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Genetics put African men most at risk of prostate cancer

Breakthrough research, and the largest study of its kind, has identified the genetic risk factors contributing to increased prostate cancer in African men.

The study, which recruited 7 500 men from eastern, southern and west Africa, is especially important because African men have a high risk of prostate cancer, writes medical scientist Wenlong Carl Chen in The Conversation, as he explains why the findings are significant and the promise they hold for future treatment.

Prostate cancer disproportionately affects men of African descent. Studies from the US and African countries report a higher occurrence of prostate cancer in men of African ancestry than in men of other ancestries.

Men of African and African Caribbean ancestry were also found to be at higher risk of developing a more aggressive form of prostate cancer and of developing it at a younger age than men of European ancestry. Prostate cancer also accounts for nearly one-quarter of all cancer cases diagnosed in Africa.

Our study aimed to uncover aspects of genetic architecture of prostate cancer that were specific to men of African descent. In other words, we wanted to understand what it is about African men’s genetic makeup that puts them at higher risk for prostate cancer.

Evidence emerging in the literature suggests that genetic risk factors significantly contribute to the development of prostate cancer.

Genetic risks can be put into two groups:

Hereditary risk factors or germline mutations: There are rare genetic mutations in genes, such as BRCA1 and BRCA2, that have been linked to increased risks for developing cancers. Mutations in BRCA2, particularly, are linked to higher risks of developing more aggressive prostate cancer.

Single nucleotide polymorphisms or variants: These are common genetic variants linked to increased disease risk. Each variant by itself confers a very small increase in risk. But several variants combined may raise the risk profiles for a disease.

In this study, we assessed the risk contributed by inherited genetic variants to prostate cancer.

Despite the high burden of disease, genetic studies of prostate cancer in continental African populations are limited. The technology needed for these studies is typically very expensive and requires specialised instruments, which are scarce in Africa.

Unique aspects

To better understand the genetic causes of disease, we needed to study diverse populations, particularly African populations, which have much higher genetic diversity than other populations. As the place of origin of Homo sapiens, the African population is much older than others, and has therefore had more time to accumulate genetic variations.

Ours is the largest study to date to investigate the ancestry-specific genetic architectures and disease associations for prostate cancer across multiple regions in sub-Saharan Africa.

Numerous studies like this have been conducted worldwide. But participation from Africa, both in terms of researchers and study participants, is very low.

How we did it

Our consortium, the Men of African Descent, Carcinoma of the Prostate (MADCaP), was formed in 2016. Hospitals and universities in five African countries – Nigeria, Ghana, Senegal, Uganda and South Africa – partnered with several US-based universities to form the consortium. The US National Institute of Health provided funding.

The African centres enrolled men with newly diagnosed prostate cancer and, as controls, men of the same population groups who did not have cancer.

Demographic, social, economic, and clinical information and bio-samples were collected from the participants.

Our study consisted of 3 963 prostate cancer cases and 3 509 controls. Most bio-sample processing and genotyping was performed in Africa, using a custom genotyping array. A “genotyping array” provides information on hundreds of thousands of DNA variants.

This specific one was designed and optimised to capture African genetic variations.

What we found

We identified three loci (genetic regions) with a strong association with increased prostate cancer incidence. The lead signals within these loci were common in African populations but were almost absent in non-African populations.

Although these three loci were previously found in other populations, our signals within these loci are unique to African populations. They would not have been found if we had not studied African populations.

There are also differences within Africa. The genetic parts that contribute to prostate cancer risk differ by geographical population.

Why the research matters

It is crucial to study diseases in populations with the highest disease burden.

Our findings highlight the importance of studying the possible causes of disease in diverse populations. We found novel associations by studying the genetics of prostate cancer across Africa. These signals would not have been found in studies done outside the continent.

The genetic diversity of African populations further allowed us to fine-map the regions of associations to better understand what’s driving the signals.

Our findings pave the way for the development of genetic tools that could grade people by their degree of risk.

Another example of this was a 2019 study published in the American Journal of Human Genetics which used genetics to predict the risk of breast cancer. Women placed in higher risk groups would become eligible to enter the UK breast cancer screening programme at a much earlier age.

The results from our study will lay the foundation for the development and implementation of similar tools in an African setting.

Wenlong Carl Chen – Researcher, University of the Witwatersrand

Study details

Heterogeneous genetic architectures of prostate cancer susceptibility in sub-Saharan Africa

Rohini Janivara, Wenlong C. Chen, Ujani Hazra et al.

Published in Nature Genetics on 2 October 2024

Abstract

Men of African descent have the highest prostate cancer incidence and mortality rates, yet the genetic basis of prostate cancer in African men has been understudied. We used genomic data from 3 963 cases and 3 509 controls from Ghana, Nigeria, Senegal, South Africa and Uganda to infer ancestry-specific genetic architectures and fine-map disease associations. Fifteen independent associations at 8q24.21, 6q22.1 and 11q13.3 reached genome-wide significance, including four new associations. Intriguingly, multiple lead associations are private alleles, a pattern arising from recent mutations and the out-of-Africa bottleneck. These African-specific alleles contribute to haplotypes with odds ratios above 2.4. We found that the genetic architecture of prostate cancer differs across Africa, with effect size differences contributing more to this heterogeneity than allele frequency differences. Population genetic analyses reveal that African prostate cancer associations are largely governed by neutral evolution. Collectively, our findings emphasise the utility of conducting genetic studies that use diverse populations.

 

Nature Genetics article – Heterogeneous genetic architectures of prostate cancer susceptibility in sub-Saharan Africa (Open access)

 

PubMed article – Polygenic Risk Scores for Prediction of Breast Cancer and Breast Cancer Subtypes (Open access)

 

The Conversation article – African men most at risk of prostate cancer – new study flags genetic causes (Creative Commons Licence)

 

See more from MedicalBrief archives:

 

Prostate cancer risk higher for black men – US study

 

Unequal burden of prostate cancer for Africa

 

Experts call for comprehensive, large-scale response to slash Africa’s cancer burden

 

Cancer deaths doubling, could soar to 1m in sub-Saharan Africa by 2030

 

 

 

 

 

 

 

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