Combined associations of a polygenic risk score and classical risk factors with breast cancer risk.
Kapoor PM., Mavaddat N., Choudhury PP., Wilcox AN., Lindström S., Behrens S., Michailidou K., Dennis J., Bolla MK., Wang Q., Jung A., Abu-Ful Z., Ahearn T., Andrulis IL., Anton-Culver H., Arndt V., Aronson KJ., Auer PL., Freeman LEB., Becher H., Beckmann MW., Beeghly-Fadiel A., Benitez J., Bernstein L., Bojesen SE., Brauch H., Brenner H., Brüning T., Cai Q., Campa D., Canzian F., Carracedo A., Carter BD., Castelao JE., Chanock SJ., Chatterjee N., Chenevix-Trench G., Clarke CL., Couch FJ., Cox A., Cross SS., Czene K., Dai JY., Earp HS., Ekici AB., Eliassen AH., Eriksson M., Evans DG., Fasching PA., Figueroa J., Fritschi L., Gabrielson M., Gago-Dominguez M., Gao C., Gapstur SM., Gaudet MM., Giles GG., González-Neira A., Guénel P., Haeberle L., Haiman CA., Håkansson N., Hall P., Hamann U., Hatse S., Heyworth J., Holleczek B., Hoover RN., Hopper JL., Howell A., Hunter DJ., ABCTB Investigators None., kConFab/AOCS Investigators None., John EM., Jones ME., Kaaks R., Keeman R., Kitahara CM., Ko Y-D., Koutros S., Kurian AW., Lambrechts D., Marchand LL., Lee E., Lejbkowicz F., Linet M., Lissowska J., Llaneza A., MacInnis RJ., Martinez ME., Maurer T., McLean C., Neuhausen SL., Newman WG., Norman A., O'Brien KM., Olshan AF., Olson JE., Olsson H., Orr N., Perou CM., Pita G., Polley EC., Prentice RL., Rennert G., Rennert HS., Ruddy KJ., Sandler DP., Saunders C., Schoemaker MJ., Schöttker B., Schumacher F., Scott C., Scott RJ., Shu X-O., Smeets A., Southey MC., Spinelli JJ., Stone J., Swerdlow AJ., Tamimi RM., Taylor JA., Troester MA., Vachon CM., van Veen EM., Wang X., Weinberg CR., Weltens C., Willett W., Winham SJ., Wolk A., Yang XR., Zheng W., Ziogas A., Dunning AM., Pharoah PDP., Schmidt MK., Kraft P., Easton DF., Milne RL., García-Closas M., Chang-Claude J.
We evaluated the joint associations between a new 313-variant PRS (PRS313) and questionnaire-based breast cancer risk factors for women of European ancestry, using 72,284 cases and 80,354 controls from the Breast Cancer Association Consortium. Interactions were evaluated using standard logistic regression, and a newly developed case-only method, for breast cancer risk overall and by estrogen receptor status. After accounting for multiple testing, we did not find evidence that per-standard deviation PRS313 odds ratio differed across strata defined by individual risk factors. Goodness-of-fit tests did not reject the assumption of a multiplicative model between PRS313 and each risk factor. Variation in projected absolute lifetime risk of breast cancer associated with classical risk factors was greater for women with higher genetic risk (PRS313 and family history), and on average 17.5% higher in the highest vs lowest deciles of genetic risk. These findings have implications for risk prevention for women at increased risk of breast cancer.