| 1. |
- Low, Yen Ling, et al.
(författare)
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Multi-Variant Pathway Association Analysis Reveals the Importance of Genetic Determinants of Estrogen Metabolism in Breast and Endometrial Cancer Susceptibility
- 2010
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Ingår i: PLoS genetics. - : Public Library of Science (PLoS). - 1553-7390 .- 1553-7404. ; 6:7, s. e1001012-
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Tidskriftsartikel (refereegranskat)abstract
- Despite the central role of estrogen exposure in breast and endometrial cancer development and numerous studies of genes in the estrogen metabolic pathway, polymorphisms within the pathway have not been consistently associated with these cancers. We posit that this is due to the complexity of multiple weak genetic effects within the metabolic pathway that can only be effectively detected through multi-variant analysis. We conducted a comprehensive association analysis of the estrogen metabolic pathway by interrogating 239 tagSNPs within 35 genes of the pathway in three tumor samples. The discovery sample consisted of 1,596 breast cancer cases, 719 endometrial cancer cases, and 1,730 controls from Sweden; and the validation sample included 2,245 breast cancer cases and 1,287 controls from Finland. We performed admixture maximum likelihood (AML)-based global tests to evaluate the cumulative effect from multiple SNPs within the whole metabolic pathway and three sub-pathways for androgen synthesis, androgen-to-estrogen conversion, and estrogen removal. In the discovery sample, although no single polymorphism was significant after correction for multiple testing, the pathway-based AML global test suggested association with both breast (rho(global) = 0.034) and endometrial (rho(global) = 0.052) cancers. Further testing revealed the association to be focused on polymorphisms within the androgen-to-estrogen conversion sub-pathway, for both breast (rho(global) = 0.008) and endometrial cancer (rho(global) = 0.014). The sub-pathway association was validated in the Finnish sample of breast cancer (rho(global) = 0.015). Further tumor subtype analysis demonstrated that the association of the androgen-to-estrogen conversion sub-pathway was confined to postmenopausal women with sporadic estrogen receptor positive tumors (rho(global) = 0.0003). Gene-based AML analysis suggested CYP19A1 and UGT2B4 to be the major players within the sub-pathway. Our study indicates that the composite genetic determinants related to the androgen-estrogen conversion are important for the induction of two hormone-associated cancers, particularly for the hormone-driven breast tumour subtypes.
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| 2. |
- Salmela, Elina, et al.
(författare)
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Swedish population substructure revealed by genome-wide single nucleotide polymorphism data
- 2011
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Ingår i: PLOS ONE. - : Public Library of Science (PLoS). - 1932-6203. ; 6:2, s. e16747-
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Tidskriftsartikel (refereegranskat)abstract
- The use of genome-wide single nucleotide polymorphism (SNP) data has recently proven useful in the study of human population structure. We have studied the internal genetic structure of the Swedish population using more than 350,000 SNPs from 1525 Swedes from all over the country genotyped on the Illumina HumanHap550 array. We have also compared them to 3212 worldwide reference samples, including Finns, northern Germans, British and Russians, based on the more than 29,000 SNPs that overlap between the Illumina and Affymetrix 250K Sty arrays. The Swedes--especially southern Swedes--were genetically close to the Germans and British, while their genetic distance to Finns was substantially longer. The overall structure within Sweden appeared clinal, and the substructure in the southern and middle parts was subtle. In contrast, the northern part of Sweden, Norrland, exhibited pronounced genetic differences both within the area and relative to the rest of the country. These distinctive genetic features of Norrland probably result mainly from isolation by distance and genetic drift caused by low population density. The internal structure within Sweden (F(ST) = 0.0005 between provinces) was stronger than that in many Central European populations, although smaller than what has been observed for instance in Finland; importantly, it is of the magnitude that may hamper association studies with a moderate number of markers if cases and controls are not properly matched geographically. Overall, our results underline the potential of genome-wide data in analyzing substructure in populations that might otherwise appear relatively homogeneous, such as the Swedes.
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| 3. |
- Sandberg, Maria E. C., et al.
(författare)
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Influence of radiotherapy for the first tumor on aggressiveness of contralateral breast cancer
- 2013
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Ingår i: International Journal of Cancer. - : Wiley. - 0020-7136 .- 1097-0215. ; 132:10, s. 2388-2394
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Tidskriftsartikel (refereegranskat)abstract
- We aimed to investigate if characteristics of contralateral breast cancer (CBC) are influenced by adjuvant radiotherapy for the first breast cancer. Using information from population-based registers and medical records, we analyzed two cohorts comprising all women with CBC diagnosed >3 months after their first cancer (809 patients in Stockholm 19762005 and 750 patients in South Sweden 19772005). We used Poisson regression to calculate risk of distant metastasis after CBC, comparing patients treated and not treated with radiotherapy for the first cancer. Logistic regression was used to estimate odds ratio (OR) of more aggressive tumor characteristics in the second cancer, compared to the first. For patients with CBC in Stockholm with <5 years between the cancers radiotherapy for the first cancer conferred a nearly doubled risk of distant metastasis [incidence rate ratio (IRR) = 1.91; 95% confidence interval (CI): 1.272.88], compared to those not treated with radiotherapy. This was replicated in the South Swedish cohort [IRR = 2.12 (95% CI: 1.403.23)]. In Stockholm, we found an increased odds that, following radiotherapy, a second cancer was of more advanced TNM-stage [OR 2.16 (95% CI 1.134.11)] and higher histological grade [OR = 2.00 (95% CI 1.083.72)] compared to the first, for patients with CBC with <5 years between the cancers. No effect on any of the investigated outcomes was seen for patients diagnosed with CBC >5 years from the first cancer. In conclusion, patients diagnosed with CBC within 5 years had worse prognosis and more aggressive tumor characteristics of the second cancer, if they had received radiotherapy for their first cancer, compared to no radiotherapy.
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| 4. |
- Stevens, Kristen N, et al.
(författare)
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19p13.1 is a triple negative-specific breast cancer susceptibility locus
- 2012
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Ingår i: Cancer Research. - 0008-5472 .- 1538-7445. ; 72, s. 1795-
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Tidskriftsartikel (refereegranskat)abstract
- The 19p13.1 breast cancer susceptibility locus is a modifier of breast cancer risk in BRCA1 mutation carriers and is also associated with risk of ovarian cancer. Here we investigated 19p13.1 variation and risk of breast cancer subtypes, defined by estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor-2 (HER2) status, using 48,869 breast cancer cases and 49,787 controls from the Breast Cancer Association Consortium (BCAC). Variants from 19p13.1 were not associated with breast cancer overall or with ER-positive breast cancer but were significantly associated with ER-negative breast cancer risk [rs8170 Odds Ratio (OR)=1.10, 95% Confidence Interval (CI) 1.05 - 1.15, p=3.49 x 10-5] and triple negative (TN) (ER, PR and HER2 negative) breast cancer [rs8170 OR=1.22, 95% CI 1.13 - 1.31, p=2.22 x 10-7]. However, rs8170 was no longer associated with ER-negative breast cancer risk when TN cases were excluded [OR=0.98, 95% CI 0.89 - 1.07, p=0.62]. In addition, a combined analysis of TN cases from BCAC and the Triple Negative Breast Cancer Consortium (TNBCC) (n=3,566) identified a genome-wide significant association between rs8170 and TN breast cancer risk [OR=1.25, 95% CI 1.18 - 1.33, p=3.31 x 10-13]. Thus, 19p13.1 is the first triple negative-specific breast cancer risk locus and the first locus specific to a histological subtype defined by ER, PR, and HER2 to be identified. These findings provide convincing evidence that genetic susceptibility to breast cancer varies by tumor subtype and that triple negative tumors and other subtypes likely arise through distinct etiologic pathways.
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