19p13.1 Is a triple-negative-specific breast cancer susceptibility locus

Kristen N. Stevens, Zachary Fredericksen, Celine M Vachon, Xianshu Wang, Sara Margolin, Annika Lindblom, Heli Nevanlinna, Dario Greco, Kristiina Aittomak̈i, Carl Blomqvist, Jenny Chang-Claude, Alina Vrieling, Dieter Flesch-Janys, Hans Peter Sinn, Shan Wang-Gohrke, Stefan Nickels, Hiltrud Brauch, Yon-Dschun Ko, Hans-Peter Fischer, Rita K. Schmutzler & 4 others John L. Hopper, Melissa C. Southey, Graham G. Giles, Catriona A. McLean

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Abstract

The 19p13.1 breast cancer susceptibility locus is a modifier of breast cancer risk in BRCA1 mutation carriers and is also associated with the 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 OR, 1.10; 95% confidence interval (CI), 1.05-1.15; P = 3.49 × 10 -5] and triple-negative (ER-, PR-, and HER2-negative) breast cancer (rs8170: OR, 1.22; 95% CI, 1.13-1.31; P = 2.22 × 10 -7). However, rs8170 was no longer associated with ERnegative breast cancer risk when triple-negative cases were excluded (OR, 0.98; 95% CI, 0.89-1.07; P = 0.62). In addition, a combined analysis of triple-negative cases from BCAC and the Triple Negative Breast Cancer Consortium (TNBCC; N = 3,566) identified a genome-wide significant association between rs8170 and triple-negative breast cancer risk (OR, 1.25; 95% CI, 1.18-1.33; P=3.31×10 -13]. Thus, 19p13.1 is the first triple-negative- specific breast cancer risk locus and the first locus specific to a histologic 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.

Original languageEnglish
Pages (from-to)1795-1803
Number of pages9
JournalCancer Research
Volume72
Issue number7
DOIs
Publication statusPublished - 1 Apr 2012
Externally publishedYes

Cite this

Stevens, K. N., Fredericksen, Z., Vachon, C. M., Wang, X., Margolin, S., Lindblom, A., ... McLean, C. A. (2012). 19p13.1 Is a triple-negative-specific breast cancer susceptibility locus. Cancer Research, 72(7), 1795-1803. https://doi.org/10.1158/0008-5472.CAN-11-3364
Stevens, Kristen N. ; Fredericksen, Zachary ; Vachon, Celine M ; Wang, Xianshu ; Margolin, Sara ; Lindblom, Annika ; Nevanlinna, Heli ; Greco, Dario ; Aittomak̈i, Kristiina ; Blomqvist, Carl ; Chang-Claude, Jenny ; Vrieling, Alina ; Flesch-Janys, Dieter ; Sinn, Hans Peter ; Wang-Gohrke, Shan ; Nickels, Stefan ; Brauch, Hiltrud ; Ko, Yon-Dschun ; Fischer, Hans-Peter ; Schmutzler, Rita K. ; Hopper, John L. ; Southey, Melissa C. ; Giles, Graham G. ; McLean, Catriona A. / 19p13.1 Is a triple-negative-specific breast cancer susceptibility locus. In: Cancer Research. 2012 ; Vol. 72, No. 7. pp. 1795-1803.
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abstract = "The 19p13.1 breast cancer susceptibility locus is a modifier of breast cancer risk in BRCA1 mutation carriers and is also associated with the 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 OR, 1.10; 95{\%} confidence interval (CI), 1.05-1.15; P = 3.49 × 10 -5] and triple-negative (ER-, PR-, and HER2-negative) breast cancer (rs8170: OR, 1.22; 95{\%} CI, 1.13-1.31; P = 2.22 × 10 -7). However, rs8170 was no longer associated with ERnegative breast cancer risk when triple-negative cases were excluded (OR, 0.98; 95{\%} CI, 0.89-1.07; P = 0.62). In addition, a combined analysis of triple-negative cases from BCAC and the Triple Negative Breast Cancer Consortium (TNBCC; N = 3,566) identified a genome-wide significant association between rs8170 and triple-negative breast cancer risk (OR, 1.25; 95{\%} CI, 1.18-1.33; P=3.31×10 -13]. Thus, 19p13.1 is the first triple-negative- specific breast cancer risk locus and the first locus specific to a histologic 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.",
author = "Stevens, {Kristen N.} and Zachary Fredericksen and Vachon, {Celine M} and Xianshu Wang and Sara Margolin and Annika Lindblom and Heli Nevanlinna and Dario Greco and Kristiina Aittomak̈i and Carl Blomqvist and Jenny Chang-Claude and Alina Vrieling and Dieter Flesch-Janys and Sinn, {Hans Peter} and Shan Wang-Gohrke and Stefan Nickels and Hiltrud Brauch and Yon-Dschun Ko and Hans-Peter Fischer and Schmutzler, {Rita K.} and Hopper, {John L.} and Southey, {Melissa C.} and Giles, {Graham G.} and McLean, {Catriona A.}",
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Stevens, KN, Fredericksen, Z, Vachon, CM, Wang, X, Margolin, S, Lindblom, A, Nevanlinna, H, Greco, D, Aittomak̈i, K, Blomqvist, C, Chang-Claude, J, Vrieling, A, Flesch-Janys, D, Sinn, HP, Wang-Gohrke, S, Nickels, S, Brauch, H, Ko, Y-D, Fischer, H-P, Schmutzler, RK, Hopper, JL, Southey, MC, Giles, GG & McLean, CA 2012, '19p13.1 Is a triple-negative-specific breast cancer susceptibility locus', Cancer Research, vol. 72, no. 7, pp. 1795-1803. https://doi.org/10.1158/0008-5472.CAN-11-3364

19p13.1 Is a triple-negative-specific breast cancer susceptibility locus. / Stevens, Kristen N.; Fredericksen, Zachary; Vachon, Celine M; Wang, Xianshu; Margolin, Sara; Lindblom, Annika; Nevanlinna, Heli; Greco, Dario; Aittomak̈i, Kristiina; Blomqvist, Carl; Chang-Claude, Jenny; Vrieling, Alina; Flesch-Janys, Dieter; Sinn, Hans Peter; Wang-Gohrke, Shan; Nickels, Stefan; Brauch, Hiltrud; Ko, Yon-Dschun; Fischer, Hans-Peter; Schmutzler, Rita K.; Hopper, John L.; Southey, Melissa C.; Giles, Graham G.; McLean, Catriona A.

In: Cancer Research, Vol. 72, No. 7, 01.04.2012, p. 1795-1803.

Research output: Contribution to journalArticleResearchpeer-review

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T1 - 19p13.1 Is a triple-negative-specific breast cancer susceptibility locus

AU - Stevens, Kristen N.

AU - Fredericksen, Zachary

AU - Vachon, Celine M

AU - Wang, Xianshu

AU - Margolin, Sara

AU - Lindblom, Annika

AU - Nevanlinna, Heli

AU - Greco, Dario

AU - Aittomak̈i, Kristiina

AU - Blomqvist, Carl

AU - Chang-Claude, Jenny

AU - Vrieling, Alina

AU - Flesch-Janys, Dieter

AU - Sinn, Hans Peter

AU - Wang-Gohrke, Shan

AU - Nickels, Stefan

AU - Brauch, Hiltrud

AU - Ko, Yon-Dschun

AU - Fischer, Hans-Peter

AU - Schmutzler, Rita K.

AU - Hopper, John L.

AU - Southey, Melissa C.

AU - Giles, Graham G.

AU - McLean, Catriona A.

PY - 2012/4/1

Y1 - 2012/4/1

N2 - The 19p13.1 breast cancer susceptibility locus is a modifier of breast cancer risk in BRCA1 mutation carriers and is also associated with the 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 OR, 1.10; 95% confidence interval (CI), 1.05-1.15; P = 3.49 × 10 -5] and triple-negative (ER-, PR-, and HER2-negative) breast cancer (rs8170: OR, 1.22; 95% CI, 1.13-1.31; P = 2.22 × 10 -7). However, rs8170 was no longer associated with ERnegative breast cancer risk when triple-negative cases were excluded (OR, 0.98; 95% CI, 0.89-1.07; P = 0.62). In addition, a combined analysis of triple-negative cases from BCAC and the Triple Negative Breast Cancer Consortium (TNBCC; N = 3,566) identified a genome-wide significant association between rs8170 and triple-negative breast cancer risk (OR, 1.25; 95% CI, 1.18-1.33; P=3.31×10 -13]. Thus, 19p13.1 is the first triple-negative- specific breast cancer risk locus and the first locus specific to a histologic 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.

AB - The 19p13.1 breast cancer susceptibility locus is a modifier of breast cancer risk in BRCA1 mutation carriers and is also associated with the 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 OR, 1.10; 95% confidence interval (CI), 1.05-1.15; P = 3.49 × 10 -5] and triple-negative (ER-, PR-, and HER2-negative) breast cancer (rs8170: OR, 1.22; 95% CI, 1.13-1.31; P = 2.22 × 10 -7). However, rs8170 was no longer associated with ERnegative breast cancer risk when triple-negative cases were excluded (OR, 0.98; 95% CI, 0.89-1.07; P = 0.62). In addition, a combined analysis of triple-negative cases from BCAC and the Triple Negative Breast Cancer Consortium (TNBCC; N = 3,566) identified a genome-wide significant association between rs8170 and triple-negative breast cancer risk (OR, 1.25; 95% CI, 1.18-1.33; P=3.31×10 -13]. Thus, 19p13.1 is the first triple-negative- specific breast cancer risk locus and the first locus specific to a histologic 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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Stevens KN, Fredericksen Z, Vachon CM, Wang X, Margolin S, Lindblom A et al. 19p13.1 Is a triple-negative-specific breast cancer susceptibility locus. Cancer Research. 2012 Apr 1;72(7):1795-1803. https://doi.org/10.1158/0008-5472.CAN-11-3364