Confirmation of 5p12 as a susceptibility locus for progesterone-receptor- positive, lower grade breast cancer
Milne RL., Goode EL., García-Closas M., Couch FJ., Severi G., Hein R., Fredericksen Z., Malats N., Zamora MP., Pérez JIA., Benítez J., Dörk T., Schürmann P., Karstens JH., Hillemanns P., Cox A., Brock IW., Elliot G., Cross SS., Seal S., Turnbull C., Renwick A., Rahman N., Shen CY., Yu JC., Huang CS., Hou MF., Nordestgaard BG., Bojesen SE., Lanng C., Alnæs GG., Kristensen V., Børrensen-Dale AL., Hopper JL., Dite GS., Apicella C., Southey MC., Lambrechts D., Yesilyurt BT., Floris G., Leunen K., Sangrajrang S., Gaborieau V., Brennan P., McKay J., Chang-Claude J., Wang-Gohrke S., Radice P., Peterlongo P., Manoukian S., Barile M., Giles GG., Baglietto L., John EM., Miron A., Chanock SJ., Lissowska J., Sherman ME., Figueroa JD., Bogdanova NV., Antonenkova NN., Zalutsky IV., Rogov YI., Fasching PA., Bayer CM., Ekici AB., Beckmann MW., Brenner H., Müller H., Arndt V., Stegmaier C., Andrulis IL., Knight JA., Glendon G., Mulligan AM., Mannermaa A., Kataja V., Kosma VM., Hartikainen JM., Meindl A., Heil J., Bartram CR., Schmutzler RK., Thomas GD., Hoover RN., Fletcher O., Gibson LJ., Dos Santos Silva I., Peto J., Nickels S., Flesch-Janys D., Anton-Culver H., Ziogas A., Sawyer E., Tomlinson I., Kerin M., Miller N., Schmidt MK., Broeks A., Van't Veer LJ.
Background: The single-nucleotide polymorphism (SNP) 5p12-rs10941679 has been found to be associated with risk of breast cancer, particularly estrogen receptor (ER)-positive disease. We aimed to further explore this association overall, and by tumor histopathology, in the Breast Cancer Association Consortium. Methods: Data were combined from 37 studies, including 40,972 invasive cases, 1,398 cases of ductal carcinoma in situ (DCIS), and 46,334 controls, all of white European ancestry, as well as 3,007 invasive cases and 2,337 controls of Asian ancestry. Associations overall and by tumor invasiveness and histopathology were assessed using logistic regression. Results: For white Europeans, the per-allele OR associated with 5p12-rs10941679 was 1.11 (95% CI = 1.08-1.14, P = 7 × 10-18) for invasive breast cancer and 1.10 (95% CI = 1.01-1.21, P = 0.03) for DCIS. For Asian women, the estimated OR for invasive disease was similar (OR = 1.07, 95%CI = 0.99-1.15, P = 0.09). Further analyses suggested that the association in white Europeans was largely limited to progesterone receptor (PR)- positive disease (per-allele OR = 1.16, 95% CI = 1.12-1.20, P = 1 × 10-18 vs. OR = 1.03, 95% CI = 0.99-1.07, P = 0.2 for PR-negative disease; Pheterogeneity = 2 × 10 -7); heterogeneity by ER status was not observed (P= 0.2) once PR status was accounted for. The association was also stronger for lower grade tumors [per-allele OR (95% CI) = 1.20 (1.14-1.25), 1.13 (1.09-1.16), and 1.04 (0.99-1.08) for grade 1, 2, and 3/4, respectively; Ptrend = 5 × 10 -7]. Conclusion: 5p12 is a breast cancer susceptibility locus for PR-positive, lower grade breast cancer. Impact: Multicenter fine-mapping studies of this region are needed as a first step to identifying the causal variant or variants. ©2011 AACR.