Dataset Information

Genome-wide association study of germline variants and breast cancer-specific mortality.

ABSTRACT:

Background

We examined the associations between germline variants and breast cancer mortality using a large meta-analysis of women of European ancestry.

Methods

Meta-analyses included summary estimates based on Cox models of twelve datasets using ~10.4 million variants for 96,661 women with breast cancer and 7697 events (breast cancer-specific deaths). Oestrogen receptor (ER)-specific analyses were based on 64,171 ER-positive (4116) and 16,172 ER-negative (2125) patients. We evaluated the probability of a signal to be a true positive using the Bayesian false discovery probability (BFDP).

Results

We did not find any variant associated with breast cancer-specific mortality at P < 5 × 10^-8. For ER-positive disease, the most significantly associated variant was chr7:rs4717568 (BFDP = 7%, P = 1.28 × 10^-7, hazard ratio [HR] = 0.88, 95% confidence interval [CI] = 0.84-0.92); the closest gene is AUTS2. For ER-negative disease, the most significant variant was chr7:rs67918676 (BFDP = 11%, P = 1.38 × 10^-7, HR = 1.27, 95% CI = 1.16-1.39); located within a long intergenic non-coding RNA gene (AC004009.3), close to the HOXA gene cluster.

Conclusions

We uncovered germline variants on chromosome 7 at BFDP < 15% close to genes for which there is biological evidence related to breast cancer outcome. However, the paucity of variants associated with mortality at genome-wide significance underpins the challenge in providing genetic-based individualised prognostic information for breast cancer patients.

SUBMITTER: Escala-Garcia M

PROVIDER: S-EPMC6461853 | biostudies-literature | 2019 Mar

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Genome-wide association study of germline variants and breast cancer-specific mortality.

Escala-Garcia Maria M Guo Qi Q Dörk Thilo T Canisius Sander S Keeman Renske R Dennis Joe J Beesley Jonathan J Lecarpentier Julie J Bolla Manjeet K MK Wang Qin Q Abraham Jean J Andrulis Irene L IL Anton-Culver Hoda H Arndt Volker V Auer Paul L PL Beckmann Matthias W MW Behrens Sabine S Benitez Javier J Bermisheva Marina M Bernstein Leslie L Blomqvist Carl C Boeckx Bram B Bojesen Stig E SE Bonanni Bernardo B Børresen-Dale Anne-Lise AL Brauch Hiltrud H Brenner Hermann H Brentnall Adam A Brinton Louise L Broberg Per P Brock Ian W IW Brucker Sara Y SY Burwinkel Barbara B Caldas Carlos C Caldés Trinidad T Campa Daniele D Canzian Federico F Carracedo Angel A Carter Brian D BD Castelao Jose E JE Chang-Claude Jenny J Chanock Stephen J SJ Chenevix-Trench Georgia G Cheng Ting-Yuan David TD Chin Suet-Feung SF Clarke Christine L CL Cordina-Duverger Emilie E Couch Fergus J FJ Cox David G DG Cox Angela A Cross Simon S SS Czene Kamila K Daly Mary B MB Devilee Peter P Dunn Janet A JA Dunning Alison M AM Durcan Lorraine L Dwek Miriam M Earl Helena M HM Ekici Arif B AB Eliassen A Heather AH Ellberg Carolina C Engel Christoph C Eriksson Mikael M Evans D Gareth DG Figueroa Jonine J Flesch-Janys Dieter D Flyger Henrik H Gabrielson Marike M Gago-Dominguez Manuela M Galle Eva E Gapstur Susan M SM García-Closas Montserrat M García-Sáenz José A JA Gaudet Mia M MM George Angela A Georgoulias Vassilios V Giles Graham G GG Glendon Gord G Goldgar David E DE González-Neira Anna A Alnæs Grethe I Grenaker GIG Grip Mervi M Guénel Pascal P Haeberle Lothar L Hahnen Eric E Haiman Christopher A CA Håkansson Niclas N Hall Per P Hamann Ute U Hankinson Susan S Harkness Elaine F EF Harrington Patricia A PA Hart Steven N SN Hartikainen Jaana M JM Hein Alexander A Hillemanns Peter P Hiller Louise L Holleczek Bernd B Hollestelle Antoinette A Hooning Maartje J MJ Hoover Robert N RN Hopper John L JL Howell Anthony A Huang Guanmengqian G Humphreys Keith K Hunter David J DJ Janni Wolfgang W John Esther M EM Jones Michael E ME Jukkola-Vuorinen Arja A Jung Audrey A Kaaks Rudolf R Kabisch Maria M Kaczmarek Katarzyna K Kerin Michael J MJ Khan Sofia S Khusnutdinova Elza E Kiiski Johanna I JI Kitahara Cari M CM Knight Julia A JA Ko Yon-Dschun YD Koppert Linetta B LB Kosma Veli-Matti VM Kraft Peter P Kristensen Vessela N VN Krüger Ute U Kühl Tabea T Lambrechts Diether D Le Marchand Loic L Lee Eunjung E Lejbkowicz Flavio F Li Lian L Lindblom Annika A Lindström Sara S Linet Martha M Lissowska Jolanta J Lo Wing-Yee WY Loibl Sibylle S Lubiński Jan J Lux Michael P MP MacInnis Robert J RJ Maierthaler Melanie M Maishman Tom T Makalic Enes E Mannermaa Arto A Manoochehri Mehdi M Manoukian Siranoush S Margolin Sara S Martinez Maria Elena ME Mavroudis Dimitrios D McLean Catriona C Meindl Alfons A Middha Pooja P Miller Nicola N Milne Roger L RL Moreno Fernando F Mulligan Anna Marie AM Mulot Claire C Nassir Rami R Neuhausen Susan L SL Newman William T WT Nielsen Sune F SF Nordestgaard Børge G BG Norman Aaron A Olsson Håkan H Orr Nick N Pankratz V Shane VS Park-Simon Tjoung-Won TW Perez Jose I A JIA Pérez-Barrios Clara C Peterlongo Paolo P Petridis Christos C Pinchev Mila M Prajzendanc Karoliona K Prentice Ross R Presneau Nadege N Prokofieva Darya D Pylkäs Katri K Rack Brigitte B Radice Paolo P Ramachandran Dhanya D Rennert Gadi G Rennert Hedy S HS Rhenius Valerie V Romero Atocha A Roylance Rebecca R Saloustros Emmanouil E Sawyer Elinor J EJ Schmidt Daniel F DF Schmutzler Rita K RK Schneeweiss Andreas A Schoemaker Minouk J MJ Schumacher Fredrick F Schwentner Lukas L Scott Rodney J RJ Scott Christopher C Seynaeve Caroline C Shah Mitul M Simard Jacques J Smeets Ann A Sohn Christof C Southey Melissa C MC Swerdlow Anthony J AJ Talhouk Aline A Tamimi Rulla M RM Tapper William J WJ Teixeira Manuel R MR Tengström Maria M Terry Mary Beth MB Thöne Kathrin K Tollenaar Rob A E M RAEM Tomlinson Ian I Torres Diana D Truong Thérèse T Turman Constance C Turnbull Clare C Ulmer Hans-Ulrich HU Untch Michael M Vachon Celine C van Asperen Christi J CJ van den Ouweland Ans M W AMW van Veen Elke M EM Wendt Camilla C Whittemore Alice S AS Willett Walter W Winqvist Robert R Wolk Alicja A Yang Xiaohong R XR Zhang Yan Y Easton Douglas F DF Fasching Peter A PA Nevanlinna Heli H Eccles Diana M DM Pharoah Paul D P PDP Schmidt Marjanka K MK

British journal of cancer 20190221 6

<h4>Background</h4>We examined the associations between germline variants and breast cancer mortality using a large meta-analysis of women of European ancestry.<h4>Methods</h4>Meta-analyses included summary estimates based on Cox models of twelve datasets using ~10.4 million variants for 96,661 women with breast cancer and 7697 events (breast cancer-specific deaths). Oestrogen receptor (ER)-specific analyses were based on 64,171 ER-positive (4116) and 16,172 ER-negative (2125) patients. We evalu ...[more]

PMID: 30787463

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Project description:In breast tumors, somatic mutation frequencies in TP53 and PIK3CA vary by tumor subtype and ancestry. Emerging data suggest tumor mutation status is associated with germline variants and genetic ancestry. We aimed to identify germline variants that are associated with somatic TP53 or PIK3CA mutation status in breast tumors. A genome-wide association study was conducted in 2,850 women of European ancestry with breast cancer using TP53 and PIK3CA mutation status (positive or negative) as well as specific functional categories [e.g., TP53 gain-of-function (GOF) and loss-of-function, PIK3CA activating] as phenotypes. Germline variants showing evidence of association were selected for validation analyses and tested in multiple independent datasets. Discovery association analyses found five variants associated with TP53 mutation status with P values <1 × 10-6 and 33 variants with P values <1 × 10-5. Forty-four variants were associated with PIK3CA mutation status with P values <1 × 10-5. In validation analyses, only variants at the ESR1 locus were associated with TP53 mutation status after multiple comparisons corrections. Combined analyses in European and Malaysian populations found ESR1 locus variants rs9383938 and rs9479090 associated with the presence of TP53 mutations overall (P values 2 × 10-11 and 4.6 × 10-10, respectively). rs9383938 also showed association with TP53 GOF mutations (P value 6.1 × 10-7). rs9479090 showed suggestive evidence (P value 0.02) for association with TP53 mutation status in African ancestry populations. No other variants were significantly associated with TP53 or PIK3CA mutation status. Larger studies are needed to confirm these findings and determine if additional variants contribute to ancestry-specific differences in mutation frequency.SignificanceEmerging data show ancestry-specific differences in TP53 and PIK3CA mutation frequency in breast tumors suggesting that germline variants may influence somatic mutational processes. This study identified variants near ESR1 associated with TP53 mutation status and identified additional loci with suggestive association which may provide biological insight into observed differences.

Project description:BackgroundIn breast tumors, somatic mutation frequencies in TP53 and PIK3CA vary by tumor subtype and ancestry. HER2 positive and triple negative breast cancers (TNBC) have a higher frequency of TP53 somatic mutations than other subtypes. PIK3CA mutations are more frequently observed in hormone receptor positive tumors. Emerging data suggest tumor mutation status is associated with germline variants and genetic ancestry. We aimed to identify germline variants that are associated with somatic TP53 or PIK3CA mutation status in breast tumors.MethodsA genome-wide association study was conducted using breast cancer mutation status of TP53 and PIK3CA and functional mutation categories including TP53 gain of function (GOF) and loss of function mutations and PIK3CA activating/hotspot mutations. The discovery analysis consisted of 2850 European ancestry women from three datasets. Germline variants showing evidence of association with somatic mutations were selected for validation analyses based on predicted function, allele frequency, and proximity to known cancer genes or risk loci. Candidate variants were assessed for association with mutation status in a multi-ancestry validation study, a Malaysian study, and a study of African American/Black women with TNBC.ResultsThe discovery Germline x Mutation (GxM) association study found five variants associated with one or more TP53 phenotypes with P values <1×10-6, 33 variants associated with one or more TP53 phenotypes with P values <1×10-5, and 44 variants associated with one or more PIK3CA phenotypes with P values <1×10-5. In the multi-ancestry and Malaysian validation studies, germline ESR1 locus variant, rs9383938, was associated with the presence of TP53 mutations overall (P values 6.8×10-5 and 9.8×10-8, respectively) and TP53 GOF mutations (P value 8.4×10-6). Multiple variants showed suggestive evidence of association with PIK3CA mutation status in the validation studies, but none were significant after correction for multiple comparisons.ConclusionsWe found evidence that germline variants were associated with TP53 and PIK3CA mutation status in breast cancers. Variants near the estrogen receptor alpha gene, ESR1, were significantly associated with overall TP53 mutations and GOF mutations. Larger multi-ancestry studies are needed to confirm these findings and determine if these variants contribute to ancestry-specific differences in mutation frequency.

Dataset Information

Genome-wide association study of germline variants and breast cancer-specific mortality.

Background

Methods

Results

Conclusions

Publications

Genome-wide association study of germline variants and breast cancer-specific mortality.

Similar Datasets

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