Novel associations between common breast cancer susceptibility variants and risk-predicting mammographic density measures

Jennifer Stone, Deborah J. Thompson, Isabel Dos Santos Silva, Christopher Scott, Rulla M. Tamimi, Sara Lindstrom, Peter Kraft, Aditi Hazra, Jingmei Li, Louise Eriksson, Kamila Czene, Per Hall, Matt Jensen, Julie M Cunningham, Janet E Olson, Kristen Purrington, Fergus J Couch, Judith Brown, Jean Leyland, Ruth M L WarrenRobert N. Luben, Kay Tee Khaw, Paula Smith, Nicholas J. Wareham, Sebastian M. Jud, Katharina Heusinger, Matthias W. Beckmann, Julie A. Douglas, Kaanan P. Shah, Heang Ping Chan, Mark A. Helvie, Loic Le Marchand, Laurence N. Kolonel, Christy Woolcott, Gertraud Maskarinec, Christopher Haiman, Graham G. Giles, Laura Baglietto, Kavitha Krishnan, Melissa C. Southey, Carmel Apicella, Irene L. Andrulis, Julia A. Knight, Giske Ursin, Grethe I Grenaker Alnaes, Vessela N. Kristensen, Anne Lise Borresen-Dale, Inger Torhild Gram, Manjeet K. Bolla, Qin Wang, Kyriaki Michailidou, Joe Dennis, Jacques Simard, Paul Pharoah, Alison M. Dunning, Douglas F. Easton, Peter A. Fasching, V. Shane Pankratz, John L. Hopper, Celine M Vachon

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Abstract

Mammographic density measures adjusted for age and body mass index (BMI) are heritable predictors of breast cancer risk, but few mammographic density-associated genetic variants have been identified. Using data for 10,727 women from two international consortia, we estimated associations between 77 common breast cancer susceptibility variants and absolute dense area, percent dense area and absolute nondense area adjusted for study, age, and BMI using mixed linear modeling. We found strong support for established associations between rs10995190 (in the region of ZNF365), rs2046210(ESR1), and rs3817198 (LSP1) and adjusted absolute and percent dense areas (all P <10-5). Of 41 recently discovered breast cancer susceptibility variants, associations were found between rs1432679(EBF1), rs17817449 (MIR1972-2: FTO), rs12710696 (2p24.1), and rs3757318 (ESR1) and adjusted absolute and percent dense areas, respectively. There were associations between rs6001930 (MKL1) and both adjusted absolute dense and nondense areas, and between rs17356907 (NTN4) and adjusted absolute nondense area. Trends in all but two associations were consistent with those for breast cancer risk. Results suggested that 18% of breast cancer susceptibility variants were associated with at least one mammographic density measure. Genetic variants at multiple loci were associated with both breast cancer risk and the mammographic density measures. Further understanding of the underlying mechanisms at these loci could help identify etiologic pathways implicated in how mammographic density predicts breast cancer risk.

Original languageEnglish (US)
Pages (from-to)2457-2467
Number of pages11
JournalCancer Research
Volume75
Issue number12
DOIs
StatePublished - Jun 15 2015

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Breast Neoplasms
Body Mass Index
Breast Density

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

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Novel associations between common breast cancer susceptibility variants and risk-predicting mammographic density measures. / Stone, Jennifer; Thompson, Deborah J.; Dos Santos Silva, Isabel; Scott, Christopher; Tamimi, Rulla M.; Lindstrom, Sara; Kraft, Peter; Hazra, Aditi; Li, Jingmei; Eriksson, Louise; Czene, Kamila; Hall, Per; Jensen, Matt; Cunningham, Julie M; Olson, Janet E; Purrington, Kristen; Couch, Fergus J; Brown, Judith; Leyland, Jean; Warren, Ruth M L; Luben, Robert N.; Khaw, Kay Tee; Smith, Paula; Wareham, Nicholas J.; Jud, Sebastian M.; Heusinger, Katharina; Beckmann, Matthias W.; Douglas, Julie A.; Shah, Kaanan P.; Chan, Heang Ping; Helvie, Mark A.; Marchand, Loic Le; Kolonel, Laurence N.; Woolcott, Christy; Maskarinec, Gertraud; Haiman, Christopher; Giles, Graham G.; Baglietto, Laura; Krishnan, Kavitha; Southey, Melissa C.; Apicella, Carmel; Andrulis, Irene L.; Knight, Julia A.; Ursin, Giske; Alnaes, Grethe I Grenaker; Kristensen, Vessela N.; Borresen-Dale, Anne Lise; Gram, Inger Torhild; Bolla, Manjeet K.; Wang, Qin; Michailidou, Kyriaki; Dennis, Joe; Simard, Jacques; Pharoah, Paul; Dunning, Alison M.; Easton, Douglas F.; Fasching, Peter A.; Pankratz, V. Shane; Hopper, John L.; Vachon, Celine M.

In: Cancer Research, Vol. 75, No. 12, 15.06.2015, p. 2457-2467.

Research output: Contribution to journalArticle

Stone, J, Thompson, DJ, Dos Santos Silva, I, Scott, C, Tamimi, RM, Lindstrom, S, Kraft, P, Hazra, A, Li, J, Eriksson, L, Czene, K, Hall, P, Jensen, M, Cunningham, JM, Olson, JE, Purrington, K, Couch, FJ, Brown, J, Leyland, J, Warren, RML, Luben, RN, Khaw, KT, Smith, P, Wareham, NJ, Jud, SM, Heusinger, K, Beckmann, MW, Douglas, JA, Shah, KP, Chan, HP, Helvie, MA, Marchand, LL, Kolonel, LN, Woolcott, C, Maskarinec, G, Haiman, C, Giles, GG, Baglietto, L, Krishnan, K, Southey, MC, Apicella, C, Andrulis, IL, Knight, JA, Ursin, G, Alnaes, GIG, Kristensen, VN, Borresen-Dale, AL, Gram, IT, Bolla, MK, Wang, Q, Michailidou, K, Dennis, J, Simard, J, Pharoah, P, Dunning, AM, Easton, DF, Fasching, PA, Pankratz, VS, Hopper, JL & Vachon, CM 2015, 'Novel associations between common breast cancer susceptibility variants and risk-predicting mammographic density measures', Cancer Research, vol. 75, no. 12, pp. 2457-2467. https://doi.org/10.1158/0008-5472.CAN-14-2012
Stone, Jennifer ; Thompson, Deborah J. ; Dos Santos Silva, Isabel ; Scott, Christopher ; Tamimi, Rulla M. ; Lindstrom, Sara ; Kraft, Peter ; Hazra, Aditi ; Li, Jingmei ; Eriksson, Louise ; Czene, Kamila ; Hall, Per ; Jensen, Matt ; Cunningham, Julie M ; Olson, Janet E ; Purrington, Kristen ; Couch, Fergus J ; Brown, Judith ; Leyland, Jean ; Warren, Ruth M L ; Luben, Robert N. ; Khaw, Kay Tee ; Smith, Paula ; Wareham, Nicholas J. ; Jud, Sebastian M. ; Heusinger, Katharina ; Beckmann, Matthias W. ; Douglas, Julie A. ; Shah, Kaanan P. ; Chan, Heang Ping ; Helvie, Mark A. ; Marchand, Loic Le ; Kolonel, Laurence N. ; Woolcott, Christy ; Maskarinec, Gertraud ; Haiman, Christopher ; Giles, Graham G. ; Baglietto, Laura ; Krishnan, Kavitha ; Southey, Melissa C. ; Apicella, Carmel ; Andrulis, Irene L. ; Knight, Julia A. ; Ursin, Giske ; Alnaes, Grethe I Grenaker ; Kristensen, Vessela N. ; Borresen-Dale, Anne Lise ; Gram, Inger Torhild ; Bolla, Manjeet K. ; Wang, Qin ; Michailidou, Kyriaki ; Dennis, Joe ; Simard, Jacques ; Pharoah, Paul ; Dunning, Alison M. ; Easton, Douglas F. ; Fasching, Peter A. ; Pankratz, V. Shane ; Hopper, John L. ; Vachon, Celine M. / Novel associations between common breast cancer susceptibility variants and risk-predicting mammographic density measures. In: Cancer Research. 2015 ; Vol. 75, No. 12. pp. 2457-2467.
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abstract = "Mammographic density measures adjusted for age and body mass index (BMI) are heritable predictors of breast cancer risk, but few mammographic density-associated genetic variants have been identified. Using data for 10,727 women from two international consortia, we estimated associations between 77 common breast cancer susceptibility variants and absolute dense area, percent dense area and absolute nondense area adjusted for study, age, and BMI using mixed linear modeling. We found strong support for established associations between rs10995190 (in the region of ZNF365), rs2046210(ESR1), and rs3817198 (LSP1) and adjusted absolute and percent dense areas (all P <10-5). Of 41 recently discovered breast cancer susceptibility variants, associations were found between rs1432679(EBF1), rs17817449 (MIR1972-2: FTO), rs12710696 (2p24.1), and rs3757318 (ESR1) and adjusted absolute and percent dense areas, respectively. There were associations between rs6001930 (MKL1) and both adjusted absolute dense and nondense areas, and between rs17356907 (NTN4) and adjusted absolute nondense area. Trends in all but two associations were consistent with those for breast cancer risk. Results suggested that 18{\%} of breast cancer susceptibility variants were associated with at least one mammographic density measure. Genetic variants at multiple loci were associated with both breast cancer risk and the mammographic density measures. Further understanding of the underlying mechanisms at these loci could help identify etiologic pathways implicated in how mammographic density predicts breast cancer risk.",
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T1 - Novel associations between common breast cancer susceptibility variants and risk-predicting mammographic density measures

AU - Stone, Jennifer

AU - Thompson, Deborah J.

AU - Dos Santos Silva, Isabel

AU - Scott, Christopher

AU - Tamimi, Rulla M.

AU - Lindstrom, Sara

AU - Kraft, Peter

AU - Hazra, Aditi

AU - Li, Jingmei

AU - Eriksson, Louise

AU - Czene, Kamila

AU - Hall, Per

AU - Jensen, Matt

AU - Cunningham, Julie M

AU - Olson, Janet E

AU - Purrington, Kristen

AU - Couch, Fergus J

AU - Brown, Judith

AU - Leyland, Jean

AU - Warren, Ruth M L

AU - Luben, Robert N.

AU - Khaw, Kay Tee

AU - Smith, Paula

AU - Wareham, Nicholas J.

AU - Jud, Sebastian M.

AU - Heusinger, Katharina

AU - Beckmann, Matthias W.

AU - Douglas, Julie A.

AU - Shah, Kaanan P.

AU - Chan, Heang Ping

AU - Helvie, Mark A.

AU - Marchand, Loic Le

AU - Kolonel, Laurence N.

AU - Woolcott, Christy

AU - Maskarinec, Gertraud

AU - Haiman, Christopher

AU - Giles, Graham G.

AU - Baglietto, Laura

AU - Krishnan, Kavitha

AU - Southey, Melissa C.

AU - Apicella, Carmel

AU - Andrulis, Irene L.

AU - Knight, Julia A.

AU - Ursin, Giske

AU - Alnaes, Grethe I Grenaker

AU - Kristensen, Vessela N.

AU - Borresen-Dale, Anne Lise

AU - Gram, Inger Torhild

AU - Bolla, Manjeet K.

AU - Wang, Qin

AU - Michailidou, Kyriaki

AU - Dennis, Joe

AU - Simard, Jacques

AU - Pharoah, Paul

AU - Dunning, Alison M.

AU - Easton, Douglas F.

AU - Fasching, Peter A.

AU - Pankratz, V. Shane

AU - Hopper, John L.

AU - Vachon, Celine M

PY - 2015/6/15

Y1 - 2015/6/15

N2 - Mammographic density measures adjusted for age and body mass index (BMI) are heritable predictors of breast cancer risk, but few mammographic density-associated genetic variants have been identified. Using data for 10,727 women from two international consortia, we estimated associations between 77 common breast cancer susceptibility variants and absolute dense area, percent dense area and absolute nondense area adjusted for study, age, and BMI using mixed linear modeling. We found strong support for established associations between rs10995190 (in the region of ZNF365), rs2046210(ESR1), and rs3817198 (LSP1) and adjusted absolute and percent dense areas (all P <10-5). Of 41 recently discovered breast cancer susceptibility variants, associations were found between rs1432679(EBF1), rs17817449 (MIR1972-2: FTO), rs12710696 (2p24.1), and rs3757318 (ESR1) and adjusted absolute and percent dense areas, respectively. There were associations between rs6001930 (MKL1) and both adjusted absolute dense and nondense areas, and between rs17356907 (NTN4) and adjusted absolute nondense area. Trends in all but two associations were consistent with those for breast cancer risk. Results suggested that 18% of breast cancer susceptibility variants were associated with at least one mammographic density measure. Genetic variants at multiple loci were associated with both breast cancer risk and the mammographic density measures. Further understanding of the underlying mechanisms at these loci could help identify etiologic pathways implicated in how mammographic density predicts breast cancer risk.

AB - Mammographic density measures adjusted for age and body mass index (BMI) are heritable predictors of breast cancer risk, but few mammographic density-associated genetic variants have been identified. Using data for 10,727 women from two international consortia, we estimated associations between 77 common breast cancer susceptibility variants and absolute dense area, percent dense area and absolute nondense area adjusted for study, age, and BMI using mixed linear modeling. We found strong support for established associations between rs10995190 (in the region of ZNF365), rs2046210(ESR1), and rs3817198 (LSP1) and adjusted absolute and percent dense areas (all P <10-5). Of 41 recently discovered breast cancer susceptibility variants, associations were found between rs1432679(EBF1), rs17817449 (MIR1972-2: FTO), rs12710696 (2p24.1), and rs3757318 (ESR1) and adjusted absolute and percent dense areas, respectively. There were associations between rs6001930 (MKL1) and both adjusted absolute dense and nondense areas, and between rs17356907 (NTN4) and adjusted absolute nondense area. Trends in all but two associations were consistent with those for breast cancer risk. Results suggested that 18% of breast cancer susceptibility variants were associated with at least one mammographic density measure. Genetic variants at multiple loci were associated with both breast cancer risk and the mammographic density measures. Further understanding of the underlying mechanisms at these loci could help identify etiologic pathways implicated in how mammographic density predicts breast cancer risk.

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