MP57-01 GERMLINE MUTATIONS IN DNA REPAIR GENES ARE SIGNIFICANTLY ENRICHED IN LETHAL PROSTATE CANCER AND ARE ASSOCIATED WITH DISEASE SURVIVAL

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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PD20-04 GERMLINE MUTATIONS IN DNA REPAIR GENES ARE INDEPENDENT PREDICTORS OF GRADE RECLASSIFICATION IN ACTIVE SURVEILLANCE FOR PROSTATE CANCER PATIENTS

The Journal of Urology ◽

10.1016/j.juro.2018.02.1008 ◽

2018 ◽

Vol 199 (4S) ◽

Author(s):

H. Ballentine Carter ◽

Mufaddal Mamawala ◽

Tricia Landis ◽

Kathleen Wiley ◽

Isaacs William B. ◽

...

Keyword(s):

Prostate Cancer ◽

Dna Repair ◽

Cancer Patients ◽

Active Surveillance ◽

Germline Mutations ◽

Dna Repair Genes ◽

Repair Genes

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Clinical and genetic determinants of toxicity and quality-of-life (QOL) outcomes for SBRT in Asian prostate cancer.

Journal of Clinical Oncology ◽

10.1200/jco.2019.37.7_suppl.95 ◽

2019 ◽

Vol 37 (7_suppl) ◽

pp. 95-95

Author(s):

Janice Ser Huey Tan ◽

Sheena Xue Fei Tan ◽

Youquan Li ◽

Jeffrey Kit Loong Tuan ◽

Terence Wee Kiat Tan ◽

...

Keyword(s):

Quality Of Life ◽

Prostate Cancer ◽

Dna Repair ◽

Germline Mutations ◽

Dna Repair Genes ◽

Demographic Differences ◽

Patient Reported ◽

Asian Men ◽

Repair Genes

95 Background: There is limited data on clinical and patient-reported quality of life (PRO-QOL) outcomes after stereotactic body radiotherapy (SBRT) in Asian men with localised prostate cancer. Demographic differences with regard to PRO-QOL outcomes may be due to variation in germline genetics. We therefore conduct a single-institution prospective phase II trial of prostate SBRT in Asian men with intermediate-risk prostate cancers (IR-PCa). Additionally, we investigated association of dosimetric and genetic factors with outcomes. Methods: Patients with biopsy-proven NCCN-defined IR-PCa were recruited. SBRT was delivered at 36.25 Gy/5fr using a Linac-based RapidArc technique. Adverse events (AEs) were assessed with CTCAEv4.0 and IPSS; PRO-QOL assessed using the EPIC instrument at baseline, 1 and 2-year post-SBRT. Germline genetics were profiled by whole exome sequencing (30X). Results: 65 patients were recruited over the period of 2014-2016 (median follow-up = 30 mo). We observed 4 acute ≥G2 gastrointestinal (GI) events (3 fecal urgency, 1 diarrhea). Longitudinal assessment of acute genitourinary (GU) events by IPSS showed worsened symptoms that peaked at 1 wk post-SBRT (44.6% vs 6.2% at 1 mo for men reporting scale upgrade). There was no significant association between acute GU effects (by IPSS) and dosimetric parameters of the irradiated urethra and bladder. PRO-QOL scores demonstrated minimal change over time across all domains; however, sexual bother in the top 50th percentile subgroup at baseline indicated ≥20% worsening of scores for 10/32 (31%) at 12 mo and 5/12 (42%) at 24 mo; which was not associated with Dosemax to the penile bulb (P = 0.1). We observed a high frequency of germline mutations in DNA repair genes (N = 10; 15.4%), including two BRCA2 stop-gain and frameshift mutations. In particular, BRCA2 mutations were detected in 2 of 4 cases with ≥G2 GI effects, independent of rectal dose. Conclusions: While prostate SBRT is well tolerated in our Asian cohort, there appears to be demographic differences in sexual bother compared to Caucasian cohorts. Interestingly, we observed a higher than expected prevalence for germline mutations in DNA repair genes, which may predict treatment response. Clinical trial information: NCT02313298.

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Germline Mutations in DNA Repair Genes in Patients With Metastatic Castration-resistant Prostate Cancer

In Vivo ◽

10.21873/invivo.11971 ◽

2020 ◽

Vol 34 (4) ◽

pp. 1773-1778

Author(s):

KLAUDIA HOLECKOVA ◽

KATARINA BALUCHOVA ◽

MARK HIVES ◽

LUDOVIT MUSAK ◽

JAN KLIMENT ◽

...

Keyword(s):

Prostate Cancer ◽

Dna Repair ◽

Germline Mutations ◽

Dna Repair Genes ◽

Castration Resistant Prostate Cancer ◽

Castration Resistant ◽

Repair Genes

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Germline mutations in DNA repair genes in a large series of unselected Chinese prostate cancer patients.

Journal of Clinical Oncology ◽

10.1200/jco.2020.38.15_suppl.e17523 ◽

2020 ◽

Vol 38 (15_suppl) ◽

pp. e17523-e17523

Author(s):

Yu Wei ◽

Yao Zhu ◽

Junlong Wu ◽

Dingwei Ye ◽

Hao Zeng ◽

...

Keyword(s):

Prostate Cancer ◽

Dna Repair ◽

Genetic Testing ◽

Family History ◽

High Risk ◽

Cancer Patients ◽

Germline Mutations ◽

Dna Repair Genes ◽

History Of ◽

Repair Genes

e17523 Background: Germline DNA repair gene (DRG) mutations has emerged as a potential determinant of cancer risk and therapeutic response in PCa. Despite substantial advances in delineating the germline mutation in DRGs among Caucasian population, the prevalence of mutations in DRGs are largely unknown among a large series of unselected prostate cancer patients in Chinese population. Methods: We enrolled 1003 prostate cancer patients from three different hospitals in China, unselected for family history of cancer or age at diagnosis. All patients received germline genetic testing using a clinician-selected multi-gene panel. The 18 DNA repair genes and HOXB13, which has established or emerging potential clinical actionability in PCa, were analyzed in our study. Results: A total of 94 (9.7%) deleterious germline mutations were identified among the 1003 unselected prostate cancer patients. Of these, 5.6% patients carried a BRCA1 or BRCA2 mutations (5.2% in BRCA2 and 0.4% in BRCA1), 3.6% patients carried other DRG mutations (including 10 genes) and 0.5% patients carried HOXB13 mutations. Besides, variants with uncertain significance (VUS) were found in approximately 45% patients. We also divided 633 metastatic PCa patients into 542 de novo metastastic PCa and 91 recurrent metastastic PCa and found mutation frequencies did not differ between these two groups (9.0% vs 11.6%, p = 0.6). Patients with younger age of onset or family history of cancers were more likely to harbour germline mutations in DRGs. However, the rate of germline mutations were still at a high level for patients more than 70 years old (6.7%) and patients without family history of cancers (7.5%). There is no statistically significant difference in the mutation frequencies between patients with metastasis and without metastasis (7.5% vs 9.2%, p = 0.4), which may be because 85% patients without metastasis in our cohort were in high to very high risk group or have lymph node metastasis. Conclusions: To our knowledge, our study reported the largested series of Chinese PCa patients who received germline genetic testing. Our study provided a rationality for germline genetic testing criteria from high risk to metastastic PCa regardless of family history considering the high proportion. In addition, we recommended a multigene panel covering 13 genes ( ATM, BRCA1, BRCA2, CHEK2, FANCA, HOXB13, MSH2, MSH6, NBN, PALB2, RAD51C, RAD51D, TP53) in China. Nevertheless, the high prevalence of VUS (45%) in Chinese PCa patients warrant further efforts.

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Multigene panel analysis identified germline mutations of DNA repair genes in breast and ovarian cancer

Molecular Genetics & Genomic Medicine ◽

10.1002/mgg3.157 ◽

2015 ◽

Vol 3 (5) ◽

pp. 459-466 ◽

Cited By ~ 46

Author(s):

Yosuke Hirotsu ◽

Hiroshi Nakagomi ◽

Ikuko Sakamoto ◽

Kenji Amemiya ◽

Toshio Oyama ◽

...

Keyword(s):

Ovarian Cancer ◽

Dna Repair ◽

Germline Mutations ◽

Dna Repair Genes ◽

Panel Analysis ◽

Breast And Ovarian Cancer ◽

Repair Genes ◽

Multigene Panel

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

JNCI Journal of the National Cancer Institute ◽

10.1093/jnci/djaa132 ◽

2020 ◽

Cited By ~ 1

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.

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