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Pathogenic variants reveal candidate genes for prostate cancer germline testing for men of African ancestry

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2025

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Gheybi, Kazzem
Soh, Pamela X. Y.
Jiang, Jue
Mbeki, Tumisang M. N.
Louw, Melanie
Burns, Daniel
Mundra, Piyushkumar
Kiriy, Daria
Hasan, Md. Mehedi
Jaratlerdsiri, Weerachai
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http://nbn-resolving.de/urn:nbn:de:bsz:352-2-1dxlyve4hramu9
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https://doi.org/10.1038/s41467-025-63865-6
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CC BY 4.0

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Nature Communications. Springer. 2025, 16(1), 8799. eISSN 2041-1723. Verfügbar unter: doi: 10.1038/s41467-025-63865-6

Zusammenfassung

Prostate cancer (PCa) germline testing, while gaining momentum, is ancestry restrictive and African exclusive. Through whole genome sequencing for 217 African ancestral cases (186 southern African, 31 Pan representative), we identify 172 potentially pathogenic variants in 78 DNA damage repair or PCa related genes. Prevalence for reported (13/217, 5.99%) and cumulative predicted (24/217, 11.06%) variants of significance (11 genes) falls below that reported for non-Africans. Conversely, BRCA1 , HOXB13, CDK12, MLH1, MSH2 , and BRIP1 remain unimpacted. Through pathogenic ranking based on variant frequency and functionality, clinical presentation and tumour-matched biallelic inactivation, top-ranked candidates include PREX2, POLE, FAT1, BRCA2, POLQ, LRP1B and ATM . Besides notable impact of DNA polymerases, including POLG , Fanconi anaemia genes include FANCD2 , FANCA, FANCG, ERCC4, FANCE and FANCI , while DNA mismatch repair genes MSH3 and PMS1 outranked known namesakes MSH6 and PMS2 . This study provides insights into the spectrum of African-relevant potentially pathogenic PCa variants, highlighting much-needed gene candidates for ancestry-inclusive germline testing.

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ISO 690GHEYBI, Kazzem, Pamela X. Y. SOH, Jue JIANG, Tumisang M. N. MBEKI, Melanie LOUW, Daniel BURNS, Piyushkumar MUNDRA, Daria KIRIY, Md. Mehedi HASAN, Weerachai JARATLERDSIRI, Maphuti Tebogo LEBELO, Raymond A. CAMPBELL, Mulalo B. RADZUMA, Mukudeni NENZHELELE, Muvhulawa OBIDA, Martin OBIDA, Winstar M. OMBUKI, Micah O. OYARO, Sean M. PATRICK, Massimo LODA, David C. WEDGE, Robert G. BRISTOW, Daniel S. BREWER, Colin S. COOPER, Jüri REIMAND, Geraldine CANCEL-TASSIN, Olivier CUSSENOT, Chris M. HOVENS, Niall M. COCORAN, Phillip D. STRICKER, Thorsten SCHLOMM, Gail S. PRINS, Karina Dalsgaard SØRENSEN, G. Steven S. BOVA, Mark N. BROOK, Benedict BRORS, Adam BUTLER, Kevin C. L. CHENG, Niall M. CORCORAN, Francesco FAVERO, Clarissa GERHAUSER, Abraham GIHAWI, Etsehiwot G. GIRMA, Vincent J. GNANAPRAGASAM, Andreas J. GRUBER, Anis HAMID, Vanessa M. HAYES, Housheng Hansen HE, Eddie Luidy IMADA, G. Maria JAKOBSDOTTIR, Weerachai JARATLERSIRI, Jue JIANG, Chol-Hee JUNG, Francesca KHANI, Philippe LAMY, Gregory LEEMAN, Pavlo LUTSIK, Luigi MARCHIONNI, Ramyar MOLANIA, Anthony T. PAPENFUSS, Diogo PELLEGRINA, Bernard POPE, Lucio R. QUEIROZ, Tobias RAUSCH, Jüri REIMAND, Brain ROBINSON, Atef SAHLI, Pamela X. Y. SOH, Sebastian UHRIG, Yaobo XU, Takafumi N. YAMAGUCHI, Claudio ZANETTINI, M. S. Riana BORNMAN, Peter Mungai NGUGI, Winstar M. OMBUKI, Sean M. PATRICK, Daniel M. MOREIRA, Ikenna C. MADUEKE, Maria ARGOS, Irene E. J. BARNHOORN, Lynn BIRCH, Jenna CRADDOCK, G. Nicolo’ FANELLI, Eva Ferlev JENSBY, Hagen E. A. FÖRTSCH, Jessie GAMXAMUB, Kazzem GHEYBI, Abraham GIHAWI, Tingting GONG, Md. Mehedi HASAN, Vivien HOLMES, Ruotian HUANG, Zsofia KOTE-JARAI, Maphuti Tebogo LEBELO, Pavlo LUTSIK, Umuna MAENDO, Tumisang M. N. MBEKI, Reginald MENOE, Muriuki Elias NYAGA, Willis OYIEKO, Joyce SHIRINDE, Golda STELLMACHER, Avraam TAPINOS, Korawich UTHAYOPAS, Douglas I. WALKER, Edwin O. O. WALONG, Githui Sheila WANJIKU, Allan YIENYA, Kangping ZHOU, Joachim WEISCHENFELDT, Shingai B. A. MUTAMBIRWA, Peter M. NGUGI, David M. THOMAS, Zsofia KOTE-JARAI, Rosalind A. EELES, M. S. Riana BORNMAN, Vanessa M. HAYES, 2025. Pathogenic variants reveal candidate genes for prostate cancer germline testing for men of African ancestry. In: Nature Communications. Springer. 2025, 16(1), 8799. eISSN 2041-1723. Verfügbar unter: doi: 10.1038/s41467-025-63865-6
BibTex
@article{Gheybi2025-10-02Patho-76181,
  title={Pathogenic variants reveal candidate genes for prostate cancer germline testing for men of African ancestry},
  year={2025},
  doi={10.1038/s41467-025-63865-6},
  number={1},
  volume={16},
  journal={Nature Communications},
  author={Gheybi, Kazzem and Soh, Pamela X. Y. and Jiang, Jue and Mbeki, Tumisang M. N. and Louw, Melanie and Burns, Daniel and Mundra, Piyushkumar and Kiriy, Daria and Hasan, Md. Mehedi and Jaratlerdsiri, Weerachai and Lebelo, Maphuti Tebogo and Campbell, Raymond A. and Radzuma, Mulalo B. and Nenzhelele, Mukudeni and Obida, Muvhulawa and Obida, Martin and Ombuki, Winstar M. and Oyaro, Micah O. and Patrick, Sean M. and Loda, Massimo and Wedge, David C. and Bristow, Robert G. and Brewer, Daniel S. and Cooper, Colin S. and Reimand, Jüri and Cancel-Tassin, Geraldine and Cussenot, Olivier and Hovens, Chris M. and Cocoran, Niall M. and Stricker, Phillip D. and Schlomm, Thorsten and Prins, Gail S. and Sørensen, Karina Dalsgaard and Bova, G. Steven S. and Brook, Mark N. and Brors, Benedict and Butler, Adam and Cheng, Kevin C. L. and Corcoran, Niall M. and Favero, Francesco and Gerhauser, Clarissa and Gihawi, Abraham and Girma, Etsehiwot G. and Gnanapragasam, Vincent J. and Gruber, Andreas J. and Hamid, Anis and Hayes, Vanessa M. and He, Housheng Hansen and Imada, Eddie Luidy and Jakobsdottir, G. Maria and Jaratlersiri, Weerachai and Jiang, Jue and Jung, Chol-Hee and Khani, Francesca and Lamy, Philippe and Leeman, Gregory and Lutsik, Pavlo and Marchionni, Luigi and Molania, Ramyar and Papenfuss, Anthony T. and Pellegrina, Diogo and Pope, Bernard and Queiroz, Lucio R. and Rausch, Tobias and Reimand, Jüri and Robinson, Brain and Sahli, Atef and Soh, Pamela X. Y. and Uhrig, Sebastian and Xu, Yaobo and Yamaguchi, Takafumi N. and Zanettini, Claudio and Bornman, M. S. Riana and Ngugi, Peter Mungai and Ombuki, Winstar M. and Patrick, Sean M. and Moreira, Daniel M. and Madueke, Ikenna C. and Argos, Maria and Barnhoorn, Irene E. J. and Birch, Lynn and Craddock, Jenna and Fanelli, G. Nicolo’ and Jensby, Eva Ferlev and Förtsch, Hagen E. A. and Gamxamub, Jessie and Gheybi, Kazzem and Gihawi, Abraham and Gong, Tingting and Hasan, Md. Mehedi and Holmes, Vivien and Huang, Ruotian and Kote-Jarai, Zsofia and Lebelo, Maphuti Tebogo and Lutsik, Pavlo and Maendo, Umuna and Mbeki, Tumisang M. N. and Menoe, Reginald and Nyaga, Muriuki Elias and Oyieko, Willis and Shirinde, Joyce and Stellmacher, Golda and Tapinos, Avraam and Uthayopas, Korawich and Walker, Douglas I. and Walong, Edwin O. O. and Wanjiku, Githui Sheila and Yienya, Allan and Zhou, Kangping and Weischenfeldt, Joachim and Mutambirwa, Shingai B. A. and Ngugi, Peter M. and Thomas, David M. and Kote-Jarai, Zsofia and Eeles, Rosalind A. and Bornman, M. S. Riana and Hayes, Vanessa M.},
  note={Article Number: 8799}
}
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    <dc:contributor>Soh, Pamela X. Y.</dc:contributor>
    <dc:contributor>Bornman, M. S. Riana</dc:contributor>
    <dc:creator>Ombuki, Winstar M.</dc:creator>
    <dc:creator>Jiang, Jue</dc:creator>
    <dc:contributor>Marchionni, Luigi</dc:contributor>
    <dc:creator>Fanelli, G. Nicolo’</dc:creator>
    <dc:contributor>Walong, Edwin O. O.</dc:contributor>
    <dc:contributor>Patrick, Sean M.</dc:contributor>
    <dc:contributor>Leeman, Gregory</dc:contributor>
    <dc:contributor>Madueke, Ikenna C.</dc:contributor>
    <dc:creator>Cancel-Tassin, Geraldine</dc:creator>
    <dc:contributor>Pellegrina, Diogo</dc:contributor>
    <dc:creator>Pope, Bernard</dc:creator>
    <dc:creator>Argos, Maria</dc:creator>
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