DNA Damage Repair Genes in Prostate Cancer - (HJF 557-19)

Prostate cancer patients with DDRG mutations are increasingly considered for targeted cancer therapies. Currently available DDRG mutation tests rely on a rather small number of genes which are not often mutated in African American prostate cancer patients. This invention describes a robust data set on inherited mutations which can be used to develop a more useful DDRG mutation test for African American and Caucasian men.

Applications and Advantages

Identification of newly recognized inherited mutations not detected by commercially available DDRG mutation tests.
Development of a more useful DDRG germline mutation test for predicting, diagnosing, and/or prognosing prostate cancer in African American and Caucasian men.
Precision therapy and precision management of prostate cancer.

Innovation Description

Prostate cancer (CaP) is the most prevalent malignancy with disproportionately higher incidence and mortality rates among African American men.Mutations in DNA damage repair genes (DDRGs) are now known to be associated with the aggressive form of CaP. However, currently available DDRG mutation tests were developed based on the genomic studies over-represented by Caucasian CaP patients and they rely on a rather small number of genes which are not often mutated in African American CaP patients.

Researchers at Henry M. Jackson Foundation (HJF) and Uniformed Services University for Health Sciences (USU) have developed foundational data by profiling all known DDRGs in an unbiased way using the DNA of a cohort of 600 patients, collected equally from Caucasian and African American men matched for age and stage of the disease. This data set revealed several inherited DDRG mutations (“germline mutations”) that were significantly high in African American men compared to Caucasian men. The researchers also noticed that a higher percentage of African American men compared to Caucasian men inherited a targetable subset of DDRGs belonging to the RAD gene family. Such inherited mutations were associated with poor disease outcome and progression in African American men.

By potentially targeting these newly recognized inherited mutations, new genetic tests can be developed to address some of the disparities African American CaP patients underwent for a long time. Ultimately, having a better understanding of these race specific genetic mutations would allow physicians to treat CaP patients with precision medicine in the future. HJF seeks co-development partners and/or licensees for developing an improved CaP diagnostic kit based on this mutation panel.

Figure: Homologous recombination (HR) DDRG Pathway based Germline Mutations Profiling in African American (AA) and European Ancestry (EA) Men.

(a) Frequency of germline mutations in HR pathway in AA and EA men
(b) The pie chart indicates the genes (RAD51, BRCA1, BRCA2, BLM, NBN) harboring 15 HR pathway mutations
(c) Patients with variants in HR pathway had developed biochemical recurrence (BCR) faster than the patients without HR mutations, when longitudinally followed up after radical prostatectomy (RP) (P = 0.022, HR 3.34) (Kohaar et al., Nat Comm 2022)

Inventors

Gyorgy Petrovics, Ph.D. (HJF)
Shiv Srivastava, Ph.D. (USU)

Innovation Status

This invention explored all DNA damage repair genes (DDRGs) in the human genome for potential germline mutations in prostate cancer patients focusing on African Americans (AA). Whole genome sequencing (WGS) was performed in 600 prostate cancer patients (300 of them AA) and analyzed for germline mutations in all (over 200) DDRGs.

Publication: Kohaar I et al. Nat Commun. Mar 15, 2022. PMID: 35292633.