Genetic testing is an important part of personalized diagnosis and treatment of prostate cancer (PCa). |
Recent clinical studies have highlighted specific genes (e.g., BRCA 1/2, PALB2, CHEK, HOXB13) and single nucleotide polymorphisms as special genes of interest. |
One future goal of genetic testing is to detect men harboring an increased risk of lethal PCa. |
1 Introduction
2 Methods
2.1 Search Strategies and Sources
Study | Focus | Comment |
---|---|---|
Kerr et al. [29] | LS, BRCA1/2 | LS ↑ PCa risk |
Huynh-Le et al. [45] | SNPs | Age-specific risk for PCa calculated with the PHS |
Cybulski et al. [39] | BRCA1, CHEK2, NBS1, HOXB13, SNPs | CHEK2 is associated with ↑ detection of PCa and ↑ number of SNPs |
Patel et al. [34] | BRCA1/2 | BRCA2 ↑ risk of PCa with a GS ≥ 8 |
Yang et al. [55] | PALB2 | No correlation found with PCa |
Mersch et al. [35] | BRCA1/2 | BRCA2 is associated with ↑ age-specific risk for PCa |
Silvestri et al. [36] | BRCA 1/2 | BRCA2 is associated with ↑ risk for PCa and aggressive forms |
Pakkanen et al. [25] | Hereditary vs. SPCa | Earlier disease onset and higher PSA in patients with FH |
Heise et al. [58] | PON1 | No correlation found with PCa |
Rosenthal et al. [50] | MGPT | ↑ number of genetic mutations in pan-cancer gene panels than in single-syndrome gene panel testing |
Pritzlaff et al. [48] | MGPT | BRCA1/2, ATM, BRIP1, CHEK2, NBN, BRAD1, MSH2, MSH6, MLH1, PMS2, EpCAM mutations in 9.4% of patients with hereditary PCa |
Sutcliffe et al. [37] | CHECK2 | Among CHEK2 mutation carriers, PCa was the second-most common tumor with 20% |
Ābele et al. [59] | NBS1 | No correlation found with PCa |
Kwon et al. [52] | MGPT | 13.8% of patients with PCa had PVs, mostly in BRCA2 |
Mantere et al. [56] | FANCA/FANCG/FANCI | No correlation with PCa |
Heise et al. [41] | HOXB13 | HOXB13 mutations ↑ risk for PCa and a ↓ OS |
Wallander et al. [47] | SNPs | |
Pilié et al. [49] | MGPT | 10.8% pathogenic and likely pathogenic mutation among patients with cancer |
Ewing et al. [40] | HOXB13 | HOXB13 mutations ↑ risk for PCa, especially for early-onset disease |
Momozawa et al. [51] | MGPT | 2.8% of patients with PCa had PVs, associated with early disease onset |
Slavin et al. [54] | cfDNA | 3.4% mutation of cfDNA in PCa |
Page et al. [32] | BRCA 1/2 | ↑ incidence of PCa among BRCA2 carriers with ↑ rate of early-onset disease and ↑ rate of clinically significant cancers |
Cremers et al. [46] | SNPs | No tool to differ between sporadic and hereditary PCa |
Southey et al. [38] | CHECK2, PALB2, ATM | CHEK2 was associated with ↑ risk for PCa |
Seibert et al. [44] | SNPs | PHS to calculate age of onset of PCa |
MacInnis et al. [42] | HOXB13 | HOXB13 carriers have a 16.4-fold ↑ age-specific-risk |
Chandrasekar et al. [27] | Hereditary vs. SPCa | 19.5% germline mutation among suspected hereditary PCa connected to an HCS |
Kote-Jarai et al. [43] | HOXB13 | 2.9-fold ↑ risk for PCa |
Haraldsdottir et al. [30] | LS | Patients with LS have fivefold ↑ risk for PCa |
Beebe-Dimmer et al. [26] | Hereditary vs. SPCa | FH of familial PCa ↑ 2.3-fold the risk for PCa, fourfold ↑ risk for early-onset disease among hereditary PCa |
Bancroft et al. [31] | BRCA1/2 | ↑ detection of PCa among BRCA mutation carriers |
Maia et al. [33] | BRCA1/2, LS | MMR and BRCA1/2 mutations were associated with early-onset and aggressive subtypes of PCa |
Barrow et al. [24] | LS | Tenfold ↑ risk for PCa among MSH2 mutation carriers |
Cardoso et al. [33 OR 61] | PPM1D | No clear correlation |
2.2 Data Extraction and Eligibility Criteria
2.3 Evidence Synthesis
3 Results
3.1 Hereditary Versus Sporadic Prostate Cancer
3.2 Hereditary Non-polyposis Colorectal Cancer/Lynch Mutations
3.3 Specific Predisposition Genes
3.3.1 BRCA1/2
3.3.2 CHEK2
3.3.3 HOXB13
3.4 Single Nucleotide Polymorphism Genotyping
3.5 Multigene Panel Testing
3.6 Germline Mutation Testing in Cell-Free Circulation Tumor DNA
3.7 Additional Tested Genes
4 Current Guideline Recommendations for Genetic Testing
European Association of Urology [16] | European Society for Medical Oncology [59] | ||
---|---|---|---|
Early PSA screening in patients with a FH of PCa and age > 45 years | Germline testing in all men with high-risk/very high-risk regional or metastatic PCa | Early PSA screening in patients with a FH of PCa > 45 years | Patients with a first-degree relative diagnosed < 55 years |
Early PSA screening in BRCA2 carriers older > 40 years | Any patient with a FH of germline mutations/cancers should be considered for germline testing | Early PSA screening in BRCA1/2 carriers > 40 years | Personal diagnosis < 55 years and a first-degree relative with PCa at any age, or death of a first-degree relative < 60 years |
Early genetic sequencing of the primary tumor/biopsy or metastasis at the state of metastasis and as soon as mCRPC | Consider somatic testing in MSI-H, dMMR or HRR genes for treatment selection in metastatic PCa | Germline testing for BRCA2 and other DDR genes associated with cancer predisposition syndromes in men with advanced PCa regardless of tumor features or FH | Patients with two close blood relatives on the same family side with at least one diagnosed < 55 years |
Ashkenazi Jewish ancestry | Consider somatic tumor testing for HRR and dMMR genes in patients with mCRPC | Patients with any first-degree relative with hereditary PCa and a diagnosis < 50 years, or tumor sequencing showing mutations in hereditary PCa genes | |
Intraductal histology | Consider germline screening for men with localized PCa with a FH of hereditary cancer (e.g., BCa, OCa or PCa) | Patients with high-risk localized PCa and a strong FH of specific cancers (BCa, OCa, pancreatic, gastrointestinal, lymphoma) | |
Patients with pathogenic mutations in cancer-risk genes identified through tumor testing should be referred for germline testing and genetic counseling | Offer germline testing to patients with mHSPC and in patients with mCRPC regardless of age and FH |