| 11. |
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| 12. |
- 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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| 13. |
- Li, Jingmei, et al.
(författare)
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Breast cancer genetic risk profile is differentially associated with interval and screen-detected breast cancers
- 2015
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Ingår i: Annals of Oncology. - Stockholm : Karolinska Institutet, Dept of Medical Epidemiology and Biostatistics. - 0923-7534. ; 26:3, s. 517-522
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Tidskriftsartikel (refereegranskat)abstract
- Background: Polygenic risk profiles computed from multiple common susceptibility alleles for breast cancer have been shown to identify women at different levels of breast cancer risk. We evaluated whether this genetic risk stratification can also be applied to discriminate between screen-detected and interval cancers, which are usually associated with clinicopathological and survival differences. Patients and methods: A 77-SNP polygenic risk score (PRS) was constructed for breast cancer overall and by estrogen-receptor (ER) status. PRS was inspected as a continuous (per standard deviation increment) variable in a case-only design. Modification of the PRS by mammographic density was evaluated by fitting an additional interaction term. Results: PRS weighted by breast cancer overall estimates was found to be differentially associated with 1,865 screen-detected and 782 interval cancers in the LIBRO-1 study (age-adjusted ORperSD [95% confidence interval]=0.91 [0.83-0.99], p=0.023). The association was found to be more significant for PRS weighted by ER-positive breast cancer estimates (ORperSD=0.90 [0.82-0.98], p=0.011). This result was corroborated by two independent studies (combined ORperSD=0.87 [0.76-1.00], p=0.058) with no evidence of heterogeneity. When enriched for “true” interval cancers among nondense breasts, the difference in the association with PRS in screen-detected and interval cancers became more pronounced (ORperSD=0.74 [0.62-0.89], p=0.001), with a significant interaction effect between PRS and mammographic density (pinteraction=0.017). Conclusion: To our knowledge, this is the first report looking into the genetic differences between screendetected and interval cancers. It is an affirmation that the two types of breast cancer may have unique underlying biology.
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| 14. |
- 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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| 15. |
- Mavaddat, Nasim, et al.
(författare)
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Prediction of Breast Cancer Risk Based on Profiling With Common Genetic Variants
- 2015
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Ingår i: Journal of the National Cancer Institute. - : Oxford University Press (OUP). - 1460-2105 .- 0027-8874. ; 107:5, s. 036-036
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Tidskriftsartikel (refereegranskat)abstract
- Background: Data for multiple common susceptibility alleles for breast cancer may be combined to identify women at different levels of breast cancer risk. Such stratification could guide preventive and screening strategies. However, empirical evidence for genetic risk stratification is lacking. Methods: We investigated the value of using 77 breast cancer-associated single nucleotide polymorphisms (SNPs) for risk stratification, in a study of 33 673 breast cancer cases and 33 381 control women of European origin. We tested all possible pair-wise multiplicative interactions and constructed a 77-SNP polygenic risk score (PRS) for breast cancer overall and by estrogen receptor (ER) status. Absolute risks of breast cancer by PRS were derived from relative risk estimates and UK incidence and mortality rates. Results: There was no strong evidence for departure from a multiplicative model for any SNP pair. Women in the highest 1% of the PRS had a three-fold increased risk of developing breast cancer compared with women in the middle quintile (odds ratio [OR] = 3.36, 95% confidence interval [CI] = 2.95 to 3.83). The ORs for ER-positive and ER-negative disease were 3.73 (95% CI = 3.24 to 4.30) and 2.80 (95% CI = 2.26 to 3.46), respectively. Lifetime risk of breast cancer for women in the lowest and highest quintiles of the PRS were 5.2% and 16.6% for a woman without family history, and 8.6% and 24.4% for a woman with a first-degree family history of breast cancer. Conclusions: The PRS stratifies breast cancer risk in women both with and without a family history of breast cancer. The observed level of risk discrimination could inform targeted screening and prevention strategies. Further discrimination may be achievable through combining the PRS with lifestyle/environmental factors, although these were not considered in this report.
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| 16. |
- Rahbin, Samin, et al.
(författare)
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Differences Between Patient and Surgeon Perspectives : A Long-Term Follow-Up of 180 Patients With Zygomaticomaxillary Complex Fractures Following Either Conservative or Surgical Treatment
- 2023
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Ingår i: Craniomaxillofacial Trauma & Reconstruction. - : Sage Publications. - 1943-3875 .- 1943-3883.
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Tidskriftsartikel (refereegranskat)abstract
- Study Design: Retrospective with follow-up. Objective: This study described the long-term outcomes of patients who received either conservative or surgical treatment for zygomaticomaxillary complex (ZMC) fractures. It accounted for the perspectives of both patients and surgeons, and explored factors associated with patient satisfaction. Methods: Patients with unilateral ZMC fractures 2007-2018 were invited to follow-up clinical examinations and photographic documentation. Patient experiences were recorded using a questionnaire. A review panel assessed computed tomography (CT) scans and photographs. Patient and surgeon perspectives of detecting functional sequelae were assessed, and a correlation matrix was used to evaluate different perspectives of perceiving malar asymmetry. Results: The study sample consisted of 180 patients, of which conservative treatment was given to 43 patients and surgical treatment to 137 patients. Median follow-up time was 72.5 months after trauma. Overall satisfaction was 92.8%, with no significant difference between treatment groups. Patients and surgeons showed marked differences in detecting functional sequelae. Predicted malar asymmetry on CT scans did not correlate to findings on photographs or reports by patients. Conclusions: A predicted sunken cheek on CT imaging does not necessarily lead to long-term visible asymmetry of the malar region. Surgeons should acknowledge different perspectives when predicting and assessing long-term sequelae of ZMC fractures, and seek consensus on when to perform surgical reconstructions.
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| 17. |
- Rahbin, Samin, et al.
(författare)
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The Volume Difference Along the External Surface of the Zygomatic Bone
- 2022
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Ingår i: The Journal of Craniofacial Surgery. - Philadephia, PA, United states : Lippincott Williams & Wilkins. - 1049-2275 .- 1536-3732. ; 33:2, s. 463-468
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Tidskriftsartikel (refereegranskat)abstract
- This study introduced the volume difference along the external surface (VDAES) of the zygomatic bone as a novel approach to assess zygomatic bone asymmetry and was the first to describe a distinctive, 4-step method of measuring it. VDAES has a potential to be used as an objective tool to evaluate dislocation and can assist surgeons in predicting risks of long-term cosmetic complications in patients with zygomaticomaxillary complex fractures. After having measured 100 healthy study participants, the observed median VDAES was 1.48 cm3 for all study participants, 2.02 cm3 for males, and 1.09 cm3 for females, with the gender difference being significant (P = 0.003). Additional studies are needed to test the hypothesis of whether VDAES is more relevant than conventional methods of clinically evaluating zygomatic bone asymmetry.
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| 18. |
- Smedby, Karin E., et al.
(författare)
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GWAS of Follicular Lymphoma Reveals Allelic Heterogeneity at 6p21.32 and Suggests Shared Genetic Susceptibility with Diffuse Large B-cell Lymphoma
- 2011
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Ingår i: PLoS Genetics. - : Public Library of Science (PLoS). - 1553-7390 .- 1553-7404. ; 7:4, s. e1001378-
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Tidskriftsartikel (refereegranskat)abstract
- Non-Hodgkin lymphoma (NHL) represents a diverse group of hematological malignancies, of which follicular lymphoma (FL) is a prevalent subtype. A previous genome-wide association study has established a marker, rs10484561 in the human leukocyte antigen (HLA) class II region on 6p21.32 associated with increased FL risk. Here, in a three-stage genome-wide association study, starting with a genome-wide scan of 379 FL cases and 791 controls followed by validation in 1,049 cases and 5,790 controls, we identified a second independent FL-associated locus on 6p21.32, rs2647012 (ORcombined = 0.64, P-combined= 2x10(-21)) located 962 bp away from rs10484561 (r(2)< 0.1 in controls). After mutual adjustment, the associations at the two SNPs remained genome-wide significant (rs2647012: ORadjusted = 0.70, P-adjusted= 4x10(-12); rs10484561: ORadjusted = 1.64, P-adjusted= 5x10(-15)). Haplotype and coalescence analyses indicated that rs2647012 arose on an evolutionarily distinct haplotype from that of rs10484561 and tags a novel allele with an opposite (protective) effect on FL risk. Moreover, in a follow-up analysis of the top 6 FL-associated SNPs in 4,449 cases of other NHL subtypes, rs10484561 was associated with risk of diffuse large B-cell lymphoma (ORcombined = 1.36, P-combined = 1.4x10(-7)). Our results reveal the presence of allelic heterogeneity within the HLA class II region influencing FL susceptibility and indicate a possible shared genetic etiology with diffuse large B-cell lymphoma. These findings suggest that the HLA class II region plays a complex yet important role in NHL.
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| 19. |
- Trinh, Thang, et al.
(författare)
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Background risk of breast cancer and the association between physical activity and mammographic density
- 2015
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Ingår i: Breast Cancer Research. - : BIOMED CENTRAL LTD. - 1465-5411 .- 1465-542X. ; 17
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Tidskriftsartikel (refereegranskat)abstract
- Introduction High physical activity has been shown to decrease the risk of breast cancer, potentially by a mechanism that also reduces mammographic density. We tested the hypothesis that the risk of developing breast cancer in the next 10 years according to the Tyrer-Cuzick prediction model influences the association between physical activity and mammographic density. Methods We conducted a population-based cross-sectional study of 38,913 Swedish women aged 4074 years. Physical activity was assessed using the validated web-questionnaire Active-Q and mammographic density was measured by the fully automated volumetric Volpara method. The 10-year risk of breast cancer was estimated using the Tyrer-Cuzick (TC) prediction model. Linear regression analyses were performed to assess the association between physical activity and volumetric mammographic density and the potential interaction with the TC breast cancer risk. Results Overall, high physical activity was associated with lower absolute dense volume. As compared to women with the lowest total activity level (<40 metabolic equivalent hours [MET-h] per day), women with the highest total activity level (>= 50 MET-h/day) had an estimated 3.4 cm(3) (95% confidence interval, 2.3-4.7) lower absolute dense volume. The inverse association was seen for any type of physical activity among women with <3.0% TC 10-year risk, but only for total and vigorous activities among women with 3.0-4.9% TC risk, and only for vigorous activity among women with >= 5.0% TC risk. The association between total activity and absolute dense volume was modified by the TC breast cancer risk (P-interaction = 0.05). As anticipated, high physical activity was also associated with lower non-dense volume. No consistent association was found between physical activity and percent dense volume. Conclusions Our results suggest that physical activity may decrease breast cancer risk through reducing mammographic density, and that the physical activity needed to reduce mammographic density may depend on background risk of breast cancer.
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