Germline variants and breast cancer survival in patients with distant metastases at primary breast cancer diagnosis

Maria Escala-Garcia; Sander Canisius; Renske Keeman; Jonathan Beesley; Hoda Anton-Culver; Volker Arndt; Annelie Augustinsson; Heiko Becher; Matthias W Beckmann; Sabine Behrens; Marina Bermisheva; Stig E Bojesen; Manjeet K Bolla; Hermann Brenner; Federico Canzian; Jose E Castelao; Jenny Chang-Claude; Stephen J Chanock; Fergus J Couch; Kamila Czene; Mary B Daly; Joe Dennis; Peter Devilee; Thilo Dörk; Alison M Dunning; Douglas F Easton; Arif B Ekici; A Heather Eliassen; Peter A Fasching; Henrik Flyger; Manuela Gago-Dominguez; Montserrat García-Closas; José A García-Sáenz; Jürgen Geisler; Graham G Giles; Mervi Grip; Melanie Gündert; Eric Hahnen; Christopher A Haiman; Niclas Håkansson; Per Hall; Ute Hamann; Jaana M Hartikainen; Bernadette A M Heemskerk-Gerritsen; Antoinette Hollestelle; Reiner Hoppe; John L Hopper; David J Hunter; William Jacot; Anna Jakubowska; kConFab/AOCS Investigators

doi:10.1038/s41598-021-99409-3

Germline variants and breast cancer survival in patients with distant metastases at primary breast cancer diagnosis

Maria Escala-Garcia, Sander Canisius, Renske Keeman, Jonathan Beesley, Hoda Anton-Culver, Volker Arndt, Annelie Augustinsson, Heiko Becher, Matthias W Beckmann, Sabine Behrens, Marina Bermisheva, Stig E Bojesen, Manjeet K Bolla, Hermann Brenner, Federico Canzian, Jose E Castelao, Jenny Chang-Claude, Stephen J Chanock, Fergus J Couch, Kamila CzeneMary B Daly, Joe Dennis, Peter Devilee, Thilo Dörk, Alison M Dunning, Douglas F Easton, Arif B Ekici, A Heather Eliassen, Peter A Fasching, Henrik Flyger, Manuela Gago-Dominguez, Montserrat García-Closas, José A García-Sáenz, Jürgen Geisler, Graham G Giles, Mervi Grip, Melanie Gündert, Eric Hahnen, Christopher A Haiman, Niclas Håkansson, Per Hall, Ute Hamann, Jaana M Hartikainen, Bernadette A M Heemskerk-Gerritsen, Antoinette Hollestelle, Reiner Hoppe, John L Hopper, David J Hunter, William Jacot, Anna Jakubowska, kConFab/AOCS Investigators

Abstract

Breast cancer metastasis accounts for most of the deaths from breast cancer. Identification of germline variants associated with survival in aggressive types of breast cancer may inform understanding of breast cancer progression and assist treatment. In this analysis, we studied the associations between germline variants and breast cancer survival for patients with distant metastases at primary breast cancer diagnosis. We used data from the Breast Cancer Association Consortium (BCAC) including 1062 women of European ancestry with metastatic breast cancer, 606 of whom died of breast cancer. We identified two germline variants on chromosome 1, rs138569520 and rs146023652, significantly associated with breast cancer-specific survival (P = 3.19 × 10-8 and 4.42 × 10-8). In silico analysis suggested a potential regulatory effect of the variants on the nearby target genes SDE2 and H3F3A. However, the variants showed no evidence of association in a smaller replication dataset. The validation dataset was obtained from the SNPs to Risk of Metastasis (StoRM) study and included 293 patients with metastatic primary breast cancer at diagnosis. Ultimately, larger replication studies are needed to confirm the identified associations.

Original language	English
Article number	19787
Journal	Scientific Reports
Volume	11
Issue number	1
Pages (from-to)	19787
ISSN	2045-2322
DOIs	https://doi.org/10.1038/s41598-021-99409-3
Publication status	Published - 5 Oct 2021

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Escala-Garcia, M., Canisius, S., Keeman, R., Beesley, J., Anton-Culver, H., Arndt, V., Augustinsson, A., Becher, H., Beckmann, M. W., Behrens, S., Bermisheva, M., Bojesen, S. E., Bolla, M. K., Brenner, H., Canzian, F., Castelao, J. E., Chang-Claude, J., Chanock, S. J., Couch, F. J., ... kConFab/AOCS Investigators (2021). Germline variants and breast cancer survival in patients with distant metastases at primary breast cancer diagnosis. Scientific Reports, 11(1), 19787. Article 19787. https://doi.org/10.1038/s41598-021-99409-3

Escala-Garcia, M, Canisius, S, Keeman, R, Beesley, J, Anton-Culver, H, Arndt, V, Augustinsson, A, Becher, H, Beckmann, MW, Behrens, S, Bermisheva, M, Bojesen, SE, Bolla, MK, Brenner, H, Canzian, F, Castelao, JE, Chang-Claude, J, Chanock, SJ, Couch, FJ, Czene, K, Daly, MB, Dennis, J, Devilee, P, Dörk, T, Dunning, AM, Easton, DF, Ekici, AB, Eliassen, AH, Fasching, PA, Flyger, H, Gago-Dominguez, M, García-Closas, M, García-Sáenz, JA, Geisler, J, Giles, GG, Grip, M, Gündert, M, Hahnen, E, Haiman, CA, Håkansson, N, Hall, P, Hamann, U, Hartikainen, JM, Heemskerk-Gerritsen, BAM, Hollestelle, A, Hoppe, R, Hopper, JL, Hunter, DJ, Jacot, W, Jakubowska, A & kConFab/AOCS Investigators 2021, 'Germline variants and breast cancer survival in patients with distant metastases at primary breast cancer diagnosis', Scientific Reports, vol. 11, no. 1, 19787, pp. 19787. https://doi.org/10.1038/s41598-021-99409-3

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title = "Germline variants and breast cancer survival in patients with distant metastases at primary breast cancer diagnosis",

abstract = "Breast cancer metastasis accounts for most of the deaths from breast cancer. Identification of germline variants associated with survival in aggressive types of breast cancer may inform understanding of breast cancer progression and assist treatment. In this analysis, we studied the associations between germline variants and breast cancer survival for patients with distant metastases at primary breast cancer diagnosis. We used data from the Breast Cancer Association Consortium (BCAC) including 1062 women of European ancestry with metastatic breast cancer, 606 of whom died of breast cancer. We identified two germline variants on chromosome 1, rs138569520 and rs146023652, significantly associated with breast cancer-specific survival (P = 3.19 × 10-8 and 4.42 × 10-8). In silico analysis suggested a potential regulatory effect of the variants on the nearby target genes SDE2 and H3F3A. However, the variants showed no evidence of association in a smaller replication dataset. The validation dataset was obtained from the SNPs to Risk of Metastasis (StoRM) study and included 293 patients with metastatic primary breast cancer at diagnosis. Ultimately, larger replication studies are needed to confirm the identified associations.",

author = "Maria Escala-Garcia and Sander Canisius and Renske Keeman and Jonathan Beesley and Hoda Anton-Culver and Volker Arndt and Annelie Augustinsson and Heiko Becher and Beckmann, {Matthias W} and Sabine Behrens and Marina Bermisheva and Bojesen, {Stig E} and Bolla, {Manjeet K} and Hermann Brenner and Federico Canzian and Castelao, {Jose E} and Jenny Chang-Claude and Chanock, {Stephen J} and Couch, {Fergus J} and Kamila Czene and Daly, {Mary B} and Joe Dennis and Peter Devilee and Thilo D{\"o}rk and Dunning, {Alison M} and Easton, {Douglas F} and Ekici, {Arif B} and Eliassen, {A Heather} and Fasching, {Peter A} and Henrik Flyger and Manuela Gago-Dominguez and Montserrat Garc{\'i}a-Closas and Garc{\'i}a-S{\'a}enz, {Jos{\'e} A} and J{\"u}rgen Geisler and Giles, {Graham G} and Mervi Grip and Melanie G{\"u}ndert and Eric Hahnen and Haiman, {Christopher A} and Niclas H{\aa}kansson and Per Hall and Ute Hamann and Hartikainen, {Jaana M} and Heemskerk-Gerritsen, {Bernadette A M} and Antoinette Hollestelle and Reiner Hoppe and Hopper, {John L} and Hunter, {David J} and William Jacot and Anna Jakubowska and {kConFab/AOCS Investigators}",

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T1 - Germline variants and breast cancer survival in patients with distant metastases at primary breast cancer diagnosis

AU - Escala-Garcia, Maria

AU - Canisius, Sander

AU - Keeman, Renske

AU - Beesley, Jonathan

AU - Anton-Culver, Hoda

AU - Arndt, Volker

AU - Augustinsson, Annelie

AU - Becher, Heiko

AU - Beckmann, Matthias W

AU - Behrens, Sabine

AU - Bermisheva, Marina

AU - Bojesen, Stig E

AU - Bolla, Manjeet K

AU - Brenner, Hermann

AU - Canzian, Federico

AU - Castelao, Jose E

AU - Chang-Claude, Jenny

AU - Chanock, Stephen J

AU - Couch, Fergus J

AU - Czene, Kamila

AU - Daly, Mary B

AU - Dennis, Joe

AU - Devilee, Peter

AU - Dörk, Thilo

AU - Dunning, Alison M

AU - Easton, Douglas F

AU - Ekici, Arif B

AU - Eliassen, A Heather

AU - Fasching, Peter A

AU - Flyger, Henrik

AU - Gago-Dominguez, Manuela

AU - García-Closas, Montserrat

AU - García-Sáenz, José A

AU - Geisler, Jürgen

AU - Giles, Graham G

AU - Grip, Mervi

AU - Gündert, Melanie

AU - Hahnen, Eric

AU - Haiman, Christopher A

AU - Håkansson, Niclas

AU - Hall, Per

AU - Hamann, Ute

AU - Hartikainen, Jaana M

AU - Heemskerk-Gerritsen, Bernadette A M

AU - Hollestelle, Antoinette

AU - Hoppe, Reiner

AU - Hopper, John L

AU - Hunter, David J

AU - Jacot, William

AU - Jakubowska, Anna

AU - kConFab/AOCS Investigators

PY - 2021/10/5

Y1 - 2021/10/5

N2 - Breast cancer metastasis accounts for most of the deaths from breast cancer. Identification of germline variants associated with survival in aggressive types of breast cancer may inform understanding of breast cancer progression and assist treatment. In this analysis, we studied the associations between germline variants and breast cancer survival for patients with distant metastases at primary breast cancer diagnosis. We used data from the Breast Cancer Association Consortium (BCAC) including 1062 women of European ancestry with metastatic breast cancer, 606 of whom died of breast cancer. We identified two germline variants on chromosome 1, rs138569520 and rs146023652, significantly associated with breast cancer-specific survival (P = 3.19 × 10-8 and 4.42 × 10-8). In silico analysis suggested a potential regulatory effect of the variants on the nearby target genes SDE2 and H3F3A. However, the variants showed no evidence of association in a smaller replication dataset. The validation dataset was obtained from the SNPs to Risk of Metastasis (StoRM) study and included 293 patients with metastatic primary breast cancer at diagnosis. Ultimately, larger replication studies are needed to confirm the identified associations.

AB - Breast cancer metastasis accounts for most of the deaths from breast cancer. Identification of germline variants associated with survival in aggressive types of breast cancer may inform understanding of breast cancer progression and assist treatment. In this analysis, we studied the associations between germline variants and breast cancer survival for patients with distant metastases at primary breast cancer diagnosis. We used data from the Breast Cancer Association Consortium (BCAC) including 1062 women of European ancestry with metastatic breast cancer, 606 of whom died of breast cancer. We identified two germline variants on chromosome 1, rs138569520 and rs146023652, significantly associated with breast cancer-specific survival (P = 3.19 × 10-8 and 4.42 × 10-8). In silico analysis suggested a potential regulatory effect of the variants on the nearby target genes SDE2 and H3F3A. However, the variants showed no evidence of association in a smaller replication dataset. The validation dataset was obtained from the SNPs to Risk of Metastasis (StoRM) study and included 293 patients with metastatic primary breast cancer at diagnosis. Ultimately, larger replication studies are needed to confirm the identified associations.

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DO - 10.1038/s41598-021-99409-3

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SN - 2045-2322

VL - 11

SP - 19787

JO - Scientific Reports

JF - Scientific Reports

IS - 1

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ER -

Germline variants and breast cancer survival in patients with distant metastases at primary breast cancer diagnosis

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