African-specific molecular taxonomy of prostate cancer

Weerachai Jaratlerdsiri ^1,2, Jue Jiang ^1,2, Tingting Gong ^1,2,3

¹Ancestry and Health Genomics Laboratory, Charles Perkins Centre, School of Medical Sciences, Faculty of Medicine and Health, University of Sydney, Camperdown, New South Wales, Australia.
²Genomics and Epigenetic Theme, Garvan Institute of Medical Research, Darlinghurst, New South Wales, Australia.
³Human Phenome Institute, Fudan University, Shanghai, China.
⁴School of Health Systems & Public Health, University of Pretoria, Pretoria, South Africa.
⁵Sydney Informatics Hub, University of Sydney, Darlington, New South Wales, Australia.
⁶Endocrine and Tumor Molecular Biology Laboratory (LABIMET), Instituto de Ciências Básicas da Saúde, Universidade Federal do Rio Grande do Sul, Porto Alegre, Brazil.
⁷Laboratory of Genetics, Instituto de Ciências Biológicas, Universidade Federal do Rio Grande, Rio Grande, Brazil.
⁸National Health Laboratory Services, Johannesburg, South Africa.
⁹Department of Tissue Pathology and Diagnostic Oncology, Royal Prince Alfred Hospital and Central Clinical School, University of Sydney, Sydney, New South Wales, Australia.
¹⁰Kalafong Academic Hospital, Pretoria, South Africa.
¹¹Medical Oncology, Chris O'Brien Lifehouse, Royal Prince Alfred Hospital and Faculty of Medicine and Health, University of Sydney, Camperdown, New South Wales, Australia.
¹²NSW Health Pathology, Sydney, New South Wales, Australia.
¹³Division of Cancer Sciences, University of Manchester, Manchester, UK.
¹⁴Department of Urology, Sefako Makgatho Health Science University, Dr George Mukhari Academic Hospital, Medunsa, South Africa.
¹⁵Department of Urology, St Vincent's Hospital, Darlinghurst, New South Wales, Australia.
¹⁶Ancestry and Health Genomics Laboratory, Charles Perkins Centre, School of Medical Sciences, Faculty of Medicine and Health, University of Sydney, Camperdown, New South Wales, Australia. vanessa.hayes@sydney.edu.au.
¹⁷Genomics and Epigenetic Theme, Garvan Institute of Medical Research, Darlinghurst, New South Wales, Australia. vanessa.hayes@sydney.edu.au.
¹⁸School of Health Systems & Public Health, University of Pretoria, Pretoria, South Africa. vanessa.hayes@sydney.edu.au.
¹⁹Faculty of Health Sciences, University of Limpopo, Mankweng, South Africa. vanessa.hayes@sydney.edu.au.

⁰Ancestry and Health Genomics Laboratory, Charles Perkins Centre, School of Medical Sciences, Faculty of Medicine and Health, University of Sydney, Camperdown, New South Wales, Australia.

Nature +

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August 31, 2022

View abstract on PubMed

Summary

Prostate cancer shows significant geo-ethnic disparities, particularly in African populations. This study identifies ancestry-specific genomic alterations and mutational processes, revealing global mutational subtypes that impact clinical outcomes and highlight gene-environment interactions.

Area Of Science

Genomics
Cancer Research
Population Genetics

Background

Prostate cancer exhibits significant geo-ethnic disparities, with higher mortality rates in sub-Saharan Africa.
Genetic and non-genetic factors contributing to these disparities, along with associated mutational processes, remain largely unknown.
African ancestry is a recognized risk factor for prostate cancer.

Purpose Of The Study

To generate a comprehensive cancer genomics resource for sub-Saharan Africa.
To identify ancestry-specific genetic alterations and mutational signatures in prostate cancer.
To establish a molecular taxonomy of prostate cancer based on ancestry and mutational processes.

Main Methods

Whole-genome sequencing of 183 treatment-naive prostate cancer samples from patients of African and European ancestry.
Identification and analysis of approximately 2 million somatic variants.
Inclusion of Chinese Asian data to define and validate global mutational subtypes (GMS).

Main Results

Discovery of significant African-ancestry-specific findings, including elevated tumor mutational burden, increased genome alteration, and specific driver genes (NCOA2, STK19, DDX11L1, PCAT1, SETBP1).
Development of a molecular taxonomy for prostate cancer defined by global mutational subtypes (GMS) differentiated by ancestry.
Identification of GMS-B and GMS-D as specific to African populations, GMS-A as universal, and GMS-C (copy-number losses) as African-European restricted and predictive of poor outcomes.

Conclusions

Global mutational subtypes reveal distinct evolutionary trajectories and mutational processes in prostate cancer.
Both common genetic and environmental factors likely contribute to observed ethnic disparities in prostate cancer.
The findings underscore the importance of including diverse ancestries in cancer genomics studies and suggest GMS subtypes can serve as a proxy for intrinsic and extrinsic mutational processes.

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