| 1. |
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| 2. |
- Campa, Daniele, et al.
(författare)
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Interactions Between Genetic Variants and Breast Cancer Risk Factors in the Breast and Prostate Cancer Cohort Consortium
- 2011
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Ingår i: Journal of the National Cancer Institute. - : Oxford University Press (OUP). - 0027-8874 .- 1460-2105. ; 103:16, s. 1252-1263
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Tidskriftsartikel (refereegranskat)abstract
- Background Recently, several genome-wide association studies have identified various genetic susceptibility loci for breast cancer. Relatively little is known about the possible interactions between these loci and the established risk factors for breast cancer. Methods To assess interactions between single-nucleotide polymorphisms (SNPs) and established risk factors, we prospectively collected DNA samples and questionnaire data from 8576 breast cancer case subjects and 11 892 control subjects nested within the National Cancer Institute's Breast and Prostate Cancer Cohort Consortium (BPC3). We genotyped 17 germline SNPs (FGFR2-rs2981582, FGFR2-rs3750817, TNRC9-rs3803662, 2q35-rs13387042, MAP3K1-rs889312, 8q24-rs13281615, CASP8-rs1045485, LSP1-rs3817198, COL1A1-rs2075555, COX11-rs6504950, RNF146-rs2180341, 6q25-rs2046210, SLC4A7-rs4973768, NOTCH2-rs11249433, 5p12-rs4415084, 5p12-rs10941679, RAD51L1-rs999737), and odds ratios were estimated by logistic regression to confirm previously reported associations with breast cancer risk. We performed likelihood ratio test to assess interactions between 17 SNPs and nine established risk factors (age at menarche, parity, age at menopause, use of hormone replacement therapy, family history, height, body mass index, smoking status, and alcohol consumption), and a correction for multiple testing of 153 tests (adjusted P value threshold = .05/153 = 3 x 10(-4)) was done. Casecase comparisons were performed for possible differential associations of polymorphisms by subgroups of tumor stage, estrogen and progesterone receptor status, and age at diagnosis. All statistical tests were two-sided. Results We confirmed the association of 14 SNPs with breast cancer risk (P(trend) = 2.57 x 10(-3) -3.96 x 10(-19)). Three SNPs (LSP1-rs3817198, COL1A1-rs2075555, and RNF146-rs2180341) did not show association with breast cancer risk. After accounting for multiple testing, no statistically significant interactions were detected between the 17 SNPs and the nine risk factors. We also confirmed that SNPs in FGFR2 and TNRC9 were associated with greater risk of estrogen receptor-positive than estrogen receptor-negative breast cancer (P(heterogeneity) = .0016 for FGFR2-rs2981582 and P(heterogeneity) = .0053 for TNRC9-rs3803662). SNP 5p12-rs10941679 was statistically significantly associated with greater risk of progesterone receptor-positive than progesterone receptor-negative breast cancer (P(heterogeneity) = .0028). Conclusion This study does not support the hypothesis that known common breast cancer susceptibility loci strongly modify the associations between established risk factors and breast cancer.
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| 3. |
- Canzian, Federico, et al.
(författare)
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Comprehensive analysis of common genetic variation in 61 genes related to steroid hormone and insulin-like growth factor-I metabolism and breast cancer risk in the NCI breast and prostate cancer cohort consortium.
- 2010
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Ingår i: Human Molecular Genetics. - : Oxford University Press (OUP). - 0964-6906 .- 1460-2083. ; 19:19, s. 3873-84
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Tidskriftsartikel (refereegranskat)abstract
- There is extensive evidence that increases in blood and tissue concentrations of steroid hormones and of insulin-like growth factor I (IGF-I) are associated with breast cancer risk. However, studies of common variation in genes involved in steroid hormone and IGF-I metabolism have yet to provide convincing evidence that such variants predict breast cancer risk. The Breast and Prostate Cancer Cohort Consortium (BPC3) is a collaboration of large US and European cohorts. We genotyped 1416 tagging single nucleotide polymorphisms (SNPs) in 37 steroid hormone metabolism genes and 24 IGF-I pathway genes in 6292 cases of breast cancer and 8135 controls, mostly Caucasian, postmenopausal women from the BPC3. We also imputed 3921 additional SNPs in the regions of interest. None of the SNPs tested was significantly associated with breast cancer risk, after correction for multiple comparisons. The results remained null when cases and controls were stratified by age at diagnosis/recruitment, advanced or nonadvanced disease, body mass index, with or without in situ cases; or restricted to Caucasians. Among 770 estrogen receptor-negative cases, an SNP located 3' of growth hormone receptor (GHR) was marginally associated with increased risk after correction for multiple testing (P(trend) = 1.5 × 10(-4)). We found no significant overall associations between breast cancer and common germline variation in 61 genes involved in steroid hormone and IGF-I metabolism in this large, comprehensive study. Although previous studies have shown that variations in these genes can influence endogenous hormone levels, the magnitude of the effect of single SNPs does not appear to be sufficient to alter breast cancer risk.
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| 4. |
- Canzian, Federico, et al.
(författare)
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Genetic polymorphisms of the GNRH1 and GNRHR genes and risk of breast cancer in the National Cancer Institute Breast and Prostate Cancer Cohort Consortium (BPC3).
- 2009
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Ingår i: BMC cancer. - : Springer Science and Business Media LLC. - 1471-2407. ; 9, s. 257-
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: Gonadotropin releasing hormone (GNRH1) triggers the release of follicle stimulating hormone and luteinizing hormone from the pituitary. Genetic variants in the gene encoding GNRH1 or its receptor may influence breast cancer risk by modulating production of ovarian steroid hormones. We studied the association between breast cancer risk and polymorphisms in genes that code for GNRH1 and its receptor (GNRHR) in the large National Cancer Institute Breast and Prostate Cancer Cohort Consortium (NCI-BPC3). METHODS: We sequenced exons of GNRH1 and GNRHR in 95 invasive breast cancer cases. Resulting single nucleotide polymorphisms (SNPs) were genotyped and used to identify haplotype-tagging SNPs (htSNPS) in a panel of 349 healthy women. The htSNPs were genotyped in 5,603 invasive breast cancer cases and 7,480 controls from the Cancer Prevention Study-II (CPS-II), European Prospective Investigation on Cancer and Nutrition (EPIC), Multiethnic Cohort (MEC), Nurses' Health Study (NHS), and Women's Health Study (WHS). Circulating levels of sex steroids (androstenedione, estradiol, estrone and testosterone) were also measured in 4713 study subjects. RESULTS: Breast cancer risk was not associated with any polymorphism or haplotype in the GNRH1 and GNRHR genes, nor were there any statistically significant interactions with known breast cancer risk factors. Polymorphisms in these two genes were not strongly associated with circulating hormone levels. CONCLUSION: Common variants of the GNRH1 and GNRHR genes are not associated with risk of invasive breast cancer in Caucasians.
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| 5. |
- Couch, Fergus J., et al.
(författare)
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AURKA F31I polymorphism and breast cancer risk in BRCA1 and BRCA2 mutation carriers: A consortium of investigators of modifiers of BRCA1/2 study
- 2007
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Ingår i: Cancer Epidemiology Biomarkers & Prevention. - 1538-7755. ; 16:7, s. 1416-1421
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Tidskriftsartikel (refereegranskat)abstract
- The AURKA oncogene is associated with abnormal chromosome segregation and aneuploidy and predisposition to cancer. Amplification of AURKA has been detected at higher frequency in tumors from BRCA1 and BRCA2 mutation carriers than in sporadic breast tumors, suggesting that overexpression of AURKA and inactivation of BRCA1 and BRCA2 cooperate during tumor development and progression. The F31I polymorphism in AURKA has been associated with breast cancer risk in the homozygous state in prior studies. We evaluated whether the AURKA F31I polymorphism modifies breast cancer risk in BRCA1 and BRCA2 mutation carriers from the Consortium of Investigators of Modifiers of BRCA1/2. Consortium of Investigators of Modifiers of BRCA1/2 was established to provide sufficient statistical power through increased numbers of mutation carriers to identify polymorphisms that act as modifiers of cancer risk and can refine breast cancer risk estimates in BRCA1 and BRCA2 mutation carriers. A total of 4,935 BRCA1 and 2,241 BRCA2 mutation carriers and 11 individuals carrying both BRCA1 and BRCA2 mutations was genotyped for F31I. Overall, homozygosity for the 311 allele was not significantly associated with breast cancer risk in BRCA1 and BRCA2 carriers combined [hazard ratio (HR), 0.91; 95% confidence interval (95% CI), 0.77-1.061. Similarly, no significant association was seen in BRCA1 (HR, 0.90; 95% Cl, 0.75-1.08) or BRCA2 carriers (HR, 0.93; 95% CI, 0.67-1.29) or when assessing the modifying effects of either bilateral prophylactic oophorectomy or menopausal status of BRCA1 and BRCA2 carriers. In summary, the F31I polymorphism in AURKA is not associated with a modified risk of breast cancer in BRCA1 and BRCA2 carriers.
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| 6. |
- Couch, Fergus J., et al.
(författare)
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Identification of four novel susceptibility loci for oestrogen receptor negative breast cancer
- 2016
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Ingår i: Nature Communications. - : NATURE PUBLISHING GROUP. - 2041-1723. ; 7:11375, s. 1-13
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Tidskriftsartikel (refereegranskat)abstract
- Common variants in 94 loci have been associated with breast cancer including 15 loci with genome-wide significant associations (P<5 x 10(-8)) with oestrogen receptor (ER)-negative breast cancer and BRCA1-associated breast cancer risk. In this study, to identify new ER-negative susceptibility loci, we performed a meta-analysis of 11 genome-wide association studies (GWAS) consisting of 4,939 ER-negative cases and 14,352 controls, combined with 7,333 ER-negative cases and 42,468 controls and 15,252 BRCA1 mutation carriers genotyped on the iCOGS array. We identify four previously unidentified loci including two loci at 13q22 near KLF5, a 2p23.2 locus near WDR43 and a 2q33 locus near PPIL3 that display genome-wide significant associations with ER-negative breast cancer. In addition, 19 known breast cancer risk loci have genome-wide significant associations and 40 had moderate associations (P<0.05) with ER-negative disease. Using functional and eQTL studies we implicate TRMT61B and WDR43 at 2p23.2 and PPIL3 at 2q33 in ER-negative breast cancer aetiology. All ER-negative loci combined account for similar to 11% of familial relative risk for ER-negative disease and may contribute to improved ER-negative and BRCA1 breast cancer risk prediction.
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| 7. |
- Ding, Yuan C, et al.
(författare)
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A nonsynonymous polymorphism in IRS1 modifies risk of developing breast and ovarian cancers in BRCA1 and ovarian cancer in BRCA2 mutation carriers
- 2012
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Ingår i: Cancer Epidemiology, Biomarkers and Prevention. - : American Association for Cancer Research. - 1055-9965 .- 1538-7755. ; 21:8, s. 1362-1370
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: We previously reported significant associations between genetic variants in insulin receptor substrate 1 (IRS1) and breast cancer risk in women carrying BRCA1 mutations. The objectives of this study were to investigate whether the IRS1 variants modified ovarian cancer risk and were associated with breast cancer risk in a larger cohort of BRCA1 and BRCA2 mutation carriers.METHODS: IRS1 rs1801123, rs1330645, and rs1801278 were genotyped in samples from 36 centers in the Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA). Data were analyzed by a retrospective cohort approach modeling the associations with breast and ovarian cancer risks simultaneously. Analyses were stratified by BRCA1 and BRCA2 status and mutation class in BRCA1 carriers.RESULTS: Rs1801278 (Gly972Arg) was associated with ovarian cancer risk for both BRCA1 (HR, 1.43; 95% confidence interval (CI), 1.06-1.92; P = 0.019) and BRCA2 mutation carriers (HR, 2.21; 95% CI, 1.39-3.52, P = 0.0008). For BRCA1 mutation carriers, the breast cancer risk was higher in carriers with class II mutations than class I mutations (class II HR, 1.86; 95% CI, 1.28-2.70; class I HR, 0.86; 95%CI, 0.69-1.09; P(difference), 0.0006). Rs13306465 was associated with ovarian cancer risk in BRCA1 class II mutation carriers (HR, 2.42; P = 0.03).CONCLUSION: The IRS1 Gly972Arg single-nucleotide polymorphism, which affects insulin-like growth factor and insulin signaling, modifies ovarian cancer risk in BRCA1 and BRCA2 mutation carriers and breast cancer risk in BRCA1 class II mutation carriers.Impact: These findings may prove useful for risk prediction for breast and ovarian cancers in BRCA1 and BRCA2 mutation carriers.
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| 8. |
- Gaudet, Mia M, et al.
(författare)
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Pooled analysis of active cigarette smoking and invasive breast cancer risk in 14 cohort studies.
- 2017
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Ingår i: International Journal of Epidemiology. - : Oxford University Press (OUP). - 0300-5771 .- 1464-3685. ; 46:3, s. 881-893
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Tidskriftsartikel (refereegranskat)abstract
- Background: The 2014 US Surgeon General's report noted research gaps necessary to determine a causal relationship between active cigarette smoking and invasive breast cancer risk, including the role of alcohol consumption, timing of exposure, modification by menopausal status and heterogeneity by oestrogen receptor (ER) status.Methods: To address these issues, we pooled data from 14 cohort studies contributing 934 681 participants (36 060 invasive breast cancer cases). Cox proportional hazard regression models were used to calculate multivariable-adjusted hazard ratios (HRs) and 95% confidence intervals (CIs).Results: Smoking duration before first birth was positively associated with risk ( P -value for trend = 2 × 10 -7 ) with the highest HR for initiation >10 years before first birth (HR = 1.18, CI 1.12-1.24). Effect modification by current alcohol consumption was evident for the association with smoking duration before first birth ( P -value=2×10 -4 ); compared with never-smoking non-drinkers, initiation >10 years before first birth was associated with risk in every category of alcohol intake, including non-drinkers (HR = 1.15, CI 1.04-1.28) and those who consumed at least three drinks per day (1.85, 1.55-2.21). Associations with smoking before first birth were limited to risk of ER+ breast cancer ( P -value for homogeneity=3×10 -3 ). Other smoking timing and duration characteristics were associated with risk even after controlling for alcohol, but were not associated with risk in non-drinkers. Effect modification by menopause was not evident.Conclusions: Smoking, particularly if initiated before first birth, was modestly associated with ER+ breast cancer risk that was not confounded by amount of adult alcohol intake. Possible links with breast cancer provide additional motivation for young women to not initiate smoking.
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| 9. |
- Hamdi, Yosr, et al.
(författare)
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Association of breast cancer risk in BRCA1 and BRCA2 mutation carriers with genetic variants showing differential allelic expression : identification of a modifier of breast cancer risk at locus 11q22.3
- 2017
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Ingår i: Breast Cancer Research and Treatment. - : Springer Science and Business Media LLC. - 0167-6806 .- 1573-7217. ; 161:1, s. 117-134
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Tidskriftsartikel (refereegranskat)abstract
- Purpose: Cis-acting regulatory SNPs resulting in differential allelic expression (DAE) may, in part, explain the underlying phenotypic variation associated with many complex diseases. To investigate whether common variants associated with DAE were involved in breast cancer susceptibility among BRCA1 and BRCA2 mutation carriers, a list of 175 genes was developed based of their involvement in cancer-related pathways. Methods: Using data from a genome-wide map of SNPs associated with allelic expression, we assessed the association of ~320 SNPs located in the vicinity of these genes with breast and ovarian cancer risks in 15,252 BRCA1 and 8211 BRCA2 mutation carriers ascertained from 54 studies participating in the Consortium of Investigators of Modifiers of BRCA1/2. Results: We identified a region on 11q22.3 that is significantly associated with breast cancer risk in BRCA1 mutation carriers (most significant SNP rs228595 p = 7 × 10−6). This association was absent in BRCA2 carriers (p = 0.57). The 11q22.3 region notably encompasses genes such as ACAT1, NPAT, and ATM. Expression quantitative trait loci associations were observed in both normal breast and tumors across this region, namely for ACAT1, ATM, and other genes. In silico analysis revealed some overlap between top risk-associated SNPs and relevant biological features in mammary cell data, which suggests potential functional significance. Conclusion: We identified 11q22.3 as a new modifier locus in BRCA1 carriers. Replication in larger studies using estrogen receptor (ER)-negative or triple-negative (i.e., ER-, progesterone receptor-, and HER2-negative) cases could therefore be helpful to confirm the association of this locus with breast cancer risk.
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| 10. |
- Hollestelle, Antoinette, et al.
(författare)
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No clinical utility of KRAS variant rs61764370 for ovarian or breast cancer
- 2016
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Ingår i: Gynecologic Oncology. - : Elsevier BV. - 0090-8258 .- 1095-6859. ; 141:2, s. 386-401
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Tidskriftsartikel (refereegranskat)abstract
- Objective Clinical genetic testing is commercially available for rs61764370, an inherited variant residing in a KRAS 3′ UTR microRNA binding site, based on suggested associations with increased ovarian and breast cancer risk as well as with survival time. However, prior studies, emphasizing particular subgroups, were relatively small. Therefore, we comprehensively evaluated ovarian and breast cancer risks as well as clinical outcome associated with rs61764370. Methods Centralized genotyping and analysis were performed for 140,012 women enrolled in the Ovarian Cancer Association Consortium (15,357 ovarian cancer patients; 30,816 controls), the Breast Cancer Association Consortium (33,530 breast cancer patients; 37,640 controls), and the Consortium of Modifiers of BRCA1 and BRCA2 (14,765 BRCA1 and 7904 BRCA2 mutation carriers). Results We found no association with risk of ovarian cancer (OR = 0.99, 95% CI 0.94-1.04, p = 0.74) or breast cancer (OR = 0.98, 95% CI 0.94-1.01, p = 0.19) and results were consistent among mutation carriers (BRCA1, ovarian cancer HR = 1.09, 95% CI 0.97-1.23, p = 0.14, breast cancer HR = 1.04, 95% CI 0.97-1.12, p = 0.27; BRCA2, ovarian cancer HR = 0.89, 95% CI 0.71-1.13, p = 0.34, breast cancer HR = 1.06, 95% CI 0.94-1.19, p = 0.35). Null results were also obtained for associations with overall survival following ovarian cancer (HR = 0.94, 95% CI 0.83-1.07, p = 0.38), breast cancer (HR = 0.96, 95% CI 0.87-1.06, p = 0.38), and all other previously-reported associations. Conclusions rs61764370 is not associated with risk of ovarian or breast cancer nor with clinical outcome for patients with these cancers. Therefore, genotyping this variant has no clinical utility related to the prediction or management of these cancers.
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| 11. |
- Huesing, Anika, et al.
(författare)
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Prediction of breast cancer risk by genetic risk factors, overall and by hormone receptor status
- 2012
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Ingår i: Journal of Medical Genetics. - : BMJ. - 0022-2593 .- 1468-6244. ; 49:9, s. 601-608
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Tidskriftsartikel (refereegranskat)abstract
- Objective There is increasing interest in adding common genetic variants identified through genome wide association studies (GWAS) to breast cancer risk prediction models. First results from such models showed modest benefits in terms of risk discrimination. Heterogeneity of breast cancer as defined by hormone-receptor status has not been considered in this context. In this study we investigated the predictive capacity of 32 GWAS-detected common variants for breast cancer risk, alone and in combination with classical risk factors, and for tumours with different hormone receptor status. Material and methods Within the Breast and Prostate Cancer Cohort Consortium, we analysed 6009 invasive breast cancer cases and 7827 matched controls of European ancestry, with data on classical breast cancer risk factors and 32 common gene variants identified through GWAS. Discriminatory ability with respect to breast cancer of specific hormone receptor-status was assessed with the age adjusted and cohort-adjusted concordance statistic (AUROC(a)). Absolute risk scores were calculated with external reference data. Integrated discrimination improvement was used to measure improvements in risk prediction. Results We found a small but steady increase in discriminatory ability with increasing numbers of genetic variants included in the model (difference in AUROC(a) going from 2.7% to 4%). Discriminatory ability for all models varied strongly by hormone receptor status. Discussion and conclusions Adding information on common polymorphisms provides small but statistically significant improvements in the quality of breast cancer risk prediction models. We consistently observed better performance for receptor-positive cases, but the gain in discriminatory quality is not sufficient for clinical application.
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| 12. |
- Joshi, Amit D., et al.
(författare)
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Additive interactions between susceptibility single-nucleotide polymorphisms identified in genome-wide association studies and breast cancer risk factors in the Breast and Prostate Cancer Cohort Consortium
- 2014
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Ingår i: American Journal of Epidemiology. - : Oxford University Press. - 0002-9262 .- 1476-6256. ; 180:10, s. 1018-1027
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Tidskriftsartikel (refereegranskat)abstract
- Additive interactions can have public health and etiological implications but are infrequently reported. We assessed departures from additivity on the absolute risk scale between 9 established breast cancer risk factors and 23 susceptibility single-nucleotide polymorphisms (SNPs) identified from genome-wide association studies among 10,146 non-Hispanic white breast cancer cases and 12,760 controls within the National Cancer Institute's Breast and Prostate Cancer Cohort Consortium. We estimated the relative excess risk due to interaction and its 95% confidence interval for each pairwise combination of SNPs and nongenetic risk factors using age- and cohort-adjusted logistic regression models. After correction for multiple comparisons, we identified a statistically significant relative excess risk due to interaction (uncorrected P = 4.51 x 10(-5)) between a SNP in the DNA repair protein RAD51 homolog 2 gene (RAD51L1; rs10483813) and body mass index (weight (kg)/height (m)(2)). We also compared additive and multiplicative polygenic risk prediction models using per-allele odds ratio estimates from previous studies for breast-cancer susceptibility SNPs and observed that the multiplicative model had a substantially better goodness of fit than the additive model.
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| 13. |
- Lawrenson, Kate, et al.
(författare)
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Functional mechanisms underlying pleiotropic risk alleles at the 19p13.1 breast-ovarian cancer susceptibility locus
- 2016
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Ingår i: Nature Communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 7
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Tidskriftsartikel (refereegranskat)abstract
- A locus at 19p13 is associated with breast cancer (BC) and ovarian cancer (OC) risk. Here we analyse 438 SNPs in this region in 46,451 BC and 15,438 OC cases, 15,252 BRCA1 mutation carriers and 73,444 controls and identify 13 candidate causal SNPs associated with serous OC (P=9.2 × 10-20), ER-negative BC (P=1.1 × 10-13), BRCA1-associated BC (P=7.7 × 10-16) and triple negative BC (P-diff=2 × 10-5). Genotype-gene expression associations are identified for candidate target genes ANKLE1 (P=2 × 10-3) and ABHD8 (P<2 × 10-3). Chromosome conformation capture identifies interactions between four candidate SNPs and ABHD8, and luciferase assays indicate six risk alleles increased transactivation of the ADHD8 promoter. Targeted deletion of a region containing risk SNP rs56069439 in a putative enhancer induces ANKLE1 downregulation; and mRNA stability assays indicate functional effects for an ANKLE1 3′-UTR SNP. Altogether, these data suggest that multiple SNPs at 19p13 regulate ABHD8 and perhaps ANKLE1 expression, and indicate common mechanisms underlying breast and ovarian cancer risk.
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| 14. |
- Lu, Yingchang, et al.
(författare)
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A Transcriptome-Wide Association Study Among 97,898 Women to Identify Candidate Susceptibility Genes for Epithelial Ovarian Cancer Risk.
- 2018
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Ingår i: Cancer Research. - 0008-5472 .- 1538-7445. ; 78:18, s. 5419-5430
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Tidskriftsartikel (refereegranskat)abstract
- .AbstractLarge-scale genome-wide association studies (GWAS) have identified approximately 35 loci associated with epithelial ovarian cancer (EOC) risk. The majority of GWAS-identified disease susceptibility variants are located in noncoding regions, and causal genes underlying these associations remain largely unknown. Here, we performed a transcriptome-wide association study to search for novel genetic loci and plausible causal genes at known GWAS loci. We used RNA sequencing data (68 normal ovarian tissue samples from 68 individuals and 6,124 cross-tissue samples from 369 individuals) and high-density genotyping data from European descendants of the Genotype-Tissue Expression (GTEx V6) project to build ovarian and cross-tissue models of genetically regulated expression using elastic net methods. We evaluated 17,121 genes for their cis-predicted gene expression in relation to EOC risk using summary statistics data from GWAS of 97,898 women, including 29,396 EOC cases. With a Bonferroni-corrected significance level of P < 2.2 × 10−6, we identified 35 genes, including FZD4 at 11q14.2 (Z = 5.08, P = 3.83 × 10−7, the cross-tissue model; 1 Mb away from any GWAS-identified EOC risk variant), a potential novel locus for EOC risk. All other 34 significantly associated genes were located within 1 Mb of known GWAS-identified loci, including 23 genes at 6 loci not previously linked to EOC risk. Upon conditioning on nearby known EOC GWAS-identified variants, the associations for 31 genes disappeared and three genes remained (P < 1.47 × 10−3). These data identify one novel locus (FZD4) and 34 genes at 13 known EOC risk loci associated with EOC risk, providing new insights into EOC carcinogenesis.Significance: Transcriptomic analysis of a large cohort confirms earlier GWAS loci and reveals FZD4 as a novel locus associated with EOC risk. Cancer Res; 78(18); 5419–30. ©2018 AACR.
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| 15. |
- Pfeiler, Georg, et al.
(författare)
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Impact of BMI in Patients With Early Hormone Receptor-Positive Breast Cancer Receiving Endocrine Therapy With or Without Palbociclib in the PALLAS Trial
- 2023
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Ingår i: JOURNAL OF CLINICAL ONCOLOGY. - 0732-183X .- 1527-7755. ; 41:33
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Tidskriftsartikel (refereegranskat)abstract
- PURPOSEBMI affects breast cancer risk and prognosis. In contrast to cytotoxic chemotherapy, CDK4/6 inhibitors are given at a fixed dose, irrespective of BMI or weight. This preplanned analysis of the global randomized PALLAS trial investigates the impact of BMI on the side-effect profile, treatment adherence, and efficacy of palbociclib.METHODSPatients were categorized at baseline according to WHO BMI categories. Neutropenia rates were assessed with univariable and multivariable logistic regression. Time to early discontinuation of palbociclib was analyzed with Fine and Gray competing risk models. Unstratified Cox models were used to investigate the association between BMI category and time to invasive disease-free survival (iDFS). 95% CIs were derived.RESULTSOf 5,698 patients included in this analysis, 68 (1.2%) were underweight, 2,082 (36.5%) normal weight, 1,818 (31.9%) overweight, and 1,730 (30.4%) obese at baseline. In the palbociclib arm, higher BMI was associated with a significant decrease in neutropenia (unadjusted odds ratio for 1-unit change, 0.93; 95% CI, 0.91 to 0.94; adjusted for age, race ethnicity, region, chemotherapy use, and Eastern Cooperative Oncology Group at baseline, 0.93; 95% CI, 0.92 to 0.95). This translated into a significant decrease in treatment discontinuation rate with higher BMI (adjusted hazard ratio [HR] for 10-unit change, 0.75; 95% CI, 0.67 to 0.83). There was no significant improvement in iDFS with the addition of palbociclib to ET in any weight category (normal weight HR, 0.84; 95% CI, 0.63 to 1.12; overweight HR, 1.10; 95% CI, 0.82 to 1.49; and obese HR, 0.95; 95% CI, 0.69 to 1.30) in this analysis early in follow-up (31 months).CONCLUSIONThis preplanned analysis of the PALLAS trial demonstrates a significant impact of BMI on side effects, dose reductions, early treatment discontinuation, and relative dose intensity. Additional long-term follow-up will further evaluate whether BMI ultimately affects outcome. This preplanned analysis of the PALLAS trial demonstrates a significant impact of BMI on side effects, dose reductions, early treatment discontinuation, and relative dose intensity.
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| 16. |
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| 17. |
- Rebbeck, Timothy R., et al.
(författare)
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Inheritance of deleterious mutations at both BRCA1 and BRCA2 in an international sample of 32,295 women
- 2016
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Ingår i: Breast Cancer Research. - : Springer Science and Business Media LLC. - 1465-5411 .- 1465-542X. ; 18:1
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Tidskriftsartikel (refereegranskat)abstract
- Background: Most BRCA1 or BRCA2 mutation carriers have inherited a single (heterozygous) mutation. Transheterozygotes (TH) who have inherited deleterious mutations in both BRCA1 and BRCA2 are rare, and the consequences of transheterozygosity are poorly understood. Methods: From 32,295 female BRCA1/2 mutation carriers, we identified 93 TH (0.3 %). "Cases" were defined as TH, and "controls" were single mutations at BRCA1 (SH1) or BRCA2 (SH2). Matched SH1 "controls" carried a BRCA1 mutation found in the TH "case". Matched SH2 "controls" carried a BRCA2 mutation found in the TH "case". After matching the TH carriers with SH1 or SH2, 91 TH were matched to 9316 SH1, and 89 TH were matched to 3370 SH2. Results: The majority of TH (45.2 %) involved the three common Jewish mutations. TH were more likely than SH1 and SH2 women to have been ever diagnosed with breast cancer (BC; p = 0.002). TH were more likely to be diagnosed with ovarian cancer (OC) than SH2 (p = 0.017), but not SH1. Age at BC diagnosis was the same in TH vs. SH1 (p = 0.231), but was on average 4.5 years younger in TH than in SH2 (p < 0.001). BC in TH was more likely to be estrogen receptor (ER) positive (p = 0.010) or progesterone receptor (PR) positive (p = 0.013) than in SH1, but less likely to be ER positive (p < 0.001) or PR positive (p = 0.012) than SH2. Among 15 tumors from TH patients, there was no clear pattern of loss of heterozygosity (LOH) for BRCA1 or BRCA2 in either BC or OC. Conclusions: Our observations suggest that clinical TH phenotypes resemble SH1. However, TH breast tumor marker characteristics are phenotypically intermediate to SH1 and SH2.
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| 18. |
- Spurdle, Amanda B., et al.
(författare)
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Common Genetic Variation at BARD1 Is Not Associated with Breast Cancer Risk in BRCA1 or BRCA2 Mutation Carriers
- 2011
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Ingår i: Cancer Epidemiology Biomarkers & Prevention. - 1538-7755 .- 1055-9965. ; 20:5, s. 1032-1038
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Tidskriftsartikel (refereegranskat)abstract
- Background: Inherited BRCA1 and BRCA2 (BRCA1/2) mutations confer elevated breast cancer risk. Knowledge of factors that can improve breast cancer risk assessment in BRCA1/2 mutation carriers may improve personalized cancer prevention strategies. Methods: A cohort of 5,546 BRCA1 and 2,865 BRCA2 mutation carriers was used to evaluate risk of breast cancer associated with BARD1 Cys557Ser. In a second nonindependent cohort of 1,537 of BRCA1 and 839 BRCA2 mutation carriers, BARD1 haplotypes were also evaluated. Results: The BARD1 Cys557Ser variant was not significantly associated with risk of breast cancer from single SNP analysis, with a pooled effect estimate of 0.90 (95% CI: 0.71-1.15) in BRCA1 carriers and 0.87 (95% CI: 0.59-1.29) in BRCA2 carriers. Further analysis of haplotypes at BARD1 also revealed no evidence that additional common genetic variation not captured by Cys557Ser was associated with breast cancer risk. Conclusion: Evidence to date does not support a role for BARD1 variation, including the Cy557Ser variant, as a modifier of risk in BRCA1/2 mutation carriers. Impact: Interactors of BRCA1/2 have been implicated as modifiers of BRCA1/2-associated cancer risk. Our finding that BARD1 does not contribute to this risk modification may focus research on other genes that do modify BRCA1/2-associated cancer risk. Cancer Epidemiol Biomarkers Prev; 20(5); 1032-38. (C) 2011 AACR.
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| 19. |
- Vigorito, Elena, et al.
(författare)
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Fine-Scale Mapping at 9p22.2 Identifies Candidate Causal Variants That Modify Ovarian Cancer Risk in BRCA1 and BRCA2 Mutation Carriers
- 2016
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Ingår i: PLOS ONE. - : Public Library of Science (PLoS). - 1932-6203. ; 11:7
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Tidskriftsartikel (refereegranskat)abstract
- Population-based genome wide association studies have identified a locus at 9p22.2 associated with ovarian cancer risk, which also modifies ovarian cancer risk in BRCA1 and BRCA2 mutation carriers. We conducted fine-scale mapping at 9p22.2 to identify potential causal variants in BRCA1 and BRCA2 mutation carriers. Genotype data were available for 15,252 (2,462 ovarian cancer cases) BRCA1 and 8,211 (631 ovarian cancer cases) BRCA2 mutation carriers. Following genotype imputation, ovarian cancer associations were assessed for 4,873 and 5,020 SNPs in BRCA1 and BRCA2 mutation carriers respectively, within a retrospective cohort analytical framework. In BRCA1 mutation carriers one set of eight correlated candidate causal variants for ovarian cancer risk modification was identified (top SNP rs10124837, HR: 0.73, 95% CI: 0.68 to 0.79, p-value 2x 10-16). These variants were located up to 20 kb upstream of BNC2. In BRCA2 mutation carriers one region, up to 45 kb upstream of BNC2, and containing 100 correlated SNPs was identified as candidate causal (top SNP rs62543585, HR: 0.69, 95% CI: 0.59 to 0.80, p-value 1.0 x 10-6). The candidate causal in BRCA1 mutation carriers did not include the strongest associated variant at this locus in the general population. In sum, we identified a set of candidate causal variants in a region that encompasses the BNC2 transcription start site. The ovarian cancer association at 9p22.2 may be mediated by different variants in BRCA1 mutation carriers and in the general population. Thus, potentially different mechanisms may underlie ovarian cancer risk for mutation carriers and the general population.
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| 20. |
- Zeng, Chenjie, et al.
(författare)
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Identification of independent association signals and putative functional variants for breast cancer risk through fine-scale mapping of the 12p11 locus
- 2016
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Ingår i: Breast Cancer Research. - : Springer Science and Business Media LLC. - 1465-5411 .- 1465-542X. ; 18
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Tidskriftsartikel (refereegranskat)abstract
- Background: Multiple recent genome-wide association studies (GWAS) have identified a single nucleotide polymorphism (SNP), rs10771399, at 12p11 that is associated with breast cancer risk. Method: We performed a fine-scale mapping study of a 700 kb region including 441 genotyped and more than 1300 imputed genetic variants in 48,155 cases and 43,612 controls of European descent, 6269 cases and 6624 controls of East Asian descent and 1116 cases and 932 controls of African descent in the Breast Cancer Association Consortium (BCAC; http://bcac.ccge.medschl.cam.ac.uk/), and in 15,252 BRCA1 mutation carriers in the Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA). Stepwise regression analyses were performed to identify independent association signals. Data from the Encyclopedia of DNA Elements project (ENCODE) and the Cancer Genome Atlas (TCGA) were used for functional annotation. Results: Analysis of data from European descendants found evidence for four independent association signals at 12p11, represented by rs7297051 (odds ratio (OR) = 1.09, 95 % confidence interval (CI) = 1.06-1.12; P = 3 x 10(-9)), rs805510 (OR = 1.08, 95 % CI = 1.04-1.12, P = 2 x 10(-5)), and rs1871152 (OR = 1.04, 95 % CI = 1.02-1.06; P = 2 x 10(-4)) identified in the general populations, and rs113824616 (P = 7 x 10(-5)) identified in the meta-analysis of BCAC ER-negative cases and BRCA1 mutation carriers. SNPs rs7297051, rs805510 and rs113824616 were also associated with breast cancer risk at P < 0.05 in East Asians, but none of the associations were statistically significant in African descendants. Multiple candidate functional variants are located in putative enhancer sequences. Chromatin interaction data suggested that PTHLH was the likely target gene of these enhancers. Of the six variants with the strongest evidence of potential functionality, rs11049453 was statistically significantly associated with the expression of PTHLH and its nearby gene CCDC91 at P < 0.05. Conclusion: This study identified four independent association signals at 12p11 and revealed potentially functional variants, providing additional insights into the underlying biological mechanism(s) for the association observed between variants at 12p11 and breast cancer risk.
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