Germline DNA repair mutations in men with prostate cancer are less frequent in African Americans as compared with Caucasians.

2019 ◽  
Vol 37 (7_suppl) ◽  
pp. 258-258
Author(s):  
Piper L.W. Nicolosi ◽  
Elisa Ledet ◽  
Shan Yang ◽  
Scott T. Michalski ◽  
James Vu ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Dna Repair ◽  
Dna Repair Genes ◽  
Chi Square ◽  
Pathogenic Variants ◽  
Gene Panels ◽  
Sparse Methods ◽  
Repair Genes ◽  
Germline Testing ◽  
Identical Gene

258 Background: Pathogenic DNA repair defects are well described in Caucasian (C) men with prostate cancer (PCa) but comparative data on African-American (AA) men are sparse. Methods: Germline testing for DNA repair defects were assayed by Invitae (Invitae.com). Pathogenic variants in 14 genes were compared between AA and C men with PCa; these particular genes were also assessed by Pritchard et al NEJM 375:443, 2016. Identical gene panels were not used in all men, thus variations in assay numbers from gene to gene are noted. Chi square was used to compare proportions. Results: In the 14 genes, there were 16/214 (7.5%) AA men and 347/2488 (13.9%) C men with pathogenic findings (p=0.008). As shown in the Table, the most common pathogenic variants in AA men were BRCA2 (6/214, 2.8%), BRCA1 (3/213, 1.4%), PALB2 (2/182, 1.1%), ATM (2/206, 1.0%), RAD51C (1/148, 0.68%), CHEK2 (1/207, 0.48%), and PMS2 (1/212, 0.47%). In contrast to C men in this series, no AA men had pathogenic mutations in BARD1, BRIP1, MLH1, MSH2, MSH6, NBN, or RAD51D. Pathogenic CHEK2 was less commonly detected in AA as compared to C (p=0.03) in this dataset. Comparing our C men revealed no differences in the proportion of men with pathogenic findings compared to Pritchard et al (13.9% here vs 11.8%, P=0.15). Conclusions: AA men with PCa are less likely to have pathogenic DNA repair mutations among these 14 assayed DNA repair genes compared to C men. Limitations regarding lack of stage, Gleason scores, and FH are notable. Details on gene assays and comparison to Pritchard et al NEJM 375:443, 2016 [Table: see text]

Comparison of Caucasian and African-American DNA repair alterations in men with metastatic prostate cancer.

2020 ◽  
Vol 38 (6_suppl) ◽  
pp. 199-199
Author(s):  
Ellen Jaeger ◽  
Earle Frederick Burgess ◽  
Jason Zhu ◽  
Beth Dellinger ◽  
Sara Elrefai ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Dna Repair ◽  
African American ◽  
Metastatic Prostate Cancer ◽  
Dna Repair Genes ◽  
Variants Of Unknown Significance ◽  
Brca Gene ◽  
Brca1 Brca2 ◽  
Gene Panels ◽  
Repair Genes

199 Background: Data on germline DNA repair defects and VUS rates are sparse in African American (AA) men with metastatic prostate cancer (PCa). Methods: Germline testing data from two centers with a significant percentage of metastatic AA PCa patients were combined and compared to Caucasian American (CA) with metastatic PCa. Fourteen canonical DNA repair genes (ATM, BARD1, BRCA1, BRCA2, BRIP1, CHEK2, MLH1, MSH2, MSH6, NBN, PALB2, PMS2, RAD51C, RAD51D) were assessed in all tested patients (pts) using a pathogenic/likely pathogenic (P/LP) classification. Variants of unknown significance (VUS) were assessed in an Invitae-derived dataset with consistent VUS reporting. Results: A total of 105 AA men with metastatic disease were evaluated and 7/105 of these men (6.67%) had P/LP alteration. Among the AA pt alterations, there were 4 pts with BRCA2, 2 pts with BRCA1, and 1 pt with PALB2. A total of 39/417 (9.3%) of CA metastatic patients had P/LP alterations in the canonical 14 genes. No differences were detected in the AA vs CA metastatic comparison (p=0.39). A total of 1/105 (0.95%) AA pts and 23/418 (5.5%) CA had non-BRCA P/LP mutations. The number of non-BRCA P/LP mutations were lower in the AA as compared to the CA men (p=0.045). When evaluating VUS calls in the metastatic AAs using Invitae multi-gene panels, 28/92 (30.43%) pts had a VUS in the canonical 14 genes as compared to 67/366 (18.31%) of the CA men. AAs were more likely than CA to have a VUS (p=0.010). These data indicate that metastatic AA pts and CA are not significantly distinct in the P/LP alterations in 14 canonical DNA repair genes but that there were lower percentages of P/LP in the AA non-BRCA gene subset. Further, when assessing these genes, it is clear that a VUS is more likely to be called in the AA men. Conclusions: Among men with metastatic PCa, AAs have similar rates of inherited P/LP alterations in 14 well accepted DNA repair genes as compared to CA men, however the non-BRCA gene P/LP alterations were less frequent among the AAs. Variants classified as a VUS were clearly higher in these AA pts as compared to the CA pts.

scholarly journals Germline Sequencing DNA Repair Genes in 5545 Men With Aggressive and Nonaggressive Prostate Cancer

2020 ◽  
Author(s):  
Burcu F Darst ◽  
Tokhir Dadaev ◽  
Ed Saunders ◽  
Xin Sheng ◽  
Peggy Wan ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Dna Repair ◽  
Statistical Tests ◽  
European Ancestry ◽  
International Studies ◽  
Dna Repair Genes ◽  
Variant Gene ◽  
Significant Gene ◽  
Repair Genes

Abstract Background There is an urgent need to identify factors specifically associated with aggressive prostate cancer (PCa) risk. We investigated whether rare pathogenic, likely pathogenic, or deleterious (P/LP/D) germline variants in DNA repair genes are associated with aggressive PCa risk in a case-case study of aggressive vs nonaggressive disease. Methods Participants were 5545 European-ancestry men, including 2775 nonaggressive and 2770 aggressive PCa cases, which included 467 metastatic cases (16.9%). Samples were assembled from 12 international studies and germline sequenced together. Rare (minor allele frequency < 0.01) P/LP/D variants were analyzed for 155 DNA repair genes. We compared single variant, gene-based, and DNA repair pathway-based burdens by disease aggressiveness. All statistical tests are 2-sided. Results BRCA2 and PALB2 had the most statistically significant gene-based associations, with 2.5% of aggressive and 0.8% of nonaggressive cases carrying P/LP/D BRCA2 alleles (odds ratio [OR] = 3.19, 95% confidence interval [CI] = 1.94 to 5.25, P = 8.58 × 10-7) and 0.65% of aggressive and 0.11% of nonaggressive cases carrying P/LP/D PALB2 alleles (OR = 6.31, 95% CI = 1.83 to 21.68, P = 4.79 × 10-4). ATM had a nominal association, with 1.6% of aggressive and 0.8% of nonaggressive cases carrying P/LP/D ATM alleles (OR = 1.88, 95% CI = 1.10 to 3.22, P = .02). In aggregate, P/LP/D alleles within 24 literature-curated candidate PCa DNA repair genes were more common in aggressive than nonaggressive cases (carrier frequencies = 14.2% vs 10.6%, respectively; P = 5.56 × 10-5). However, this difference was non-statistically significant (P = .18) on excluding BRCA2, PALB2, and ATM. Among these 24 genes, P/LP/D carriers had a 1.06-year younger diagnosis age (95% CI = -1.65 to 0.48, P = 3.71 × 10-4). Conclusions Risk conveyed by DNA repair genes is largely driven by rare P/LP/D alleles within BRCA2, PALB2, and ATM. These findings support the importance of these genes in both screening and disease management considerations.

Abstract 2753: Landscape of somatic mutations in DNA repair genes in prostate cancer

2016 ◽  
Author(s):  
Santosh Yadav ◽  
Muralidharan Anbalagan ◽  
Melody Baddoo ◽  
Erik Flemington ◽  
Krzysztof Moroz ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Dna Repair ◽  
Somatic Mutations ◽  
Dna Repair Genes ◽  
Repair Genes

Rare Germline Pathogenic Mutations of DNA Repair Genes Are Most Strongly Associated with Grade Group 5 Prostate Cancer

2020 ◽  
Vol 3 (2) ◽  
pp. 224-230 ◽  
Author(s):  
Yishuo Wu ◽  
Hongjie Yu ◽  
Shuwei Li ◽  
Kathleen Wiley ◽  
S. Lilly Zheng ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Dna Repair ◽  
Dna Repair Genes ◽  
Grade Group ◽  
Pathogenic Mutations ◽  
Group 5 ◽  
Repair Genes

Inherited mutations in DNA repair genes in men with metastatic castration-resistant prostate cancer.

2016 ◽  
Vol 34 (15_suppl) ◽  
pp. 5009-5009 ◽  
Author(s):  
Peter Nelson ◽  
Joaquin Mateo ◽  
Himisha Beltran ◽  
Navonil De Sarkar ◽  
Olivier Elemento ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Dna Repair ◽  
Dna Repair Genes ◽  
Castration Resistant Prostate Cancer ◽  
Castration Resistant ◽  
Inherited Mutations ◽  
Repair Genes

Copy number variations in AR-associated and DNA repair genes from plasma cell-free DNA of metastatic CRPC patients.

2016 ◽  
Vol 34 (2_suppl) ◽  
pp. 281-281 ◽  
Author(s):  
Ratish Gambhira ◽  
Elisa M. Ledet ◽  
Aryeneesh Dotiwala ◽  
Diptasri Mandal ◽  
A. Oliver Sartor
Keyword(s):  
Prostate Cancer ◽  
Dna Repair ◽  
Cancer Progression ◽  
Copy Number ◽  
Genetic Alterations ◽  
Copy Number Variations ◽  
Dna Repair Genes ◽  
Prostate Cancer Progression ◽  
Free Dna ◽  
Repair Genes

281 Background: Cell-free DNA (cfDNA) present in the plasma of advanced cancer patients can reflect tumor related genetic alterations. Recent data suggests copy number variations (CNVs) in AR-associated and DNA repair pathway genes play a potential role in prostate cancer progression. Here, we performed sequencing of cfDNA from 13 mCRPC patients to evaluate its potential in elucidating tumor related genetic variations. The long-term goal of our project is to correlate cfDNA derived genetic alterations with prostate cancer progression and/or therapeutic resistance/responses. Methods: cfDNA was isolated from 13 advanced mCRPC patient plasma samples using the Qiagen circulating nucleic acid kit. 100ng of cfDNA was utilized for library construction; and the libraries were paired-end sequenced on the Illumina HiSeq 2000. The resulting data was analyzed using the GATK best practices bioinformatics pipeline and the visualized using the SNP & Variation Suite v8.x. Results: The bioanalyzer profiles of cfDNA derived from mCRPC patients is highly fragmented with an average fragment size of 306-605bp. Although, several CNVs were found across the genome, we focused analysis on CNVs related to AR associated and DNA repair genes. Our preliminary analysis of cfDNA, despite low sequencing depth, shows full or partial amplifications in AR (13/13), and other genes including FOXA1, NCOR1, NCOR2 and/or PIK3CA (7/13) and NCOR2 (10/13). For DNA repair genes partial/full amplifications were present in BRAC1, BRAC2, ATM, CDK12, MLH1 and/or MSH2 (7/13). Deletions are less reliably detected in the highly fragmented cfDNA. The majority of these CNVs have been reported in the WGS studies from metastatic CRPC tissue derived genomic DNA (cBioPortal). We are currently validating cfDNA genomic alterations by comparing it to germ line DNA derived via qPCR. Conclusions: Our preliminary study indicates that AR and DNA repair related genetic alterations could be found in the cfDNA derived from metastatic CRPC patients. This warrants more detailed examination of these cfDNA genetic alterations for identifying clinically relevant issues in mCRPC patients.

Comparison of germline mutations in African American and Caucasian men with metastatic prostate cancer.

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. 5568-5568
Author(s):  
Elisa Marie Ledet ◽  
Ellen Jaeger ◽  
Whitley Hatton ◽  
Marcus W. Moses ◽  
Alexandra Sokolova ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Prostate Cancer ◽  
Dna Repair ◽  
African American ◽  
Family History ◽  
Metastatic Prostate Cancer ◽  
Germline Mutations ◽  
Dna Repair Genes ◽  
Brca Mutations ◽  
Repair Genes

5568 Background: The relevance of germline mutations in metastatic prostate cancer is well established; however, comparison of germline genetics in African American (AA) versus Caucasian (CA) men with metastatic prostate cancer (PCa) is limited. Methods: Germline data from self-identified AA and CA metastatic PCa patients (pts) were collected from 5 academic cancer centers. Various commercial cancer-specific germline testing panels were used to evaluate 12-86 genes. Pathogenic (P) or likely pathogenic (LP) mutations, and variants of unknown significance (VUS), were reported according to ACMG guidelines. Self-reported family history (FH) was annotated for 99% of pts. Statistical analyses included Chi-squared and Fischer’s exact tests. Results: A total of 821 metastatic PCa pts were assessed: 152 AAs and 669 CAs. For P/LP alterations, AAs had a frequency of 11.2% (17/152) as compared to a frequency of 14.6% (98/669) in CAs (p = 0.302). AA pts were more likely to have a VUS than CA pts, 61% vs 43% respectively (OR = 2.09, 95%CI [1.45, 2.99], p < 0.001). BRCA mutations were similar between races, but AA were more likely to have a BRCA1 P/LP alteration (OR = 6.00, 95% CI [1.33, 27.09], p = 0.025). AA pts were less likely to have a P/LP alteration in a non-BRCA gene (OR = 0.34, 95% CI [0.15, 0.80], p = 0.013). Among DNA repair genes, there were no significant difference between AA and CA pts (p = 0.574); however, there was a trend toward AA pts having fewer P/LP alteration in a non-BRCA DNA repair genes (OR = 0.26, 95% CI [0.06, 1.08], p = 0.071). In pts with >1 first degree relative (FDR) with ovarian cancer, P/LP germline alterations were more likely in CAs (OR = 2.33, 95% CI [1.05, 5.17], p = 0.043); but there were no significant differences in AAs (p = 0.098). Those with >2 FDRs with PCa were more likely to have a P/LP change in CAs (OR = 2.32, 95% CI [1.04, 5.15], p = 0.043), but there were no difference in AAs (p = 0.700). In pts with ≥2 FDRs with breast cancer, P/LP germline alterations were more likely in both AAs (OR = 9.36, 95% CI [1.72, 50.84], p = 0.019) and CAs (OR = 3.92, 95% CI [1.79, 8.59], p = 0.001). Conclusions: We did not observe a difference in the overall frequency of germline P/LP alterations between AA and CA men with metastatic PCa but VUSs were more common in AA men. These AA men have an overall frequency of BRCA mutations similar to CA men; however, BRCA1 mutations were more prevalent in these AAs. Non-BRCA P/LP mutations are significantly less frequent in AA pts. A positive family history of >2 FDRs with breast cancer was associated with P/LP alterations in both AA and CA pts.

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