Common Breast Cancer Susceptibility Variants in<i>LSP1</i>and<i>RAD51L1</i>Are Associated with Mammographic Density Measures that Predict Breast Cancer Risk

Vachon, Celine M.; Scott, Christopher G.; Fasching, Peter A.; Hall, Per; Tamimi, Rulla M.; Li, Jingmei; Stone, Jennifer; Apicella, Carmel; Odefrey, Fabrice; Gierach, Gretchen L.; Jud, Sebastian M.; Heusinger, Katharina; Beckmann, Matthias W.; Pollán, Marina; Fernández-Navarro, Pablo; González-Neira, Anna; Benı́tez, Javier; Gils, Carla H. van; Lokate, Mariëtte; Onland‐Moret, N. Charlotte; Peeters, Petra H.M.; Brown, Judith; Leyland, Jean; Varghese, Jajini S.; Easton, Douglas F.; Thompson, Deborah J.; Luben, Robert; Warren, Ruth; Wareham, Nicholas J.; Loos, Ruth J.F.; Khaw, Kay‐Tee; Ursin, Giske; Lee, Eunjung; Gayther, Simon A.; Ramus, Susan J.; Eeles, Rosalind; Leach, Martin O.; Kwan-Lim, Gek; Couch, Fergus J.; Giles, Graham G.; Baglietto, Laura; Krishnan, Kavitha; Southey, Melissa C.; Marchand, Loı̈c Le; Kolonel, Laurence N.; Woolcott, Christy; Maskarinec, Gertraud; Haiman, Christopher A.; Walker, Kate; Johnson, Nichola; McCormack, Valerie; Biong, Margarethe; Alnæs, Grethe I.G.; Gram, Inger Torhild; Kristensen, Vessela N.; Børresen‐Dale, Anne‐Lise; Lindström, Sara; Hankinson, Susan E.; Hunter, David J.; Andrulis, Irene L.; Knight, Julia A.; Boyd, Norman F.; Figuero, Jonine D.; Lissowska, Jolanta; Wesołowska, Ewa; Pepłońska, Beata; Bukowska, Agnieszka; Reszka, Edyta; Liu, Jing; Eriksson, Louise; Czene, Kamila; Audley, Tina; Wu, Anna H.; Pankratz, V. Shane; Hopper, John L.; dos‐Santos‐Silva, Isabel

doi:10.1158/1055-9965.epi-12-0066

Cited by 100 publications

(100 citation statements)

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“…The relation between genetic variants and MD has been studied by different groups finding significant associations with several inter and intragenic SNPs. [5][6][7][8][9][10] In relation with the pooled cross-sectional analysis 11 of common breast cancer susceptibility variants and MD, the SNP rs10483813 in gene RAD51L1 was not assessed in our study, while the association between the rs3817198 variant in gene LSP1 with MD was not statistically significant (p 5 0.2676) although the OR was in the same direction (OR (per minor allele increase and likelihood high vs. low density) 5 1.16; CI 5 0.89-1.51) (see Supporting Information File 7). Finally, the two previous genome-wide association studies (GWAS) 12,13 have identified new genetic variants associated with MD, one in gene ZNF365 (rs10995190) and another between genes TBX5 and TBX3 (rs1265507).…”

Section: Epidemiologymentioning

confidence: 99%

Genome wide association study identifies a novel putative mammographic density locus at 1q12‐q21

Fernández-Navarro

González‐Neira

Pita

et al. 2014

Intl Journal of Cancer

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Mammographic density (MD) is an intermediate phenotype for breast cancer. Previous studies have identified genetic variants associated with MD; however, much of the genetic contribution to MD is unexplained. We conducted a two-stage genomewide association analysis among the participants in the "Determinants of Density in Mammographies in Spain" study, together with a replication analysis in women from the Australian MD Twins and Sisters Study. Our discovery set covered a total of 3,351 Caucasian women aged 45 to 68 years, recruited from Spanish breast cancer screening centres. MD was blindly assessed by a single reader using Boyd's scale. A two-stage approach was employed, including a feature selection phase exploring 575,374 SNPs in 239 pairs of women with extreme phenotypes and a verification stage for the 183 selected SNPs in the remaining sample (2,873 women). Replication was conducted in 1,786 women aged 40 to 70 years old recruited via the Australian Twin Registry, where MD were measured using Cumulus-3.0, assessing 14 SNPs with a p value <0.10 in stage 2.

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Section: Epidemiologymentioning

confidence: 99%

Genome wide association study identifies a novel putative mammographic density locus at 1q12‐q21

Fernández-Navarro

González‐Neira

Pita

et al. 2014

Intl Journal of Cancer

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“…An international consortium, DENSNP, pooled together 19 studies (16,895 Caucasian women) with data on established breast cancer susceptibility variants and quantitative mammographic density measures [19]. The initial publication pooled cross-sectional analyses of common breast cancer susceptibility variants in 14 independent loci and mammographic density measures.…”

Section: Breast Cancer Risk Loci In Relation To Mammographic Densitymentioning

confidence: 99%

Breast Density and Breast Cancer Risk: Understanding of Biology and Risk

Pettersson

Tamimi

2014

Curr Epidemiol Rep

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Mammographic density is a strong risk factor for breast cancer, independent of other known risk factors. While a number of hypotheses have been proposed, the biological mechanisms underlying the association between mammographic density and breast cancer remain, however, largely unknown. Understanding these mechanisms may help identify opportunities to reduce mammographic density and ultimately breast cancer risk. We review three major areas of research that may help us better understand the biologic underpinnings of mammographic density: heritability and genetics, breast tissue histology and (molecular) pathology, and experimental studies. We summarize the main consistent findings in the literature and identify key areas for future research.

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“…Desmoplastic tissues were radiographically detected as areas denser than the fat and designated mammographic densities (3)(4)(5). High mammographic density is one of the strongest risk factors for breast cancer development and is associated with common breast cancer susceptibility variants ( 6 ).…”

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Desmoplasia: A Response or a Niche?

DeClerck

2012

Cancer Discovery

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Summary: Desmoplasia-the presence of a rich stroma around a tumor-has long been associated with a poor clinical outcome in patients with cancer. It is considered to be a response to the presence of invasive tumor cells. There is now evidence that desmoplasia is the result of coordinated changes in several stromal cells under the control of a single gene product, CD36, whose repression leads to a decrease in fat accumulation and an increase in matrix deposition. The presence of these changes in tumor-free human breast tissue strongly suggests that desmoplasia may precede and not always follow the presence of malignant cells. This concept has an important clinical implication for women at high risk of developing breast carcinoma, considering that the presence of desmoplasia in normal breast tissue detected in the form of mammographic density is one of the strongest risk factors. Cancer Discov; 2(9); 772-4. ©2012 AACR.Commentary on DeFilippis et al., p. 826 (7).The term desmoplasia (from the Greek word desmos, to fetter or restrain ; and plasis, formation ), has been used by pathologists for more than a century in reference to the formation of excessive connective tissue around invasive carcinoma, primarily but not exclusively of the breast ( 1 ). Desmoplastic tissues are characterized by alterations of the tumor stroma that can range from an abundance of cellular elements such as fi broblasts, vascular cells, and immune cells with little extracellular matrix (ECM) to the presence of an abundant collagen-rich ECM with a minimum of cells, mainly fi broblasts and myofi broblasts. Initially considered to represent a condensation of preexisting collagen fi bers, desmoplasia in fact is the result of an increased synthesis of ECM proteins and collagen by stromal cells such as myofi broblasts ( 2 ). The presence of desmoplasia in aggressive tumors was counterintuitive, in view of the fact that a dense ECM represents a barrier against cancer invasion and metastasis. It was therefore considered to be a reaction and response of the host tissue against invasive cancer cells, and accordingly designated "desmoplastic response or reaction."This idea, however, was challenged in the late 1980s, when the presence of desmoplastic tissue in normal breast became noticeable on mammography studies carried out on women screened for risk of breast cancer. Desmoplastic tissues were radiographically detected as areas denser than the fat and designated mammographic densities ( 3-5 ). High mammographic density is one of the strongest risk factors for breast cancer development and is associated with common breast cancer susceptibility variants ( 6 ).The discovery that desmoplastic lesions can be present in the absence of tumor cells suggests that desmoplasia may not be-as initially thought-a reaction to invasive malignant cells, but a preexisting condition favoring the development of a malignancy. However, there has not been any solid explanation in support of this possibility.In this issue of Cancer Discovery , DeFilippis and colleagues ( 7 )...

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Common Breast Cancer Susceptibility Variants inLSP1andRAD51L1Are Associated with Mammographic Density Measures that Predict Breast Cancer Risk

Cited by 100 publications

References 31 publications

Genome wide association study identifies a novel putative mammographic density locus at 1q12‐q21

Genome wide association study identifies a novel putative mammographic density locus at 1q12‐q21

Breast Density and Breast Cancer Risk: Understanding of Biology and Risk

Desmoplasia: A Response or a Niche?

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