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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.

SUBMITTER: Escala-Garcia M

PROVIDER: S-EPMC8492709 | biostudies-literature | 2021 Oct

REPOSITORIES: biostudies-literature

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

Escala-Garcia Maria M Canisius Sander S Keeman Renske R Beesley Jonathan J Anton-Culver Hoda H Arndt Volker V Augustinsson Annelie A Becher Heiko H Beckmann Matthias W MW Behrens Sabine S Bermisheva Marina M Bojesen Stig E SE Bolla Manjeet K MK Brenner Hermann H Canzian Federico F Castelao Jose E JE Chang-Claude Jenny J Chanock Stephen J SJ Couch Fergus J FJ Czene Kamila K Daly Mary B MB Dennis Joe J Devilee Peter P Dörk Thilo T Dunning Alison M AM Easton Douglas F DF Ekici Arif B AB Eliassen A Heather AH Fasching Peter A PA Flyger Henrik H Gago-Dominguez Manuela M García-Closas Montserrat M García-Sáenz José A JA Geisler Jürgen J Giles Graham G GG Grip Mervi M Gündert Melanie M Hahnen Eric E Haiman Christopher A CA Håkansson Niclas N Hall Per P Hamann Ute U Hartikainen Jaana M JM Heemskerk-Gerritsen Bernadette A M BAM Hollestelle Antoinette A Hoppe Reiner R Hopper John L JL Hunter David J DJ Jacot William W Jakubowska Anna A John Esther M EM Jung Audrey Y AY Kaaks Rudolf R Khusnutdinova Elza E Koppert Linetta B LB Kraft Peter P Kristensen Vessela N VN Kurian Allison W AW Lambrechts Diether D Le Marchand Loic L Lindblom Annika A Luben Robert N RN Lubiński Jan J Mannermaa Arto A Manoochehri Mehdi M Margolin Sara S Mavroudis Dimitrios D Muranen Taru A TA Nevanlinna Heli H Olshan Andrew F AF Olsson Håkan H Park-Simon Tjoung-Won TW Patel Alpa V AV Peterlongo Paolo P Pharoah Paul D P PDP Punie Kevin K Radice Paolo P Rennert Gad G Rennert Hedy S HS Romero Atocha A Roylance Rebecca R Rüdiger Thomas T Ruebner Matthias M Saloustros Emmanouil E Sawyer Elinor J EJ Schmutzler Rita K RK Schoemaker Minouk J MJ Scott Christopher C Southey Melissa C MC Surowy Harald H Swerdlow Anthony J AJ Tamimi Rulla M RM Teras Lauren R LR Thomas Emilie E Tomlinson Ian I Troester Melissa A MA Vachon Celine M CM Wang Qin Q Winqvist Robert R Wolk Alicja A Ziogas Argyrios A Michailidou Kyriaki K Chenevix-Trench Georgia G Bachelot Thomas T Schmidt Marjanka K MK

Scientific reports 20211005 1

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 1 ...[more]

PMID: 34611289

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Project description:Although the repertoire of somatic genetic alterations of primary breast cancers has been extensively catalogued, the genetic differences between primary and metastatic tumors have been less studied. In this study, we compared somatic mutations and gene copy number alterations of primary breast cancers and their matched metastases from patients with estrogen receptor (ER)-negative disease. DNA samples obtained from formalin-fixed paraffin-embedded ER-negative/HER2-positive (n = 9) and ER-, progesterone receptor (PR-), HER2-negative (n = 8) primary breast cancers and from paired brain or skin metastases and normal tissue were subjected to a hybridization capture-based massively parallel sequencing assay, targeting 341 key cancer genes. A large subset of nonsynonymous somatic mutations (45%) and gene copy number alterations (55%) was shared between the primary tumors and paired metastases. However, mutations restricted to either a given primary tumor or its metastasis, the acquisition of loss of heterozygosity of the wild-type allele, and clonal shifts of genes affected by somatic mutations, such as TP53 and RB1, were observed in the progression from primary tumors to metastases. No metastasis location-specific alterations were identified, but synchronous metastases showed higher concordance with the paired primary tumor than metachronous metastases. Novel potentially targetable alterations were found in the metastases relative to their matched primary tumors. These data indicate that repertoires of somatic genetic alterations in ER-negative metastatic breast cancers may differ from those of their primary tumors, even by the presence of driver and targetable somatic genetic alterations.Significance: Somatic genetic alterations in ER-negative breast cancer metastases may be distinct from those of their primary tumors, suggesting that for treatment-decision making, genetic analyses of DNA obtained from the metastatic lesion rather than from the primary tumor should be considered. Cancer Res; 78(12); 3112-21. ©2018 AACR.

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

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

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