Integrating multi-ancestry genomic and proteomic data to identify blood risk biomarkers and target proteins for breast cancer genetic risk loci

Guochong Jia¹, Jie Ping¹, Ran Tao², Jirong Long¹, Lili Liu¹, Shuai Xu¹, Heather M Munro³, Stefan Ambs⁴, Mollie E Barnard⁵, Yu Chen⁶, Ji-Yeob Choi^{7

8}, Yu-Tang Gao⁹, Montserrat Garcia-Closas¹⁰, Jian Gu¹¹, Jennifer J Hu¹², Motoki Iwasaki¹³, Esther M John¹⁴, Sun-Seog Kweon^{15

16}, Koichi Matsuda¹⁷, Keitaro Matsuo^{18

19}, Katherine Nathanson^{20

21}, Barbara Nemesure²², Olufunmilayo I Olopade²³, Tuya Pal²⁴, Sue K Park^{8

25

26}, Boyoung Park²⁷, Michael F Press²⁸, Maureen Sanderson²⁹, Dale P Sandler³⁰, Song Yao³¹, Ying Zheng³², Prisca O Adejumo³³, Thomas Ahearn¹⁰, Abenaa M Brewster³⁴, Anselm J M Hennis^{22

35}, Hidemi Ito^{36

37}, Michiaki Kubo³⁸, Eun-Sook Lee^{39

40}, Siew-Kee Low³⁸, Timothy Makumbi⁴¹, Paul Ndom⁴², Dong-Young Noh^{43

44}, Katie M O'Brien³⁰, Andrew F Olshan⁴⁵, Mojisola M Oluwasanu⁴⁶, Min-Ho Park⁴⁷, Sonya Reid⁴⁸, Taiki Yamaji¹³, Gary Zirpoli⁵, Ebonee N Butler⁴⁵, Maosheng Huang¹¹, Atara Ntekim⁴⁹, Clarice R Weinberg⁵⁰, Bingshan Li⁵¹, Dezheng Huo⁵², Daehee Kang^{7

8}, Christine Ambrosone³¹, Melissa A Troester⁴⁵, Christopher A Haiman⁵³, Xiao-Ou Shu¹, Julie R Palmer⁵, Xingyi Guo¹, Wei Zheng¹

Affiliations

¹ Division of Epidemiology, Department of Medicine, Vanderbilt Epidemiology Center, Vanderbilt-Ingram Cancer Center, Vanderbilt University Medical Center, Nashville, Tennessee, USA.
² Department of Biostatistics, Vanderbilt University Medical Center, Nashville, Tennessee, USA.
³ International Epidemiology Field Station, Vanderbilt University Medical Center, Nashville, Tennessee, USA.
⁴ Laboratory of Human Carcinogenesis, Center of Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USA.
⁵ Slone Epidemiology Center, Boston University, Boston, Massachusetts, USA.
⁶ Division of Epidemiology, Department of Population Health, NYU Grossman School of Medicine, New York, New York, USA.
⁷ Department of Biomedical Sciences, Seoul National University Graduate School, Seoul, South Korea.
⁸ Department of Preventive Medicine, Seoul National University College of Medicine, Seoul, South Korea.
⁹ State Key Laboratory of Oncogene and Related Genes & Department of Epidemiology, Shanghai Cancer Institute, Renji Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China.
¹⁰ Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, Maryland, USA.
¹¹ Department of Epidemiology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA.
¹² Department of Public Health Sciences, University of Miami School of Medicine, Miami, Florida, USA.
¹³ Division of Epidemiology, National Cancer Center Institute for Cancer Control, Tokyo, Japan.
¹⁴ Departments of Epidemiology & Population Health and of Medicine, Stanford University School of Medicine, Stanford, California, USA.
¹⁵ Department of Preventive Medicine, Chonnam National University Medical School, Hwasun, South Korea.
¹⁶ Jeonnam Regional Cancer Center, Chonnam National University Hwasun Hospital, Hwasun, South Korea.
¹⁷ Laboratory of Clinical Genome Sequencing, Graduate School of Frontier Sciences, The University of Tokyo, Tokyo, Japan.
¹⁸ Division of Cancer Epidemiology and Prevention, Aichi Cancer Center Research Institute, Nagoya, Japan.
¹⁹ Division of Cancer Epidemiology, Nagoya University Graduate School of Medicine, Nagoya, Japan.
²⁰ Division of Hematology/Oncology, Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA.
²¹ Basser Center for BRCA, Abramson Cancer Center, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA.
²² Department of Family, Population and Preventive Medicine, Renaissance School of Medicine, Stony Brook University, Stony Brook, New York, USA.
²³ Center for Clinical Cancer Genetics and Global Health, Department of Medicine, The University of Chicago, Chicago, Illinois, USA.
²⁴ Division of Genetic Medicine, Department of Medicine, Vanderbilt-Ingram Cancer Center, Vanderbilt University Medical Center, Nashville, Tennessee, USA.
²⁵ Integrated Major in Innovative Medical Science, Seoul National University College of Medicine, Seoul, South Korea.
²⁶ Cancer Research Institute, Seoul National University, Seoul, South Korea.
²⁷ Department of Preventive Medicine, Hanyang University College of Medicine, Seoul, South Korea.
²⁸ Department of Pathology, Norris Comprehensive Cancer Center, University of Southern California, Los Angeles, California, USA.
²⁹ Department of Family and Community Medicine, Meharry Medical College, Nashville, Tennessee, USA.
³⁰ Epidemiology Branch, National Institute of Environmental Health Sciences, National Institutes of Health, Research Triangle Park, North Carolina, USA.
³¹ Department of Cancer Prevention and Control, Roswell Park Comprehensive Cancer Center, Buffalo, New York, USA.
³² Shanghai Municipal Center for Disease Control and Prevention, Shanghai, China.
³³ Department of Nursing, College of Medicine, University of Ibadan, Nigeria.
³⁴ Department of Clinical Cancer Prevention, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA.
³⁵ George Alleyne Chronic Disease Research Centre, University of the West Indies, Bridgetown, Barbados.
³⁶ Division of Cancer Information and Control, Aichi Cancer Center Research Institute, Nagoya, Japan.
³⁷ Department of Descriptive Cancer Epidemiology, Nagoya University Graduate School of Medicine, Nagoya, Japan.
³⁸ RIKEN Center for Integrative Medical Sciences, Yokohama, Japan.
³⁹ National Cancer Center Graduate School of Cancer Science and Policy, Goyang, South Korea.
⁴⁰ Hospital, National Cancer Center, Goyang, South Korea.
⁴¹ Department of Surgery, Mulago Hospital, Kampala, Uganda.
⁴² Yaounde General Hospital, Yaounde, Cameroon.
⁴³ College of Medicine, Cancer Research Institute, Seoul National University, Seoul, South Korea.
⁴⁴ Department of Surgery, Seoul National University Hospital, Seoul, South Korea.
⁴⁵ Department of Epidemiology and Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA.
⁴⁶ Department of Health Promotion and Education, College of Medicine, University of Ibadan, Nigeria.
⁴⁷ Department of Surgery, Chonnam National University Medical School, South Korea.
⁴⁸ Division of Hematology and Oncology, Department of Medicine, Vanderbilt-Ingram Cancer Center, Vanderbilt University Medical Center, Nashville, Tennessee, USA.
⁴⁹ Department of Radiation Oncology, College of Medicine, University of Ibadan, Nigeria.
⁵⁰ Biostatistics and Computational Biology Branch, National Institutes of Environmental Health Sciences, Research Triangle Park, North Carolina, USA.
⁵¹ Department of Molecular Physiology & Biophysics, Vanderbilt Genetics Institute, Vanderbilt University, Nashville, Tennessee, USA.
⁵² Department of Public Health Sciences, The University of Chicago, Chicago, Illinois, USA.
⁵³ Department of Preventive Medicine, Keck School of Medicine of USC, Los Angeles, California, USA.

PMID: 40658085
PMCID: PMC12406259
DOI: 10.1002/ijc.70041

Integrating multi-ancestry genomic and proteomic data to identify blood risk biomarkers and target proteins for breast cancer genetic risk loci

Guochong Jia et al. Int J Cancer. 2025.

. 2025 Nov 15;157(10):2071-2080.

doi: 10.1002/ijc.70041. Epub 2025 Jul 14.

Authors

Affiliations

¹ Division of Epidemiology, Department of Medicine, Vanderbilt Epidemiology Center, Vanderbilt-Ingram Cancer Center, Vanderbilt University Medical Center, Nashville, Tennessee, USA.
² Department of Biostatistics, Vanderbilt University Medical Center, Nashville, Tennessee, USA.
³ International Epidemiology Field Station, Vanderbilt University Medical Center, Nashville, Tennessee, USA.
⁴ Laboratory of Human Carcinogenesis, Center of Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USA.
⁵ Slone Epidemiology Center, Boston University, Boston, Massachusetts, USA.
⁶ Division of Epidemiology, Department of Population Health, NYU Grossman School of Medicine, New York, New York, USA.
⁷ Department of Biomedical Sciences, Seoul National University Graduate School, Seoul, South Korea.
⁸ Department of Preventive Medicine, Seoul National University College of Medicine, Seoul, South Korea.
⁹ State Key Laboratory of Oncogene and Related Genes & Department of Epidemiology, Shanghai Cancer Institute, Renji Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China.
¹⁰ Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, Maryland, USA.
¹¹ Department of Epidemiology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA.
¹² Department of Public Health Sciences, University of Miami School of Medicine, Miami, Florida, USA.
¹³ Division of Epidemiology, National Cancer Center Institute for Cancer Control, Tokyo, Japan.
¹⁴ Departments of Epidemiology & Population Health and of Medicine, Stanford University School of Medicine, Stanford, California, USA.
¹⁵ Department of Preventive Medicine, Chonnam National University Medical School, Hwasun, South Korea.
¹⁶ Jeonnam Regional Cancer Center, Chonnam National University Hwasun Hospital, Hwasun, South Korea.
¹⁷ Laboratory of Clinical Genome Sequencing, Graduate School of Frontier Sciences, The University of Tokyo, Tokyo, Japan.
¹⁸ Division of Cancer Epidemiology and Prevention, Aichi Cancer Center Research Institute, Nagoya, Japan.
¹⁹ Division of Cancer Epidemiology, Nagoya University Graduate School of Medicine, Nagoya, Japan.
²⁰ Division of Hematology/Oncology, Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA.
²¹ Basser Center for BRCA, Abramson Cancer Center, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA.
²² Department of Family, Population and Preventive Medicine, Renaissance School of Medicine, Stony Brook University, Stony Brook, New York, USA.
²³ Center for Clinical Cancer Genetics and Global Health, Department of Medicine, The University of Chicago, Chicago, Illinois, USA.
²⁴ Division of Genetic Medicine, Department of Medicine, Vanderbilt-Ingram Cancer Center, Vanderbilt University Medical Center, Nashville, Tennessee, USA.
²⁵ Integrated Major in Innovative Medical Science, Seoul National University College of Medicine, Seoul, South Korea.
²⁶ Cancer Research Institute, Seoul National University, Seoul, South Korea.
²⁷ Department of Preventive Medicine, Hanyang University College of Medicine, Seoul, South Korea.
²⁸ Department of Pathology, Norris Comprehensive Cancer Center, University of Southern California, Los Angeles, California, USA.
²⁹ Department of Family and Community Medicine, Meharry Medical College, Nashville, Tennessee, USA.
³⁰ Epidemiology Branch, National Institute of Environmental Health Sciences, National Institutes of Health, Research Triangle Park, North Carolina, USA.
³¹ Department of Cancer Prevention and Control, Roswell Park Comprehensive Cancer Center, Buffalo, New York, USA.
³² Shanghai Municipal Center for Disease Control and Prevention, Shanghai, China.
³³ Department of Nursing, College of Medicine, University of Ibadan, Nigeria.
³⁴ Department of Clinical Cancer Prevention, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA.
³⁵ George Alleyne Chronic Disease Research Centre, University of the West Indies, Bridgetown, Barbados.
³⁶ Division of Cancer Information and Control, Aichi Cancer Center Research Institute, Nagoya, Japan.
³⁷ Department of Descriptive Cancer Epidemiology, Nagoya University Graduate School of Medicine, Nagoya, Japan.
³⁸ RIKEN Center for Integrative Medical Sciences, Yokohama, Japan.
³⁹ National Cancer Center Graduate School of Cancer Science and Policy, Goyang, South Korea.
⁴⁰ Hospital, National Cancer Center, Goyang, South Korea.
⁴¹ Department of Surgery, Mulago Hospital, Kampala, Uganda.
⁴² Yaounde General Hospital, Yaounde, Cameroon.
⁴³ College of Medicine, Cancer Research Institute, Seoul National University, Seoul, South Korea.
⁴⁴ Department of Surgery, Seoul National University Hospital, Seoul, South Korea.
⁴⁵ Department of Epidemiology and Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA.
⁴⁶ Department of Health Promotion and Education, College of Medicine, University of Ibadan, Nigeria.
⁴⁷ Department of Surgery, Chonnam National University Medical School, South Korea.
⁴⁸ Division of Hematology and Oncology, Department of Medicine, Vanderbilt-Ingram Cancer Center, Vanderbilt University Medical Center, Nashville, Tennessee, USA.
⁴⁹ Department of Radiation Oncology, College of Medicine, University of Ibadan, Nigeria.
⁵⁰ Biostatistics and Computational Biology Branch, National Institutes of Environmental Health Sciences, Research Triangle Park, North Carolina, USA.
⁵¹ Department of Molecular Physiology & Biophysics, Vanderbilt Genetics Institute, Vanderbilt University, Nashville, Tennessee, USA.
⁵² Department of Public Health Sciences, The University of Chicago, Chicago, Illinois, USA.
⁵³ Department of Preventive Medicine, Keck School of Medicine of USC, Los Angeles, California, USA.

PMID: 40658085
PMCID: PMC12406259
DOI: 10.1002/ijc.70041

Abstract

Genome-wide association studies (GWAS) have identified more than 200 risk loci for breast cancer. However, target genes and their encoded proteins in these loci remain largely unknown. In this study, we utilized genetic prediction models for 1349 circulating proteins derived from individuals of African (n = 1871) and European (n = 7213) ancestry to investigate genetically predicted protein levels in association with breast cancer risk among females of African (n = 40,138), Asian (n = 137,677), and European (n = 247,173) ancestry. We identified 51 blood protein biomarkers associated with breast cancer risk, overall or by subtypes, at a false discovery rate (FDR) < 0.05, including 27 proteins encoded by genes located at least 1 Mb away from any of the known risk loci identified in GWAS. Of them, 32 proteins showed significant associations with breast cancer risk at the Bonferroni-corrected significance level (p < 2.45 × 10^-4). Of the 24 proteins located at GWAS-identified risk loci, associations for 14 proteins were significantly attenuated after adjustment for the index risk variant of each respective locus, suggesting that these proteins may be target proteins for the risk loci. Encoding gene expression levels in normal breast tissue could be genetically predicted for 23 of the 51 identified proteins, and 13 encoding genes were associated with breast cancer risk in the same direction (p < .05). Our study identified potential protein targets of GWAS risk loci and biomarkers for breast cancer risk and provided additional insights into breast cancer genetics and etiology.

Keywords: biomarker; breast cancer; multi‐ancestry; plasma protein.

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Conflict of interest statement

Olufunmilayo I. Olopade (O.I.O) has potential personal conflict of interests involving affiliations or financial relationships with CancerIQ and TempusAI. Atara Ntekim (A.N) received research support from Roche. Other authors declare no competing interests related to this study. Michael F. Press (M.F.P) has potential personal conflict of interests involving affiliations or financial relationships with AstraZeneca, Inc., Eli Lilly & Company, Novartis Pharmaceuticals Corp., Zymeworks, Inc., and TORL Biotherapeutics.

Figures

**Figure 1.**
Study design overview for protein-coding gene expression prediction and association analysis in breast cancer

See this image and copyright information in PMC

References

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Integrating multi-ancestry genomic and proteomic data to identify blood risk biomarkers and target proteins for breast cancer genetic risk loci

Affiliations

Integrating multi-ancestry genomic and proteomic data to identify blood risk biomarkers and target proteins for breast cancer genetic risk loci

Authors

Affiliations

Abstract

Conflict of interest statement

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