade, Julie R. Palmer, Montserrat Garcia-Closas, Dezheng Huo, Christopher A. Haiman. Evaluating a polygenic risk score for breast cancer in women of African ancestry [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 2320.
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    URL: Article
    DOI: 10.1158/1538-7445.AM2020-2320
    RVK:
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    RVK:
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    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2020
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  • 4
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    Functional Polymorphisms in UDP-Glucuronosyl Transferases and Recurrence in Tamoxifen-Treated Breast Cancer Survivors
    American Association for Cancer Research (AACR) ; 2011
    In:  Cancer Epidemiology, Biomarkers & Prevention Vol. 20, No. 9 ( 2011-09-01), p. 1937-1943
    Details
    In: Cancer Epidemiology, Biomarkers & Prevention, American Association for Cancer Research (AACR), Vol. 20, No. 9 ( 2011-09-01), p. 1937-1943
    Abstract: Background: Tamoxifen is oxidized by cytochrome-P450 enzymes (e.g., CYP2D6) to two active metabolites, which are eliminated via glucuronidation by UDP-glucuronosyl transferases (UGT). We measured the association between functional polymorphisms in key UGTs (UGT2B15*2, UGT2B7*2, and UGT1A8*3) and the recurrence rate among breast cancer survivors. Methods: We used the Danish Breast Cancer Cooperative Group registry to identify 541 cases of recurrent breast cancer among women with estrogen receptor-positive tumors treated with tamoxifen for at least 1 year (ER+/TAM+), and 300 cases of recurrent breast cancer among women with estrogen receptor-negative tumors who were not treated with tamoxifen (ER−/TAM−). We matched one control to each case on ER status, menopausal status, stage, calendar period, and county. UGT polymorphisms were genotyped from archived primary tumors. We estimated the recurrence OR for the UGT polymorphisms by using logistic regression models, with and without stratification on CYP2D6*4 genotype. Results: No UGT polymorphism was associated with breast cancer recurrence in either the ER+/TAM+ or ER−/TAM− groups [in the ER+/TAM+ group, compared with two normal alleles: adjusted OR for two UGT2B15*2 variant alleles = 1.0 (95% CI, 0.70–1.5); adjusted OR for two UGT2B7*2 variant alleles = 0.96 (95% CI, 0.65–1.4); adjusted OR for one or two UGT1A8*3 variant alleles = 0.95 (0.49–1.9)]. Associations were similar within strata of CYP2D6*4 genotype. Conclusions: Functional polymorphisms in key tamoxifen-metabolizing enzymes were not associated with breast cancer recurrence risk. Impact: Our results do not support the genotyping of key metabolic enzyme polymorphisms to predict response to tamoxifen therapy. Cancer Epidemiol Biomarkers Prev; 20(9); 1937–43. ©2011 AACR.
    Type of Medium: Online Resource
    ISSN: 1055-9965 , 1538-7755
    URL: Article
    DOI: 10.1158/1055-9965.EPI-11-0419
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2011
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  • 5
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    Abstract C49: Relation of family history of cancer to risk of ER+, ER-, and triple-negative breast cancer in African American women
    American Association for Cancer Research (AACR) ; 2016
    In:  Cancer Epidemiology, Biomarkers & Prevention Vol. 25, No. 3_Supplement ( 2016-03-01), p. C49-C49
    Details
    In: Cancer Epidemiology, Biomarkers & Prevention, American Association for Cancer Research (AACR), Vol. 25, No. 3_Supplement ( 2016-03-01), p. C49-C49
    Abstract: Introduction: Family history of breast cancer has been shown to be a strong risk factor for breast cancer in all populations studied. However, there are limited data related to risk of estrogen receptor negative (ER-) breast cancer in African American women, who have a disproportionately high incidence of ER- and triple negative (ER-, progesterone receptor negative, and HER2 receptor negative; TN) breast cancer. Even less information is available on whether a family history of other cancers also affects risk of ER- and TN breast cancer. Methods: Questionnaire data from the Black Women's Health Study, the Carolina Breast Cancer Study, the Multiethnic Cohort Study, and the Women's Circle of Health Study were pooled as part of the African American Breast Cancer Epidemiology and Risk (AMBER) Consortium. Breast cancer cases were classified as ER+, ER-, and TN based on pathology data from medical records and/or state cancer registries. Participants were asked about first degree relatives with a breast cancer diagnosis and the age at which the relative was diagnosed. Participants were also asked about first degree relatives with prostate, lung, colorectal, ovarian, or cervical cancer or with lymphoma or leukemia. Polytomous logistic regression models were used to calculate odds ratios (ORs) and 95% confidence intervals (CIs) for various categories of positive family history relative to no first degree relative with breast cancer or no first degree relative with any of the cancers. Multivariable analyses controlled for age, study, time period, and other potential confounders. Results: The analysis included 3,023 African American women with ER+, 1,497 with ER-, and 696 with TN breast cancer and 17,420 controls. First degree family history of breast cancer, regardless of whether first degree relatives had cancers other than breast cancer, was associated with a 70% increased risk of ER+, ER- and TN breast cancer; the ORs were 1.7 (95% CI 1.6-2.0) for ER+, 1.7 (95% CI 1.4-1.9) for ER-, and 1.7 (95% CI 1.4-2.1) for TN breast cancer. The ORs were somewhat higher if the relative was diagnosed before age 50 (2.0 for ER+, 1.9 for ER-, and 1.8 for TN). Among the six other cancer sites examined, only family history of cervical cancer was significantly associated with risk; the ORs were 2.4 (1.4-4.2) for ER- and 2.9 (1.5-5.5) for TN breast cancer and there was no association with ER+ breast cancer. The OR for family history of ovarian cancer in relation to TN breast cancer was 1.6 (0.9-2.7), which is of interest because findings from The Cancer Genome Atlas (TCGA) indicate that serous ovarian cancers and basal-like breast cancers, which are mostly triple negative, have many molecular commonalities. The ORs for a family history of both breast and prostate cancer versus no family history of any of the cancers were 3.4 (2.4-4.7) for ER+ cancer, as compared with 1.6 for breast alone (p-interaction=0.01), and 2.1 (1.2-3.7) for ER- cancer, as compared with 1.5 for breast alone (p-interaction=0.08). The OR for a family history of both breast and lung cancer was 3.3 (1.9-5.9) for TN breast cancer, compared to 1.5 for breast alone (p-interaction=0.10). The ORs for family history of breast plus two other cancers were 2.4 (1.6-3.6) for ER+, 2.8 (1.6-4.7) for ER-, and 2.7 (1.3-5.7) for TN breast cancer. Conclusion: Our results confirm that having a first degree family history of breast cancer is a strong risk factor for ER+, ER-, and TN breast cancer. The findings also suggest that having relatives with other cancers in addition to a relative with breast cancer may further increase risk. Consideration of family history of other cancers may improve risk prediction models. The association observed for family history of cervical cancer and increased risk of ER- and TN breast cancer was unexpected and needs to be replicated by other studies. Citation Format: Traci N. Bethea, Lynn Rosenberg, Nelsy Castro-Webb, Kathryn L. Lunetta, Lara E. Sucheston, Edward A. Ruiz-Narvaez, Marjory Charlot, Song Y. Park, Elisa V. Bandera, Melissa A. Troester, Christine B. Ambrosone, Julie R. Palmer. Relation of family history of cancer to risk of ER+, ER-, and triple-negative breast cancer in African American women. [abstract]. In: Proceedings of the Eighth AACR Conference on The Science of Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; Nov 13-16, 2015; Atlanta, GA. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2016;25(3 Suppl):Abstract nr C49.
    Type of Medium: Online Resource
    ISSN: 1055-9965 , 1538-7755
    URL: Article
    DOI: 10.1158/1538-7755.DISP15-C49
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2016
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  • 6
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    Abstract PD14-06: PD14-06 Polygenic risk score added to risk calculator improves prediction of breast cancer in U.S. Black women
    American Association for Cancer Research (AACR) ; 2023
    In:  Cancer Research Vol. 83, No. 5_Supplement ( 2023-03-01), p. PD14-06-PD14-06
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 83, No. 5_Supplement ( 2023-03-01), p. PD14-06-PD14-06
    Abstract: We recently derived an absolute breast cancer risk prediction model, the Black Women’s Health Study (BWHS) model, for breast cancer in U.S. Black women using data from three large case-control studies and validated it in independent prospective data from the Black Women’s Health Study (Palmer 2021). The BWHS model includes epidemiologic risk factors as well as family history of breast cancer and family history of prostate cancer. It does not include genetic variants because at the time of model development breast cancer polygenic risk scores performed poorly in women of predominantly African ancestry, primarily due to differences in allele frequency and linkage disequilibrium. More recently, Gao et al. (2022) developed and tested a polygenic risk score (PRS) using 56,943 SNPs for breast cancer in women of African ancestry (AA) based on 9,235 breast cancer cases and 10,184 controls from a large pooled analysis of studies from African American and African women; the c-statistic from cross-validation was 0.581, considerably better than in previous efforts. We evaluated whether adding this AA-PRS to the BWHS risk prediction model would improve risk stratification. We conducted a nested case-control study of 901 breast cancer cases and 1,576 controls matched on age and most recent questionnaire completed from among BWHS participants for whom genome-wide association data were available and who had not been included in the collaboration from which the PRS was derived and tested. We examined discriminatory accuracy, estimated by the area under the receiver operating characteristic curve (AUC), for the risk prediction model alone, the PRS alone, and the combination of risk prediction model and PRS, controlling for the matching factor “questionnaire cycle”. We conducted the analyses within strata of 5-year age and then combined results using inverse-variance weighting. In preliminary analyses, the AUC was 0.579 for the risk prediction model alone and 0.600 for the AA-PRS alone. When the AA-PRS and the BWHS risk prediction model were both used as predictors in a logistic regression model, the AUC increased from 0.579 to 0.622. This improvement in risk stratification is similar to what Kachuri et al. (2020) obtained in an analysis of U.K. Biobank data, where adding a PRS to epidemiologic and personal risk factors showed an improvement from 0.572 to 0.635 in women of European ancestry. The present study provides external validation of a recently derived AA PRS and demonstrates the potential for improving risk stratification for U.S. Black women by adding a PRS to a breast cancer risk prediction model that already includes family history of breast cancer. Citation Format: Gary R. Zirpoli, Kathryn L. Lunetta, Ruth M. Pfeiffer, Julie R. Palmer. PD14-06 Polygenic risk score added to risk calculator improves prediction of breast cancer in U.S. Black women [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr PD14-06.
    Type of Medium: Online Resource
    ISSN: 1538-7445
    URL: Article
    DOI: 10.1158/1538-7445.SABCS22-PD14-06
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2023
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  • 7
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    Abstract 28: Integrating genomic and transcriptomic data to identify genetic loci associated with breast cancer risk in women of African ancestry
    American Association for Cancer Research (AACR) ; 2020
    In:  Cancer Research Vol. 80, No. 16_Supplement ( 2020-08-15), p. 28-28
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 80, No. 16_Supplement ( 2020-08-15), p. 28-28
    Abstract: Background: To date, most genome-wide association studies (GWAS) of breast cancer have been conducted only among women of Asian and European ancestry. It is difficult to generalize results from those studies to women of African ancestry (AA). We conducted a large genetic association study of breast cancer in women of AA by analyzing both genetic and transcriptomic data. Methods: This collaborative study included 11,073 cases and 11,095 controls of AA who were participants in more than 15 studies conducted in the U.S. and Africa. Genotyping data were harmonized and imputed using the 1000 Genomes Project database as the reference. Imputed genotypes were used for GWAS to identify novel genetic risk loci for breast cancer. To search for susceptibility genes, we conducted a transcriptome-wide association study (TWAS), in which gene expression prediction models were built using genetic and tumor tissue RNA sequencing data from ~400 AA patients and used to impute expression levels of genes across the transcriptome for association analyses in all cases and controls included in the GWAS mentioned above. Results: We identified five loci (5p15.33, 5q31.3, 10q26.13, 18q12.1, and 19p13.11) associated with breast cancer risk at P & lt; 5 × 10−8, including a novel locus at 5q31.3 (allelic odds ratio, OR = 1.18, 95% CI = 1.11-1.25, P = 4.65 × 10−8, nearby gene, ARHGAP26). This locus was also identified in association with estrogen receptor (ER) positive breast cancer at P & lt; 5 × 10−8. Analyses stratified by ER status replicated known loci associated specifically with ER-positive (10q26.13) or ER-negative (2q14.2, 2p11.2, 5p15.33) breast cancer at P & lt; 5 × 10−8. Of the 165 lead risk SNPs reported from previous breast cancer GWAS, 35 SNPs were replicated with the same association direction at P & lt; 0.05. We constructed a polygenic risk score using these 35 replicated SNPs and the lead risk SNP at the novel locus and estimated the AUC to be 0.575. Of the 7,592 genes tested in the TWAS, we identified one gene, AC091053.1, with an association at a Bonferroni-corrected threshold of 6.64 × 10−6 (0.05/7,592). AC091053.1 is a long non-coding RNA gene at locus 11p15.4, where no risk variants have been identified in any previous breast cancer GWAS. AC091053.1 is located in the region of protein coding gene DENND2B, which acts as a regulator of MAPK1/ERK2 kinase and reduces the tumorigenic phenotype in cells. The gene AC091053.1 was associated with ER-positive breast cancer with P = 4.11 × 10−5 and ER-negative breast cancer with P = 0.032. Conclusions: Our study, the largest genetic study conducted to date in AA, identified novel breast cancer risk loci at 5q31.3 and 11p15.4 (AC091053.1) among women of AA and replicated & gt;30 associations reported in previous studies. Studies with a larger sample size are needed to further investigate genetic variants and genes associated with breast cancer risk in AA women. Citation Format: Guochong Jia, Jie Ping, Yaohua Yang, Maureen Sanderson, Qiuyin Cai, Xingyi Guo, William J. Blot, Bingshan Li, Elisa V. Bandera, Manjeet K. Bolla, Montserrat García-Closas, Douglas F. Easton, Mary K. Fadden, Jian Gu, Dezheng Huo, Esther M. John, Kathryn L. Lunetta, Olufunmilayo I. Olopade, Xiang Shu, Melissa A. Troester, Song Yao, Breast Cancer Association Consortium, Andrew F. Olshan, Christine B. Ambrosone, Christopher A. Haiman, Jirong Long, Julie R. Palmer, Wei Zheng. Integrating genomic and transcriptomic data to identify genetic loci associated with breast cancer risk in women of African ancestry [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 28.
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    URL: Article
    DOI: 10.1158/1538-7445.AM2020-28
    RVK:
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    RVK:
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    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2020
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  • 8
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    Abstract LB-285: Obesity and breast cancer subtypes in African American women participating in the AMBER Consortium
    American Association for Cancer Research (AACR) ; 2014
    In:  Cancer Research Vol. 74, No. 19_Supplement ( 2014-10-01), p. LB-285-LB-285
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 74, No. 19_Supplement ( 2014-10-01), p. LB-285-LB-285
    Abstract: Introduction. Obesity has been shown to be associated with reduced risk in premenopausal women and increased risk in postmenopausal women, with evidence coming largely from studies in white women. African American (AA) women are more likely than white women to be obese and to have central obesity (measured as a high waist to hip ratio (WHR) or waist circumference). They are also more likely to be diagnosed with ER- and triple negative (TN) breast cancers, which tend to have poorer prognosis than ER+ tumors. There is growing evidence that risk profiles for these subtypes may differ. However, few studies have evaluated the impact of general and central obesity on breast cancer subtypes in AA women. Methods. We pooled data from three studies in AA women, the Black Women Health Study, the Carolina Breast Cancer Study, and the Women's Circle of Health Study, to evaluate the association of recent body mass index (BMI), young adult BMI (at age 18-21 y), and waist to hip ratio (WHR) with breast cancer subtypes. Cases were categorized according to hormone receptor subtype as ER+, ER-, and triple negative (TN: ER-, PR-, and HER2-) based on pathology reports or cancer registry data. A total of 1,809 ER+ cases, 1,024 ER- cases (which included 478 TN cases), and 9,593 controls were included in the analyses. Odds ratios (OR) and 95% confidence intervals (CI) were computed using unconditional polytomous or regular logistic regression, as appropriate, taking into account all major risk factors for breast cancer. Results. Recent BMI was inversely associated with postmenopausal ER- breast cancer (OR: 0.74; 95% CI: 0.53-1.02), and more strongly with tumors that were also PR- and HER2- (TN), (OR: 0.61; 95% CI: 0.39-0.97 for BMI≥35 vs. & lt;25). For ER+, ORs were below one for pre-menopausal and above one for post-menopausal breast cancer, but confidence intervals included 1.0. However, among women who were thin as young adults (BMI & lt;19.4, lowest tertile), recent high BMI (≥35) was associated with more than a twofold increase in risk of postmenopausal ER+ breast cancer (OR: 2.24; 95% CI 1.46-3.43, p for interaction: 0.02). Associations between recent BMI and ER- breast cancer did not differ by young-adult BMI. There was a suggestion of increased risk for high WHR (highest vs. lowest quartile) independent of BMI, which only approached statistical significance for premenopausal ER+ tumors (OR: 1.31; 95% CI: 0.98-1.75; p for trend: 0.05). In analyses of the joint effects of recent BMI and WHR, the association of WHR with ER+ tumors in postmenopausal women was strongest for women with normal BMI (OR: 1.61; 95% CI: 1.02-2.56), p for interaction: 0.05. Conclusion. Our results indicate the need to consider subtypes when evaluating the impact of general and central obesity on breast cancer and warrant the study of mechanisms underlying these complex associations. Citation Format: Elisa V. Bandera, Urmila Chandran, Chi-Chen Hong, Christine B. Ambrosone, Melissa Troester, Kathryn L. Lunetta, Lucile Adams-Campbell, Andrew Olshan, Julie R. Palmer, Lynn Rosenberg. Obesity and breast cancer subtypes in African American women participating in the AMBER Consortium. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr LB-285. doi:10.1158/1538-7445.AM2014-LB-285
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    URL: Article
    DOI: 10.1158/1538-7445.AM2014-LB-285
    RVK:
    XA 36000
    RVK:
    XA 10000
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2014
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    Abstract 814: Gene-based analysis of the IGF signaling pathway and risk of breast cancer in African American women: The AMBER consortium
    American Association for Cancer Research (AACR) ; 2016
    In:  Cancer Research Vol. 76, No. 14_Supplement ( 2016-07-15), p. 814-814
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 76, No. 14_Supplement ( 2016-07-15), p. 814-814
    Abstract: Dysregulation of the IGF (insulin-like growth factor) signaling pathway plays a key role in cancer development. It is still unclear whether germline variation in genes in the IGF pathway may affect risk of breast cancer. We conducted a gene-based analysis of 184 genes in the IGF signaling pathway to identify genes carrying genetic variation affecting risk of breast cancer and the specific estrogen receptor (ER) subtypes. Tagging single nucleotide polymorphisms (SNPs) for each gene were selected and genotyped on a customized Illumina Exome Array. Imputation was carried out using 1000 Genomes haplotypes. The analysis included 91,627 SNPs in 3,663 breast cancer cases (including 1,983 ER positive,1,098 ER-negative) and 4,687 controls from the African American Breast Cancer Epidemiology and Risk (AMBER) consortium, a collaborative project of four large studies of breast cancer in African American women (Carolina Breast Cancer Study, Black Women's Health Study, Women's Circle of Health Study, and Multiethnic Cohort). We used a multi-locus adaptive joint (AdaJoint) test to determine the association of each gene in the IGF signaling pathway with overall breast cancer and ER subtypes. None of the 184 tested genes, including IGF, IGF binding protein (IGFBP), and IGF receptor (IGFR) genes were associated with disease after adjustment for multiple testing. At the nominal level of P≤0.01, BAIAP2 (P = 0.003), and CALM2 (P = 0.009) genes were associated with overall breast cancer; BAIAP2 (P = 0.001), and CSNK2A1 (P = 0.01) with ER+ breast cancer; and BRAF (P = 0.003), BAD (P = 0.005), and MAPK3 (P = 0.009) with ER- breast cancer. The intronic rs9913477 SNP in the BAIPA2 gene was significantly associated with overall (P = 3.2×10−7) and ER+ (P = 4.4×10−7) breast cancer at the pathway-wide level after adjusting for the total number of tested SNPs. Odds ratios and 95% confidence intervals of the risk G-allele were 1.44 (1.25, 1.66), and 1.53 (1.30, 1.81) for overall and ER+ breast cancer, respectively. BAIAP2 codes an adaptor protein, IRSp53, which functions as a substrate of the insulin receptor and IGF-1 receptor tyrosine kinases and links Rho-family small GTPases such as Rac. In vitro studies have shown that activation of Rac promotes metastatic behavior of breast cancer cells. In conclusion, we identified a SNP in BAIAP2 associated with overall and ER+ breast cancer. These results highlight the importance of the IGF signaling pathway in the pathogenesis of breast cancer. Citation Format: Edward A. Ruiz-Narvaez, Kathryn L. Lunetta, Chi-Chen Hong, Stephen A. Haddad, Song Yao, Ting-Yuan D. Cheng, Jeannette T. Bensen, Elisa V. Bandera, Christopher A. Haiman, Andrew F. Olshan, Christine B. Ambrosone, Lynn Rosenberg, Julie R. Palmer. Gene-based analysis of the IGF signaling pathway and risk of breast cancer in African American women: The AMBER consortium. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 814.
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    URL: Article
    DOI: 10.1158/1538-7445.AM2016-814
    RVK:
    XA 36000
    RVK:
    XA 10000
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2016
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    Abstract 2790: Gene-based analysis of the fibroblast growth factor receptor signaling pathway identifies an association of the FGF1 gene with risk of estrogen receptor-negative breast cancer: The AMBER consortium
    American Association for Cancer Research (AACR) ; 2015
    In:  Cancer Research Vol. 75, No. 15_Supplement ( 2015-08-01), p. 2790-2790
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 75, No. 15_Supplement ( 2015-08-01), p. 2790-2790
    Abstract: Fibroblast growth factors (FGFs) and their receptors (FGFRs) play key roles in several cellular processes such as differentiation, proliferation, migration and survival. Deregulation of the FGFR signaling pathway has been associated with human cancer including breast cancer, and GWAS-identified polymorphisms in the FGFR2 gene have been associated with risk of both overall and estrogen receptor (ER)-positive breast cancer. We conducted gene-based analysis in 26 genes in the FGFR signaling pathway to identify genes carrying genetic variation affecting risk of breast cancer and the specific ER subtypes. Tagging single nucleotide polymorphisms (SNPs) at ±10 kb of each gene were selected and genotyped in a customized Illumina Exome Array. Imputation was carried out using 1000 Genomes haplotypes. The analysis included 9,264 SNPs in 3,663 breast cancer cases (including 1,983 estrogen receptor-positive (ER+), and 1,098 estrogen receptor-negative (ER-)) and 4,687 controls from the African American Breast Cancer Epidemiology and Risk (AMBER) consortium, a collaborative study of four of the largest studies of breast cancer in African American women (Carolina Breast Cancer Study, Black Women's Health Study, Women's Circle of Health Study, and Multi-Ethnic Cohort). We used the adaptive rank-truncated product (ARTP) method implemented in R-package PIGE to determine the association of each gene in the FGFR signaling pathway with overall breast cancer, and ER subtypes. Analyses were adjusted for principal components of genetic variation to control for population stratification, age, geographic region of residence, study, and source of DNA. An alpha level of 0.002 ( = 0.05/26 genes) was used to determine statistical significance at the gene-wide level. After adjustment for multiple testing the FGF1 gene was associated with risk of ER-negative breast cancer (p = 0.001). The FGF1 gene codes for the fibroblast growth factor 1. Genetic variation in this gene has been reported to be associated with risk of ovarian cancer and with breast cancer survival. As expected, the FGFR2 gene was associated with risk of overall breast cancer (p = 0.001) and ER-positive breast cancer (p = 0.002). In summary, we found that the FGF1 gene affects risk of ER-negative breast cancer in African American women, and we confirmed the association of the FGFR2 gene with risk of overall and ER-positive breast cancer. These results highlight the importance of the FGFR signaling pathway in the pathogenesis of breast cancer, and suggest that different genes in the same pathway may be associated with different ER breast cancer subtypes. Citation Format: Edward A. Ruiz-Narvaez, Stephen Haddad, Christopher A. Haiman, Song Yao, Lara E. Sucheston-Campbell, Jeanette T. Bensen, Kathryn L. Lunetta, Andrew F. Olshan, Christine B. Ambrosone, Julie R. Palmer. Gene-based analysis of the fibroblast growth factor receptor signaling pathway identifies an association of the FGF1 gene with risk of estrogen receptor-negative breast cancer: The AMBER consortium. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 2790. doi:10.1158/1538-7445.AM2015-2790
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    URL: Article
    DOI: 10.1158/1538-7445.AM2015-2790
    RVK:
    XA 36000
    RVK:
    XA 10000
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2015
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