Genome-wide association study of germline variants and breast cancer-specific mortality.
Escala-Garcia M., Guo Q., Dörk T., Canisius S., Keeman R., Dennis J., Beesley J., Lecarpentier J., Bolla MK., Wang Q., Abraham J., Andrulis IL., Anton-Culver H., Arndt V., Auer PL., Beckmann MW., Behrens S., Benitez J., Bermisheva M., Bernstein L., Blomqvist C., Boeckx B., Bojesen SE., Bonanni B., Børresen-Dale A-L., Brauch H., Brenner H., Brentnall A., Brinton L., Broberg P., Brock IW., Brucker SY., Burwinkel B., Caldas C., Caldés T., Campa D., Canzian F., Carracedo A., Carter BD., Castelao JE., Chang-Claude J., Chanock SJ., Chenevix-Trench G., Cheng T-YD., Chin S-F., Clarke CL., NBCS Collaborators None., Cordina-Duverger E., Couch FJ., Cox DG., Cox A., Cross SS., Czene K., Daly MB., Devilee P., Dunn JA., Dunning AM., Durcan L., Dwek M., Earl HM., Ekici AB., Eliassen AH., Ellberg C., Engel C., Eriksson M., Evans DG., Figueroa J., Flesch-Janys D., Flyger H., Gabrielson M., Gago-Dominguez M., Galle E., Gapstur SM., García-Closas M., García-Sáenz JA., Gaudet MM., George A., Georgoulias V., Giles GG., Glendon G., Goldgar DE., González-Neira A., Alnæs GIG., Grip M., Guénel P., Haeberle L., Hahnen E., Haiman CA., Håkansson N., Hall P., Hamann U., Hankinson S., Harkness EF., Harrington PA., Hart SN., Hartikainen JM., Hein A., Hillemanns P., Hiller L., Holleczek B., Hollestelle A., Hooning MJ., Hoover RN., Hopper JL., Howell A., Huang G., Humphreys K., Hunter DJ., Janni W., John EM., Jones ME., Jukkola-Vuorinen A., Jung A., Kaaks R., Kabisch M., Kaczmarek K., Kerin MJ., Khan S., Khusnutdinova E., Kiiski JI., Kitahara CM., Knight JA., Ko Y-D., Koppert LB., Kosma V-M., Kraft P., Kristensen VN., Krüger U., Kühl T., Lambrechts D., Le Marchand L., Lee E., Lejbkowicz F., Li L., Lindblom A., Lindström S., Linet M., Lissowska J., Lo W-Y., Loibl S., Lubiński J., Lux MP., MacInnis RJ., Maierthaler M., Maishman T., Makalic E., Mannermaa A., Manoochehri M., Manoukian S., Margolin S., Martinez ME., Mavroudis D., McLean C., Meindl A., Middha P., Miller N., Milne RL., Moreno F., Mulligan AM., Mulot C., Nassir R., Neuhausen SL., Newman WT., Nielsen SF., Nordestgaard BG., Norman A., Olsson H., Orr N., Pankratz VS., Park-Simon T-W., Perez JIA., Pérez-Barrios C., Peterlongo P., Petridis C., Pinchev M., Prajzendanc K., Prentice R., Presneau N., Prokofieva D., Pylkäs K., Rack B., Radice P., Ramachandran D., Rennert G., Rennert HS., Rhenius V., Romero A., Roylance R., Saloustros E., Sawyer EJ., Schmidt DF., Schmutzler RK., Schneeweiss A., Schoemaker MJ., Schumacher F., Schwentner L., Scott RJ., Scott C., Seynaeve C., Shah M., Simard J., Smeets A., Sohn C., Southey MC., Swerdlow AJ., Talhouk A., Tamimi RM., Tapper WJ., Teixeira MR., Tengström M., Terry MB., Thöne K., Tollenaar RAEM., Tomlinson I., Torres D., Truong T., Turman C., Turnbull C., Ulmer H-U., Untch M., Vachon C., van Asperen CJ., van den Ouweland AMW., van Veen EM., Wendt C., Whittemore AS., Willett W., Winqvist R., Wolk A., Yang XR., Zhang Y., Easton DF., Fasching PA., Nevanlinna H., Eccles DM., Pharoah PDP., Schmidt MK.
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.