Using genome and transcriptome data from African-ancestry female participants to identify putative breast cancer susceptibility genes

Jie Ping¹, Guochong Jia¹, Qiuyin Cai¹, Xingyi Guo¹, Ran Tao^{2

3}, Christine Ambrosone⁴, Dezheng Huo⁵, Stefan Ambs⁶, Mollie E Barnard⁷, Yu Chen⁸, Montserrat Garcia-Closas⁹, Jian Gu¹⁰, Jennifer J Hu¹¹, Esther M John¹², Christopher I Li¹³, Katherine Nathanson^{14

15}, Barbara Nemesure¹⁶, Olufunmilayo I Olopade¹⁷, Tuya Pal¹⁸, Michael F Press¹⁹, Maureen Sanderson²⁰, Dale P Sandler²¹, Toshio Yoshimatsu⁵, Prisca O Adejumo²², Thomas Ahearn⁹, Abenaa M Brewster²³, Anselm J M Hennis^{24

25}, Timothy Makumbi²⁶, Paul Ndom²⁷, Katie M O'Brien²¹, Andrew F Olshan²⁸, Mojisola M Oluwasanu²⁹, Sonya Reid³⁰, Song Yao⁴, Ebonee N Butler²⁸, Maosheng Huang¹⁰, Atara Ntekim³¹, Bingshan Li³², Melissa A Troester²⁸, Julie R Palmer⁷, Christopher A Haiman³³, Jirong Long¹, Wei Zheng³⁴

Affiliations

¹ Division of Epidemiology, Department of Medicine, Vanderbilt Epidemiology Center, Vanderbilt-Ingram Cancer Center, Vanderbilt University Medical Center, Nashville, TN, USA.
² Department of Biostatistics, Vanderbilt University Medical Center, Nashville, TN, USA.
³ Vanderbilt Genetics Institute, Vanderbilt University Medical Center, Nashville, TN, USA.
⁴ Department of Cancer Prevention and Control, Roswell Park Comprehensive Cancer Center, Elm & Carlton Streets, Buffalo, NY, USA.
⁵ Department of Public Health Sciences, The University of Chicago, Chicago, IL, USA.
⁶ Laboratory of Human Carcinogenesis, Center of Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA.
⁷ Slone Epidemiology Center, Boston University, Boston, MA, USA.
⁸ Division of Epidemiology, Department of Population Health, NYU Grossman School of Medicine, New York, NY, USA.
⁹ Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, MD, USA.
¹⁰ Department of Epidemiology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
¹¹ Department of Public Health Sciences, University of Miami School of Medicine, Miami, FL, USA.
¹² Departments of Epidemiology & Population Health and of Medicine, Stanford University School of Medicine, Stanford, CA, USA.
¹³ Division of Public Health Sciences, Fred Hutchinson Cancer Center, Seattle, WA, USA.
¹⁴ Division of Hematology/Oncology, Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
¹⁵ Basser Center for BRCA, Abramson Cancer Center, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
¹⁶ Department of Family, Population and Preventive Medicine, Renaissance School of Medicine, Stony Brook University, Stony Brook, NY, USA.
¹⁷ Center for Clinical Cancer Genetics and Global Health, Department of Medicine, The University of Chicago, Chicago, IL, USA.
¹⁸ Division of Genetic Medicine, Department of Medicine, Vanderbilt-Ingram Cancer Center, Vanderbilt University Medical Center, Nashville, TN, USA.
¹⁹ Department of Pathology, Norris Comprehensive Cancer Center, University of Southern California, Los Angeles, CA, USA.
²⁰ Department of Family and Community Medicine, Meharry Medical College, Nashville, TN, USA.
²¹ Epidemiology Branch, National Institute of Environmental Health Sciences, National Institutes of Health, Research Triangle Park, NC, USA.
²² Department of Nursing, College of Medicine, University of Ibadan, Ibadan, Nigeria.
²³ Department of Clinical Cancer Prevention, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
²⁴ George Alleyne Chronic Disease Research Centre, University of the West Indies, Bridgetown, Barbados.
²⁵ Department of Family, Population and Preventive Medicine, Stony Brook University, Stony Brook, NY, USA.
²⁶ Department of Surgery, Mulago Hospital, Kampala, Uganda.
²⁷ Yaounde General Hospital, Yaounde, Cameroon.
²⁸ Department of Epidemiology and Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
²⁹ Department of Health Promotion and Education, College of Medicine, University of Ibadan, Ibadan, Nigeria.
³⁰ Division of Hematology and Oncology, Department of Medicine, Vanderbilt-Ingram Cancer Center, Vanderbilt University Medical Center, Nashville, TN, USA.
³¹ Department of Radiation Oncology, College of Medicine, University of Ibadan, Ibadan, Nigeria.
³² Department of Molecular Physiology & Biophysics, Vanderbilt Genetics Institute, Vanderbilt University, Nashville, TN, USA.
³³ Department of Preventive Medicine, Keck School of Medicine of USC, Los Angeles, CA, USA.
³⁴ Division of Epidemiology, Department of Medicine, Vanderbilt Epidemiology Center, Vanderbilt-Ingram Cancer Center, Vanderbilt University Medical Center, Nashville, TN, USA. wei.zheng@vanderbilt.edu.

PMID: 38697998
PMCID: PMC11065893
DOI: 10.1038/s41467-024-47650-5

Using genome and transcriptome data from African-ancestry female participants to identify putative breast cancer susceptibility genes

Jie Ping et al. Nat Commun. 2024.

. 2024 May 2;15(1):3718.

doi: 10.1038/s41467-024-47650-5.

Authors

Affiliations

¹ Division of Epidemiology, Department of Medicine, Vanderbilt Epidemiology Center, Vanderbilt-Ingram Cancer Center, Vanderbilt University Medical Center, Nashville, TN, USA.
² Department of Biostatistics, Vanderbilt University Medical Center, Nashville, TN, USA.
³ Vanderbilt Genetics Institute, Vanderbilt University Medical Center, Nashville, TN, USA.
⁴ Department of Cancer Prevention and Control, Roswell Park Comprehensive Cancer Center, Elm & Carlton Streets, Buffalo, NY, USA.
⁵ Department of Public Health Sciences, The University of Chicago, Chicago, IL, USA.
⁶ Laboratory of Human Carcinogenesis, Center of Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA.
⁷ Slone Epidemiology Center, Boston University, Boston, MA, USA.
⁸ Division of Epidemiology, Department of Population Health, NYU Grossman School of Medicine, New York, NY, USA.
⁹ Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, MD, USA.
¹⁰ Department of Epidemiology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
¹¹ Department of Public Health Sciences, University of Miami School of Medicine, Miami, FL, USA.
¹² Departments of Epidemiology & Population Health and of Medicine, Stanford University School of Medicine, Stanford, CA, USA.
¹³ Division of Public Health Sciences, Fred Hutchinson Cancer Center, Seattle, WA, USA.
¹⁴ Division of Hematology/Oncology, Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
¹⁵ Basser Center for BRCA, Abramson Cancer Center, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
¹⁶ Department of Family, Population and Preventive Medicine, Renaissance School of Medicine, Stony Brook University, Stony Brook, NY, USA.
¹⁷ Center for Clinical Cancer Genetics and Global Health, Department of Medicine, The University of Chicago, Chicago, IL, USA.
¹⁸ Division of Genetic Medicine, Department of Medicine, Vanderbilt-Ingram Cancer Center, Vanderbilt University Medical Center, Nashville, TN, USA.
¹⁹ Department of Pathology, Norris Comprehensive Cancer Center, University of Southern California, Los Angeles, CA, USA.
²⁰ Department of Family and Community Medicine, Meharry Medical College, Nashville, TN, USA.
²¹ Epidemiology Branch, National Institute of Environmental Health Sciences, National Institutes of Health, Research Triangle Park, NC, USA.
²² Department of Nursing, College of Medicine, University of Ibadan, Ibadan, Nigeria.
²³ Department of Clinical Cancer Prevention, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
²⁴ George Alleyne Chronic Disease Research Centre, University of the West Indies, Bridgetown, Barbados.
²⁵ Department of Family, Population and Preventive Medicine, Stony Brook University, Stony Brook, NY, USA.
²⁶ Department of Surgery, Mulago Hospital, Kampala, Uganda.
²⁷ Yaounde General Hospital, Yaounde, Cameroon.
²⁸ Department of Epidemiology and Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
²⁹ Department of Health Promotion and Education, College of Medicine, University of Ibadan, Ibadan, Nigeria.
³⁰ Division of Hematology and Oncology, Department of Medicine, Vanderbilt-Ingram Cancer Center, Vanderbilt University Medical Center, Nashville, TN, USA.
³¹ Department of Radiation Oncology, College of Medicine, University of Ibadan, Ibadan, Nigeria.
³² Department of Molecular Physiology & Biophysics, Vanderbilt Genetics Institute, Vanderbilt University, Nashville, TN, USA.
³³ Department of Preventive Medicine, Keck School of Medicine of USC, Los Angeles, CA, USA.
³⁴ Division of Epidemiology, Department of Medicine, Vanderbilt Epidemiology Center, Vanderbilt-Ingram Cancer Center, Vanderbilt University Medical Center, Nashville, TN, USA. wei.zheng@vanderbilt.edu.

PMID: 38697998
PMCID: PMC11065893
DOI: 10.1038/s41467-024-47650-5

Abstract

African-ancestry (AA) participants are underrepresented in genetics research. Here, we conducted a transcriptome-wide association study (TWAS) in AA female participants to identify putative breast cancer susceptibility genes. We built genetic models to predict levels of gene expression, exon junction, and 3' UTR alternative polyadenylation using genomic and transcriptomic data generated in normal breast tissues from 150 AA participants and then used these models to perform association analyses using genomic data from 18,034 cases and 22,104 controls. At Bonferroni-corrected P < 0.05, we identified six genes associated with breast cancer risk, including four genes not previously reported (CTD-3080P12.3, EN1, LINC01956 and NUP210L). Most of these genes showed a stronger association with risk of estrogen-receptor (ER) negative or triple-negative than ER-positive breast cancer. We also replicated the associations with 29 genes reported in previous TWAS at P < 0.05 (one-sided), providing further support for an association of these genes with breast cancer risk. Our study sheds new light on the genetic basis of breast cancer and highlights the value of conducting research in AA populations.

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Conflict of interest statement

Olufunmilayo I. Olopade is a co-founder at CancerIQ, serves as a Scientific Advisor at Tempus and is on the Board of 54gene. Atara Ntekim received research support from Roche. The authors declare no competing interests.

References

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Using genome and transcriptome data from African-ancestry female participants to identify putative breast cancer susceptibility genes

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Using genome and transcriptome data from African-ancestry female participants to identify putative breast cancer susceptibility genes

Authors

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Abstract

Conflict of interest statement

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