Genetic variation in mitotic regulatory pathway genes is associated with breast tumor grade.
Purrington KS., Slettedahl S., Bolla MK., Michailidou K., Czene K., Nevanlinna H., Bojesen SE., Andrulis IL., Cox A., Hall P., Carpenter J., Yannoukakos D., Haiman CA., Fasching PA., Mannermaa A., Winqvist R., Brenner H., Lindblom A., Chenevix-Trench G., Benitez J., Swerdlow A., Kristensen V., Guénel P., Meindl A., Darabi H., Eriksson M., Fagerholm R., Aittomäki K., Blomqvist C., Nordestgaard BG., Nielsen SF., Flyger H., Wang X., Olswold C., Olson JE., Mulligan AM., Knight JA., Tchatchou S., Reed MWR., Cross SS., Liu J., Li J., Humphreys K., Clarke C., Scott R., ABCTB Investigators None., Fostira F., Fountzilas G., Konstantopoulou I., Henderson BE., Schumacher F., Le Marchand L., Ekici AB., Hartmann A., Beckmann MW., Hartikainen JM., Kosma V-M., Kataja V., Jukkola-Vuorinen A., Pylkäs K., Kauppila S., Dieffenbach AK., Stegmaier C., Arndt V., Margolin S., Australian Ovarian Cancer Study Group None., kConFab Investigators None., Balleine R., Arias Perez JI., Pilar Zamora M., Menéndez P., Ashworth A., Jones M., Orr N., Arveux P., Kerbrat P., Truong T., Bugert P., Toland AE., Ambrosone CB., Labrèche F., Goldberg MS., Dumont M., Ziogas A., Lee E., Dite GS., Apicella C., Southey MC., Long J., Shrubsole M., Deming-Halverson S., Ficarazzi F., Barile M., Peterlongo P., Durda K., Jaworska-Bieniek K., Tollenaar RAEM., Seynaeve C., GENICA Network None., Brüning T., Ko Y-D., Van Deurzen CHM., Martens JWM., Kriege M., Figueroa JD., Chanock SJ., Lissowska J., Tomlinson I., Kerin MJ., Miller N., Schneeweiss A., Tapper WJ., Gerty SM., Durcan L., Mclean C., Milne RL., Baglietto L., dos Santos Silva I., Fletcher O., Johnson N., Van'T Veer LJ., Cornelissen S., Försti A., Torres D., Rüdiger T., Rudolph A., Flesch-Janys D., Nickels S., Weltens C., Floris G., Moisse M., Dennis J., Wang Q., Dunning AM., Shah M., Brown J., Simard J., Anton-Culver H., Neuhausen SL., Hopper JL., Bogdanova N., Dörk T., Zheng W., Radice P., Jakubowska A., Lubinski J., Devillee P., Brauch H., Hooning M., García-Closas M., Sawyer E., Burwinkel B., Marmee F., Eccles DM., Giles GG., Peto J., Schmidt M., Broeks A., Hamann U., Chang-Claude J., Lambrechts D., Pharoah PDP., Easton D., Pankratz VS., Slager S., Vachon CM., Couch FJ.
Mitotic index is an important component of histologic grade and has an etiologic role in breast tumorigenesis. Several small candidate gene studies have reported associations between variation in mitotic genes and breast cancer risk. We measured associations between 2156 single nucleotide polymorphisms (SNPs) from 194 mitotic genes and breast cancer risk, overall and by histologic grade, in the Breast Cancer Association Consortium (BCAC) iCOGS study (n = 39 067 cases; n = 42 106 controls). SNPs in TACC2 [rs17550038: odds ratio (OR) = 1.24, 95% confidence interval (CI) 1.16-1.33, P = 4.2 × 10(-10)) and EIF3H (rs799890: OR = 1.07, 95% CI 1.04-1.11, P = 8.7 × 10(-6)) were significantly associated with risk of low-grade breast cancer. The TACC2 signal was retained (rs17550038: OR = 1.15, 95% CI 1.07-1.23, P = 7.9 × 10(-5)) after adjustment for breast cancer risk SNPs in the nearby FGFR2 gene, suggesting that TACC2 is a novel, independent genome-wide significant genetic risk locus for low-grade breast cancer. While no SNPs were individually associated with high-grade disease, a pathway-level gene set analysis showed that variation across the 194 mitotic genes was associated with high-grade breast cancer risk (P = 2.1 × 10(-3)). These observations will provide insight into the contribution of mitotic defects to histological grade and the etiology of breast cancer.