Novel Germline Mutations in a Cohort of Men with Familial Prostate Cancer

Abstract

Background: Germline mutations in BRCA2 are associated with aggressive prostate cancer. Additional information regarding the clinical phenotype of germline pathogenic variants in other prostate cancer predisposition genes is required. Clinical testing has been limited by evidence, further restricting knowledge of variants that contribute to prostate cancer development. Objective: Prostate cancer patients who were first- and second-degree relatives from multi-case prostate cancer families underwent a gene panel screen to identify novel (non-BRCA) germline pathogenic variants in cancer predisposition genes and define clinical phenotypes associated with each gene. Methods: The germline genomic DNA (gDNA) of 94 index cases with verified prostate cancer from families with a minimum of two verified prostate cancer cases was screened with an 84-cancer-gene panel. Families were recruited for multi-case breast/ovarian cancer (n = 66), or multi-case prostate cancer (n = 28). Prostate cancer characteristics associated with each gene were compared with prostate cancer cases of confirmed non-mutation carriers (BRCAX), also from multi-case prostate cancer families (n = 111), and with data from the Prostate Cancer Outcomes Registry (PCOR). Results: Ninety-four prostate cancer index cases underwent gene panel testing; twenty-two index cases (22/94; 23%) were found to carry a class 4–5 (C4/5) variant. Six of twenty-two (27%) variants were not clinically notifiable, and seven of twenty-two (31.8%) variants were in BRCA1/2 genes. Nine of twenty-two (40.9%) index cases had variants identified in ATM (n = 4), CHEK2 (n = 2) and HOXB13G84 (n = 3); gDNA for all relatives of these nine cases was screened for the corresponding familial variant. The final cohort comprised 15 confirmed germline mutation carriers with prostate cancer (ATM n = 9, CHEK2 n = 2, HOXB13G84 n = 4). ATM and CHEK2-associated cancers were D’Amico intermediate or high risk, comparable to our previously published BRCA2 and BRCAX prostate cancer cohort. HOXB13G84 carriers demonstrated low- to intermediate-risk prostate cancer. In the BRCAX cohort, 53.2% of subjects demonstrated high-risk disease compared with 25% of the PCOR cohort. Conclusions:ATM and CHEK2 germline mutation carriers and the BRCAX (confirmed non-mutation carriers) cohort demonstrated high risk disease compared with the general population. Targeted genetic testing will help identify men at greater risk of prostate-cancer-specific mortality. Data correlating rare variants with clinical phenotype and familial predisposition will strengthen the clinical validity and utility of these results and establish these variants as significant in prostate cancer detection and management.

DNA Damage Repair Pathways in Prostate Cancer: A Narrative Review of Molecular Mechanisms, Emerging Biomarkers and Therapeutic Targets in Precision Oncology

“…HOXB13 was the first gene that was shown to enhance the prostate cancer risk by up to 10 times and was linked with familial cases of PCa and early-onset disease in some [23,31,33] but not all studies [43]. Specifically, the mutant HOXB13G84E has been associated with lower-risk tumor characteristics [43], early-onset disease [33] and European origin among patients [31,33]. Other alterations have been encountered in different populations, such as G135E in Chinese men and variants A128D and F240L in Portuguese men [31].…”

“…A recent study conducting genome analysis on non-BRCA-mutated PCa showed that germline ATM and CHEK2 alterations had lower penetrance than BRCA2. In addition, prostate cancer carried different genetic alterations in these genes compared to breast and ovarian cancer [43]. Germline CHEK2 mutations increase the risk for PCa development at a moderate level [23] and have been linked with aggressive or high-risk cancer [43].…”

“…In addition, prostate cancer carried different genetic alterations in these genes compared to breast and ovarian cancer [43]. Germline CHEK2 mutations increase the risk for PCa development at a moderate level [23] and have been linked with aggressive or high-risk cancer [43]. Genome analysis in patients with non-BRCA-mutated familial PCa has confirmed that mutated ATM is found in cases with advanced disease, higher PSA levels at the time of initial diagnosis and a high D'Amico score [43].…”

“…Germline CHEK2 mutations increase the risk for PCa development at a moderate level [23] and have been linked with aggressive or high-risk cancer [43]. Genome analysis in patients with non-BRCA-mutated familial PCa has confirmed that mutated ATM is found in cases with advanced disease, higher PSA levels at the time of initial diagnosis and a high D'Amico score [43]. Further studies need to be performed, mainly for ATM and PALB2, as the existing data for these two genes in PCa are limited.…”