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Pathogenic Variants in Cancer Predisposition Genes and Prostate Cancer Risk in Men of African Ancestry.

Marco Matejcic1, Yesha Patel1, Jenna Lilyquist2

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Rare pathogenic variants in DNA repair genes significantly increase aggressive prostate cancer risk in men of African ancestry. This finding supports genetic testing for risk stratification in this population.

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Area of Science:

  • Genetics
  • Oncology
  • Population Health

Background:

  • Rare pathogenic variants in DNA repair genes are linked to aggressive prostate cancer in European men.
  • The role of rare coding variation in prostate cancer risk for men of African ancestry remains unclear.

Purpose of the Study:

  • To investigate the contribution of rare coding variation in DNA repair genes to prostate cancer risk and aggressiveness in men of African ancestry.
  • To establish the association between pathogenic variants and prostate cancer in African American and Ugandan populations.

Main Methods:

  • Sequencing of 19 DNA repair and cancer predisposition genes in 2,453 African American and 1,151 Ugandan prostate cancer cases and controls.
  • Classification of rare variants as pathogenic or putatively functionally disruptive.
  • Gene and pathway-level association analyses for prostate cancer risk and disease aggressiveness.

Main Results:

  • Pathogenic variants were identified in 3.6% of cases and 2.1% of controls (OR=1.82, P=0.0044).
  • The association was stronger for aggressive disease phenotypes (OR=3.10, P=0.0022).
  • Pathogenic variants in ATM, BRCA2, PALB2, and NBN genes showed the highest risks for aggressive disease (ORs ~4-15).

Conclusions:

  • Rare pathogenic variants in DNA repair genes significantly impact aggressive prostate cancer risk in men of African ancestry.
  • Findings suggest implications for genetic panel testing and risk stratification in this high-risk population.