European polygenic risk score for prediction of breast cancer shows similar performance in Asian women

Weang-Kee Ho, Min-Min Tan, Nasim Mavaddat, Mei-Chee Tai, Shivaani Mariapun, Jingmei Li, Peh-Joo Ho, Joe Dennis, Jonathan P Tyrer, Manjeet K Bolla, Kyriaki Michailidou, Qin Wang, Daehee Kang, Ji-Yeob Choi, Suniza Jamaris, Xiao-Ou Shu, Sook-Yee Yoon, Sue K Park, Sung-Won Kim, Chen-Yang Shen, Jyh-Cherng Yu, Ern Yu Tan, Patrick Mun Yew Chan, Kenneth Muir, Artitaya Lophatananon, Anna H Wu, Daniel O Stram, Keitaro Matsuo, Hidemi Ito, Ching Wan Chan, Joanne Ngeow, Wei Sean Yong, Swee Ho Lim, Geok Hoon Lim, Ava Kwong, Tsun L Chan, Su Ming Tan, Jaime Seah, Esther M John, Allison W Kurian, Woon-Puay Koh, Chiea Chuen Khor, Motoki Iwasaki, Taiki Yamaji, Kiak Mien Veronique Tan, Kiat Tee Benita Tan, John J Spinelli, Kristan J Aronson, Siti Norhidayu Hasan, Kartini Rahmat, Anushya Vijayananthan, Xueling Sim, Paul D P Pharoah, Wei Zheng, Alison M Dunning, Jacques Simard, Rob Martinus van Dam, Cheng-Har Yip, Nur Aishah Mohd Taib, Mikael Hartman, Douglas F Easton, Soo-Hwang Teo, Antonis C Antoniou, Weang-Kee Ho, Min-Min Tan, Nasim Mavaddat, Mei-Chee Tai, Shivaani Mariapun, Jingmei Li, Peh-Joo Ho, Joe Dennis, Jonathan P Tyrer, Manjeet K Bolla, Kyriaki Michailidou, Qin Wang, Daehee Kang, Ji-Yeob Choi, Suniza Jamaris, Xiao-Ou Shu, Sook-Yee Yoon, Sue K Park, Sung-Won Kim, Chen-Yang Shen, Jyh-Cherng Yu, Ern Yu Tan, Patrick Mun Yew Chan, Kenneth Muir, Artitaya Lophatananon, Anna H Wu, Daniel O Stram, Keitaro Matsuo, Hidemi Ito, Ching Wan Chan, Joanne Ngeow, Wei Sean Yong, Swee Ho Lim, Geok Hoon Lim, Ava Kwong, Tsun L Chan, Su Ming Tan, Jaime Seah, Esther M John, Allison W Kurian, Woon-Puay Koh, Chiea Chuen Khor, Motoki Iwasaki, Taiki Yamaji, Kiak Mien Veronique Tan, Kiat Tee Benita Tan, John J Spinelli, Kristan J Aronson, Siti Norhidayu Hasan, Kartini Rahmat, Anushya Vijayananthan, Xueling Sim, Paul D P Pharoah, Wei Zheng, Alison M Dunning, Jacques Simard, Rob Martinus van Dam, Cheng-Har Yip, Nur Aishah Mohd Taib, Mikael Hartman, Douglas F Easton, Soo-Hwang Teo, Antonis C Antoniou

Abstract

Polygenic risk scores (PRS) have been shown to predict breast cancer risk in European women, but their utility in Asian women is unclear. Here we evaluate the best performing PRSs for European-ancestry women using data from 17,262 breast cancer cases and 17,695 controls of Asian ancestry from 13 case-control studies, and 10,255 Chinese women from a prospective cohort (413 incident breast cancers). Compared to women in the middle quintile of the risk distribution, women in the highest 1% of PRS distribution have a ~2.7-fold risk and women in the lowest 1% of PRS distribution has ~0.4-fold risk of developing breast cancer. There is no evidence of heterogeneity in PRS performance in Chinese, Malay and Indian women. A PRS developed for European-ancestry women is also predictive of breast cancer risk in Asian women and can help in developing risk-stratified screening programmes in Asia.

Conflict of interest statement

The authors declare no competing interests.

Figures

Fig. 1. Association between standardised 287-SNP polygenic…
Fig. 1. Association between standardised 287-SNP polygenic risk scores and breast cancer risk.
Panel a shows the results for iCogs array by study and panel b shows the results for Oncoarray. The squares represent the odds ratios (ORs) and the horizontal lines represent the corresponding 95% confidence intervals. Overall estimates within genotyping array were obtained by combining the estimates across studies using fixed-effect meta-analysis, represented by the diamond shape. I-squared and p value (two-sided) for heterogeneity were obtained by fitting a random-effects model and using generalised Q-statistic estimator (the rma() command in R). The sample size of individual studies are listed in Supplementary Table 1. The ORs and corresponding 95% confidence intervals are provided as a Source Data file.
Fig. 2. Association between percentiles of 287-SNP…
Fig. 2. Association between percentiles of 287-SNP polygenic risk scores (PRS) and breast cancer risk in combined Asian studies.
The results for overall breast cancer, oestrogen-receptor (ER)-positive breast cancer and ER-negative breast cancer are shown in Fig. 2a–c, respectively. The squares/dots represent the odds ratios (ORs) and the vertical lines represent the corresponding 95% confidence intervals, with middle quintile (40–60th) as the reference category. Solid lines represent the observed ORs, black dashed lines represent the predicted ORs of PRSs under a multiplicative polygenic model in the Asian population and the red dashed line represent the predicted OR in the European population. The analysis was conducted using 15,755 cases and 16,438 controls. Of 15,755 cases, 9989 were ER-positive breast cancer while 4611 were ER-negative breast cancer. Source data are provided in Supplementary Table 5.
Fig. 3. Association between standardised PRSs and…
Fig. 3. Association between standardised PRSs and breast cancer risk in Chinese, Malay and Indian women from Malaysia and Singapore.
Odds ratios (ORs) and AUCs were generated using data from Malaysia Breast Cancer Genetics (MyBrCa) and Singapore Breast Cancer Cohort (SGBCC) studies, stratified by ethnicity. The squares represent the odds ratios (ORs), the horizontal lines represent the corresponding 95% confidence intervals and the diamond shapes represent the overall estimates. I-squared and p value (two-sided) for heterogeneity were obtained by fitting a random-effects model and using generalised Q-statistic estimator (the rma() command in R). The number of cases and controls for each ethnicity by breast cancer subtypes are tabulated in Table 4. The sample size, ORs and corresponding 95% confidence intervals are also provided in the Source Data file.
Fig. 4. Association between percentiles of 287-SNP…
Fig. 4. Association between percentiles of 287-SNP polygenic risk scores and overall breast cancer risk in Chinese, Malay and Indian women from Malaysia and Singapore.
Results were generated using 5236/5516 Chinese cases/controls, 1084/1332 Malay cases/controls and 580/1018 Indian cases/controls from Malaysia Breast Cancer Genetics (MyBrCa) and Singapore Breast Cancer Cohort (SGBCC) studies, stratified by ethnicity. The squares represent the odds ratios (ORs) and the vertical lines represent the corresponding 95% confidence intervals, with middle quintile (40–60th) as the reference category. Solid lines represent the observed ORs and dashed lines represent the predicted ORs of PRS under a multiplicative polygenic model. Source data are provided in Supplementary Table 6.

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