Germline DNA Damage Research Articles

Germline DNA damage repair variants and prognosis of patients with high-risk or metastatic prostate cancer.

Deleterious germline variants in certain DNA repair genes are risk factors for developing aggressive prostate cancer. The objective was to quantify their prognostic impact after prostate cancer diagnosis. Men with prostate cancer, predominantly of European ancestry, were included from four cohorts with long-term follow-up. Pathogenic or likely pathogenic germline variants in 26 DNA repair genes were assessed in relation to metastasis-free survival in high-risk, localized prostate cancer and to overall survival in metastatic castration-sensitive prostate cancer (mCSPC) and metastatic castration-resistant prostate cancer (mCRPC). Among 3,525 patients initially diagnosed with non-metastatic prostate cancer, 2,594 had high-risk localized prostate cancer, 429 mCSPC, and 502 mCRPC at inclusion. BRCA2 variant carriers did not have worse metastasis-free survival in high-risk localized prostate cancer (hazard ratio [HR] 1.01, 95% confidence interval [CI] 0.69, 1.46) or overall survival in mCSPC (HR 0.46, 95% CI 0.14, 1.45) or mCRPC (HR 0.60, 95% CI 0.31, 1.17) compared to non-carriers of DNA repair variants. Among 868 additional patients with de novo metastatic (M1) prostate cancer, BRCA2 variant carriers tended to have worse overall survival (HR 1.59, 95% CI 1.01, 2.51). BRCA2 prognostic associations were not explained by radiation, PARP inhibitor, or platinum therapy. Results for other genes were limited in precision because variants were less common. Among patients with high-risk or metastatic prostate cancer who were initially diagnosed with and treated for non-metastatic tumors, germline DNA repair variants in BRCA2 do not confer a substantially worse prognosis.

Germline DNA Damage Repair Gene Alterations in Patients with Metachronous Breast and Colorectal Cancer.

A hereditary component of breast (BC) and colorectal cancer (CRC) has been described in approximately one-third of these tumor types. BC patients have an increased risk of developing CRC as a second primary tumor and vice versa. Germline genomic variants (NextSeq550, Illumina) were investigated in 24 unrelated BC and/or CRC patients and 7 relatives from 3 index patients. Fifty-six pathogenic or likely pathogenic variants were identified in 19 of 24 patients. We detected single-nucleotide variants (SNVs) in CRC predisposition genes (MLH1 and MUTYH) and other promising candidates (CDK5RAP3, MAD1L1, NOS3, and POLM). Eighteen patients presented SNVs or copy number variants (CNVs) in DNA damage repair genes. We also identified SNVs recently associated with BC or CRC predisposition (PABPC1, TYRO3, MAP3K1, SLC15A4, and LAMA1). The PABPC1c.1255C>T variant was detected in nine unrelated patients. Each patient presented at least one SNV/CNV in a candidate gene, and most had alterations in more than one gene, reinforcing a polygenic model for BC/CRC predisposition. A significant fraction of BC/CRC patients with a family history of these tumors harbored deleterious germline variants in DNA repair genes. Our findings can lead to strategies to improve the diagnosis, genetic counseling, and treatment of patients and their relatives.

Developmental and heritable genetic defects induced in mice by municipal landfill leachate

Environmental pollution by solid waste leachate is a serious environmental and public health concern. Leachate contamination and pollution of environmental matrices have been reported, but no report of embryotoxic and developmental defects, and heritable transfer of leachate-induced toxicity in mice. We investigated the ability of Aba-Eku landfill leachate to induce embryonic malformations, developmental toxicity, and germline and somatic DNA damage in the F1 of exposed pregnant mice. Pregnant mice (n = 100) were randomly distributed into 5 experimental groups of 20 animals/group and exposed to 0.2 mL of 5–75% concentrations of the leachate (v/v; Aba-Eku landfill leachate: distilled water) by daily gavage from gestational day (GD) zero to postnatal day (PND) 21. A similar treatment was given to pregnant female mice administered with distilled water (negative control). At GD 18, ten dams from the treatment and control groups were sacrificed by cervical dislocation after which the embryos were collected from the uterus for analyses of fetal morphometric and skeletal metamers respectively. We then monitored the developmental conditions of F1 mice from the remaining ten dams until they were weaned at PND 21 and sacrificed at PND 56 and PND 98 for bone marrow micronucleus and spermiogram analyses respectively. We also analyzed the leachate for inorganic and organic pollutants and calculated the Leachate Pollution Index (LPI). The leachate reduced maternal and fetal birth weight and increased fetal mortality and postnatal appearance of physiological markers in the F1 mice. There was a significant increase (p < 0.05) in the frequency of fetal skeletal malformations, micronucleated polychromatic erythrocytes, and apparent decline of epididymal sperm parameters. The concentrations of the inorganic and organic pollutants, and the LPI exceeded standard limits. Exposure of pregnant female mice to Aba-Eku landfill leachate caused embryonic defects and heritable DNA damage in subsequent generations.

Neoadjuvant talazoparib in patients with germline BRCA1/2 mutation-positive, early-stage triple-negative breast cancer: exploration of tumor BRCA mutational status

BackgroundTalazoparib monotherapy in patients with germline BRCA-mutated, early-stage triple-negative breast cancer (TNBC) showed activity in the neoadjuvant setting in the phase II NEOTALA study (NCT03499353). These biomarker analyses further assessed the mutational landscape of the patients enrolled in the NEOTALA study.MethodsBaseline tumor tissue from the NEOTALA study was tested retrospectively using FoundationOne®CDx. To further hypothesis-driven correlative analyses, agnostic heat-map visualizations of the FoundationOne®CDx tumor dataset were used to assess overall mutational landscape and identify additional candidate predictive biomarkers of response.ResultsAll patients enrolled (N = 61) had TNBC. In the biomarker analysis population, 75.0% (39/52) and 25.0% (13/52) of patients exhibited BRCA1 and BRCA2 mutations, respectively. Strong concordance (97.8%) was observed between tumor BRCA and germline BRCA mutations, and 90.5% (38/42) of patients with tumor BRCA mutations evaluable for somatic-germline-zygosity were predicted to exhibit BRCA loss of heterozygosity (LOH). No patients had non-BRCA germline DNA damage response (DDR) gene variants with known/likely pathogenicity, based on a panel of 14 non-BRCA DDR genes. Ninety-eight percent of patients had TP53 mutations. Genomic LOH, assessed continuously or categorically, was not associated with response.ConclusionThe results from this exploratory biomarker analysis support the central role of BRCA and TP53 mutations in tumor pathobiology. Furthermore, these data support assessing germline BRCA mutational status for molecular eligibility for talazoparib in patients with TNBC.

Neoadjuvant therapy in patients with pancreatic ductal adenocarcinoma (PDAC) with germline DNA damage repair (DDR) mutations: A dual institution retrospective study.

Neoadjuvant therapy in patients with pancreatic ductal adenocarcinoma (PDAC) with germline DNA damage repair (DDR) mutations: A dual institution retrospective study.

Characteristics of germline DNA damage response gene mutations in ovarian cancer in Southwest China

DNA damage response (DDR) pathways are responsible for repairing endogenous or exogenous DNA damage to maintain the stability of the cellular genome, including homologous recombination repair (HRR) pathway, mismatch repair (MMR) pathway, etc. In ovarian cancer, current studies are focused on HRR genes, especially BRCA1/2, and the results show regional and population differences. To characterize germline mutations in DDR genes in ovarian cancer in Southwest China, 432 unselected ovarian cancer patients underwent multi-gene panel testing from October 2016 to October 2020. Overall, deleterious germline mutations in DDR genes were detected in 346 patients (80.1%), and in BRCA1/2 were detected in 126 patients (29.2%). The prevalence of deleterious germline mutations in BRCA2 is higher than in other studies (patients are mainly from Eastern China), and so is the mismatch repair genes. We identified three novel BRCA1/2 mutations, two of which probably deleterious (BRCA1 p.K1622* and BRCA2 p.L2987P). Furthermore, we pointed out that deleterious mutations of FNACD2 and RECQL4 are potential ovarian cancer susceptibility genes and may predispose carriers to ovarian cancer. In conclusion, our study highlights the necessity of comprehensive germline mutation detection of DNA damage response genes in ovarian cancer patients, which is conducive to patient management and genetic counseling.

Germline DNA damage response gene mutations as predictive biomarkers of immune checkpoint inhibitor efficacy.

Impaired DNA damage response (DDR) can affect immune checkpoint inhibitors (ICI) efficacy and lead to heightened immune activation. We assessed the impact of pathogenic or likely pathogenic (P/LP) germline DDR mutations on ICI response and toxicity. A retrospective analysis of 131 cancer patients with germline DNA testing and ICI treatment was performed. Ninety-two patients were DDR-negative (DDR-), and 39 had ≥1 DDR mutation (DDR+). DDR+ patients showed higher objective response rates (ORRs) compared to DDR- in univariate and multivariable analyses, adjusting for age and metastatic disease (62% vs. 23%, unadjusted OR = 5.41; 95% CI, 2.41-12.14; adjusted OR 5.94; 95% CI, 2.35-15.06). Similar results were seen in mismatch repair (MMR), DDR pathways with intact MMR (DDR+MMRi), and homologous recombination (HR) subgroups versus DDR- (adjusted OR MMR = 24.52; 95% CI 2.72-221.38, DDR+MMRi = 4.26; 95% CI, 1.57-11.59, HR = 4.74; 95% CI, 1.49-15.11). DDR+ patients also had higher ORRs with concurrent chemotherapy (82% vs. 39% DDR-, p=0.03) or concurrent tyrosine kinase inhibitors (50% vs. 5% DDR-, p=0.03). No significant differences in immune-related adverse events were observed between DDR+ and DDR- cohorts. P/LP germline DDR mutations may enhance ICI response without significant additional toxicity.

Germline DNA Damage Response Gene Mutations in Localized Prostate Cancer.

Background and Objectives: Germline DNA damage response (DDR) gene mutations correlate with increased prostate cancer (PCa) risk and a more aggressive form of the disease. DDR mutation testing is recommended for metastatic PCa cases, while eligible information about the mutations' burden in the early-stage localized PCa is still limited. This study is aimed at the prospective detection of DDR pathway mutations in cases with localized PCa and correlation with clinical, histopathological, and radiological data. A comparison to the previously assessed cohort of the advanced PCa was performed. Materials and Methods: Germline DDR gene mutations were assessed prospectively in DNA samples from 139 patients, using a five-gene panel (BRCA1, BRCA2, ATM, CHEK2, and NBN) targeted next-generation sequencing. Results: This study revealed an almost three-fold higher risk of localized PCa among mutation carriers as compared to non-carriers (OR 2.84 and 95% CI: 0.75-20.23, p = 0.16). The prevalence of germline DDR gene mutations in PCa cases was 16.8% (18/107) and they were detected only in cases with PI-RADS 4/5 lesions. BRCA1/BRCA2/ATM mutation carriers were 2.6 times more likely to have a higher (>1) cISUP grade group compared to those with a CHEK2 mutation (p = 0.27). However, the number of cISUP > 1-grade patients with a CHEK2 mutation was significantly higher in advanced PCa than in localized PCa: 66.67% vs. 23.08% (p = 0.047). Conclusions: The results of our study suggest the potential of genetic screening for selected DDR gene mutations for early identification of cases at risk of aggressive PCa.

Abstract P5-12-06: Comprehensive analysis of DNA damage repair gene germline mutations in Chinese breast cancer patients

Abstract Background: Germline DNA damage repair (DDR) mutations has been associated with increased cancer risk, PARP inhibitor therapeutic opportunity for breast cancer (BC) patients. However, the profile of germline mutations in BC covering comprehensive DDR genes remains unclear. Methods: A total of 341 women with breast cancer who tested 102 germline related genes (including 50 DDR genes) between April 2021 to May 2022 in Guangdong Provincial People’s Hospital were identified. Variants were classified into pathogenic, likely pathogenic, variant of uncertain significance (VUS), likely benign and benign groups according to the ACMG/AMP Standards and Guidelines. We defined pathogenic and likely pathogenic variants as deleterious mutations. Results: The median age of 341 breast cancer patients was 48 (range, 20-89) at the first diagnosis of BC. A total of 47 patients (13.78%) carried 53 deleterious germline variants in 21 cancer predisposition genes, 16 of which were DDR genes. DDR deleterious mutations were detected in genes including BRCA2 (n=18), BRCA1(n=7), FANCA (n=4), PMS2 (n=4), PALB2(n=2), RECQL4(n=2), PALB2 (n=2), etc. The younger age at diagnosis (less than 40-year-old) were significantly associated with deleterious mutations in DDR pathway(P=0.02). At least one VUS was identified in 238 (69.79%) patients. The top 5 DDR VUS genes were FANCM (n=21), ATM (n=20), RAD54L (n=17), FANCD2 (n=15) and ATR (n=14). Breast or ovarian cancer family history were significantly correlated with VUS germline mutations in DDR pathway(P=0.039). Interesting, we found that patients with pCR efficacy of neoadjuvant therapy were more likely to have VUS mutations in DDR pathway (table 1). Conclusion: We provided a comprehensive view of germline DDR gene mutations in BC patients and also analyzed the association between clinical characteristics and germline DDR mutation status. DDR mutations are prevalent in Chinese BC patients. Patients with younger and breast or ovarian cancer family history were more likely to carry DDR alterations. Moreover, patients with higher frequency of DDR VUS mutations may benefit from neoadjuvant therapy. Table 1. Clinicopathological characteristics between germline mutation carriers and non-carriers Citation Format: Ning Liao, Li Cao, Guochun Zhang, Junyun Wang, Airong Yang, Yulei Wang, Kai Li, Lingzhu Wen, Chongyang Ren, Minghan Jia, Cheukfai Li, Hsiaopei Mok, Bo Chen, Jianguo Lai, Weikai Xiao. Comprehensive analysis of DNA damage repair gene germline mutations in Chinese breast cancer patients [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P5-12-06.

PROMISE Registry: A prostate cancer registry of outcomes and germline mutations for improved survival and treatment effectiveness.

TPS274 Background: Recent updates to genetic testing recommendations and approved treatment options for prostate cancer (PCa) patients (pts) have clarified the need for comprehensive genetic registries. Germline DNA damage repair (DDR) defects are present in over 10% of pts who develop metastatic castration-resistant prostate cancer (mCRPC) while 5-10% pts with localized PCa have germline pathogenic variants in DDR genes. NCCN guidelines have recently expanded to address genetic testing to include high risk localized, node positive and metastatic disease, in addition to family cancer history criteria. In May 2020, the FDA approved 2 PARP inhibitors for mCRPC treatment. Genetic registries can address the critical need to identify pts for recently approved targeted treatments, understand real-world effects of targeted therapies, and expand clinical trials examining less common mutations. PROMISE is a prospective genetic registry equipped to meet these needs. Methods: 5000 PCa pts will be screened via the online study portal and at-home germline testing to identify and enroll 500 eligible pts with germline pathogenic variants, likely pathogenic variants, and variants of uncertain significance (VUS) in the genes of interest: ATM, ATR, BARD1, BRCA1, BRCA2, BRIP1, CHEK2, FAM175A, GEN1, HOXB13, MRE11A, MLH1, MSH2, MSH6, PALB2, PMS2, PTEN, RAD51C, RAD51D, TP53 and XRCC2. Additional genes may be added as evidence emerges. Eligible pts must be assigned male at birth and have documented PCa through tissue biopsy, and/or PSA &gt;100ng/dL, and/or radiographic evidence of disease. Pts with or without prior genetic testing, including those with known pathogenic variants, are encouraged to enroll. Exclusion criteria are: inability or unwillingness to provide information for eligibility and incomplete inclusion criteria. Following germline testing, pts will be offered genetic counseling and periodic newsletters with updates on treatments and clinical trials. Every 6 months, eligible pts will complete a patient-reported outcome (PRO) survey (EORTC QLQ-C30) and updated medical records will be obtained for clinical data abstraction. Eligible pts will enter long-term follow-up. The primary endpoint is the creation of a prospective genetic registry of PCa pts. Additional endpoints include: frequency of pathogenic or likely pathogenic germline variants of interest, recruitment of a control group with a VUS in the genes of interest, association between disease characteristics and germline testing results, comparison of PROs between disease subpopulations, longitudinal outcomes, and overall survival. Study duration is 20 years (recruitment: 5 years, follow-up: 15 years). PROMISE is recruiting at 23 US sites. 1829 subjects have enrolled in the screening phase with 189 eligible for long-term follow-up. PROMISE is sponsored and managed by the Prostate Cancer Clinical Trials Consortium. Clinical trial information: NCT04995198 .

Germline DNA damage response (DDR) mutations in an East Asian (EA) cohort with prostate cancer (PCa).

373 Background: Aberrations of the DDR pathway have been shown to be prognostic of survival and predictive of PARP inhibition in PCa. Additionally, germline mutations in DDR genes are linked to PCa susceptibility. Here, we report the germline DDR mutation frequencies in an EA PCa cohort, and their associations with clinicopathological indices and outcomes. Methods: We utilized a prospectively recruited cohort of 891 EA patients, with centrally assessed Gleason’s score (GS) by an expert pathologist. Germline mutation profiling was performed by whole exome sequencing (100X) using the Illumina Novaseq (CA). Following joint genotyping, common variants of ≥1% were filtered, and only variants defined as pathogenic (P)/likely pathogenic (LP) in ClinVar or predicted to be P by CADD or REVEL were retained. We used a 32 DDR gene-set for tests of association with clinicopathological indices, biochemical relapse-free rate (bRFR), and distant metastasis-free survival (DMFS). Results: Median follow up was 54 (33-83) mo; median age at diagnosis was 70 (64-74) y. 741 (84%) men had localized PCa, 65 (7%) had N+M0, and 80 (9%) had M1 disease. Among those with localized PCa, 417 (56%) were stratified as NCCN high/very high. 5-year DMFS was 100%, 96%, 86%, and 74% for NCCN low, intermediate, high/very high, and N+M0 PCa, respectively. 31 (3.5%) men in our cohort harbored a P/LP variant in at least one of the 32 DDR genes; P/LP variants were most frequently observed for BRCA2 (N=11[1.2%]), ATM (N=6[0.7%]), and RAD50 (N=5[0.6%]). P/LP variants were more frequent in men with N+M0/M1 compared with those with localized PCa (29% vs 16%, P=0.05), and in men with GS 9-10 vs 6-8 tumors (43% vs 20%, P=0.002). Presence of P/LP DDR variants were significantly associated with bRFR (HR 2.44 [95% CI:1.0-6.1], P=0.049) in M0 patients treated with RT+/-hormonal therapy on univariable and multivariable analyses. Conclusions: Herein, we observed lower frequencies of germline DDR P/LP mutations in our EA PCa cohort than other published Chinese cohorts (Wei, et al. 2018; Wei, et al. 2020). Nonetheless, there was a strong trend for increased incidence of DDR mutations with more advanced PCa. Men with DDR mutations were more likely to fail treatment than men without. [Table: see text]

Paeoniflorin attenuates polystyrene nanoparticle-induced reduction in reproductive capacity and increase in germline apoptosis through suppressing DNA damage checkpoints in Caenorhabditis elegans

Due to high sensitivity to environmental exposures, Caenorhabditis elegans is helpful for toxicity evaluation and toxicological study of pollutants. Using this animal model, we investigated the reproductive toxicity of 20 nm polystyrene nanoparticle (PS-NP) in the range of μg/L and the following pharmacological intervention of paeoniflorin. After exposure from L1-larvae to young adults, 10–100 μg/L PS-NP could cause the reduction in reproductive capacity reflected by the endpoints of brood size and number of fertilized eggs in uterus. Meanwhile, the enhancements in germline apoptosis analyzed by AO staining and germline DNA damage as shown by alteration in HUS-1::GFP signals were detected in 10–100 μg/L PS-NP exposed nematodes, suggesting the role of DNA damage-induced germline apoptosis in mediating PS-NP toxicity on reproductive capacity. Following the exposure to 100 μg/L PS-NP, posttreatment with 25–100 mg/L paeoniflorin increased the reproductive capacity and inhibited both germline apoptosis and DNA damage. In addition, in 100 μg/L PS-NP exposed nematodes, treatment with 100 mg/L paeoniflorin modulated the expressions of genes governing germline apoptosis as indicated by the decrease in ced-3, ced-4, an egl-1 expressions and the increase in ced-9 expression. After exposure to 100 μg/L PS-NP, treatment with 100 mg/L paeoniflorin also decreased expressions of genes (cep-1, clk-2, hus-1, and mrt-2) governing germline DNA damage. Molecular docking analysis further demonstrated the binding potential of paeoniflorin with three DNA damage checkpoints (CLK-2, HUS-1, and MRT-2). Therefore, our data suggested the toxicity of PS-NP in the range of μg/L on reproductive capacity after exposure from L1-larvae to young adults, which was associated with the enhancement in DNA damage-induced germline apoptosis. More importantly, the PS-NP-induced reproductive toxicity on nematodes could be inhibited by the following paeoniflorin treatment.

Pathway-level mutation analysis in primary high-grade serous ovarian cancer and matched brain metastases

Brain metastases (BMs) in ovarian cancer (OC) are a rare event. BMs occur most frequently in high-grade serous (HGS) OC. The molecular features of BMs in HGSOC are poorly understood. We performed a whole-exome sequencing analysis of ten matched pairs of formalin-fixed paraffin-embedded samples from primary HGSOC and corresponding BMs. Enrichment significance (p value; false discovery rate) was computed using the Reactome, the Kyoto Encyclopedia of Genes and Genomes pathway collections, and the Gene Ontology Biological Processes. Germline DNA damage repair variants were found in seven cases (70%) and involved the BRCA1, BRCA2, ATM, RAD50, ERCC4, RPA1, MLHI, and ATR genes. Somatic mutations of TP53 were found in nine cases (90%) and were the only stable mutations between the primary tumor and BMs. Disturbed pathways in BMs versus primary HGSOC constituted a complex network and included the cell cycle, the degradation of the extracellular matrix, cell junction organization, nucleotide metabolism, lipid metabolism, the immune system, G-protein-coupled receptors, intracellular vesicular transport, and reaction to chemical stimuli (Golgi vesicle transport and olfactory signaling). Pathway analysis approaches allow for a more intuitive interpretation of the data as compared to considering single-gene aberrations and provide an opportunity to identify clinically informative alterations in HGSOC BM.

Rates of germline genetic testing and DNA damage response mutations found through population-based recruitment of men with incident metastatic prostate cancer.

10501 Background: Approximately 10% of men with metastatic prostate cancer (mPC) have germline DNA damage response gene mutations (gDDRm), indicating candidacy for precision treatment. Consequently, national guidelines recommend germline genetic testing be offered to all men with mPC. It is currently unclear what the rates of testing are in the community, and barriers to testing are not well understood. We conducted a population-based study to better understand current rates of germline genetic testing in men with newly diagnosed mPC, and to determine whether removing major barriers of cost and access could expand uptake of germline genetic testing. Methods: This is a prospective observational study that identifies men ages 35-79y with mPC residing in a 13-county area of Washington State through the Surveillance, Epidemiology, and End Results (SEER) program (NCT04254133). Men with new diagnoses of mPC are contacted by mailed invitation and follow-up phone inquiry. Interested men are then invited to provide informed consent and complete a questionnaire about personal and family health history. A saliva collection kit for a 30-gene targeted panel of cancer predisposition genes (Color Genomics) is mailed to participants’ homes free of charge. Results are issued by phone and/or email with genetic counseling support, including discussion about cascade genetic testing if relevant. Results: As of Feb 9, 2022, 484 men with incident mPC diagnosed 1/2018-6/2021 were identified through SEER. 430 men were reached via a letter to their home address sent &gt; 3 months after diagnosis. 175 of 430 (40.6%) men expressed interest and completed the questionnaire, the majority preferring to complete testing through mail after a phone-initiated introduction to the study. 164 of 175 men completed the consent process and were eligible. Of these 164 men, 45 (27.4%) reported prior genetic testing, and reports were requested and reviewed to ensure adequate testing. Ultimately, 121 of 164 (73.8%) participants initiated and 101/121 (83.5%) have completed genetic testing through the study. Nine percent (9/101) of participants completing testing as part of the study were found to have gDDRm. Conclusions: We used a population-based approach to understand the proportion of men with mPC undergoing germline genetic testing through clinical care, and the subsequent uptake of genetic testing when access and cost barriers are removed. The uptake of guideline-based germline genetic testing among men with mPC in the community prior to study enrollment is only 27.4%. With study interventions in the form of free testing through mail, and phone-based support, 83.5% of men in this community successfully completed testing. Further work in this study will aim to elucidate and attempt to eliminate other barriers in germline genetic testing to further improve testing rates in this community.

Characteristics of germline DNA damage response gene mutations in ovarian cancer in Southwest China.

e17606 Background: DNA damage response (DDR) pathway is responsible for repairing endogenous or exogenous DNA damage to maintain the stability of the cell genome. Germline mutations of DDR genes are potentially predictive and prognostic biomarkers for oncotherapy and may predispose carries to some malignancies. We aimed to profile the characteristics of germline DDR gene mutations in ovarian cancer treated in our center to provide highlight on regional disparity and susceptibility genes. Methods: We retrospectively and unselectively enrolled a cohort of patients diagnosed as advanced epithelial ovarian cancer from October 2016 to October 2020, who had complete clinicopathological data and signed informed consent for gene testing. In total, peripheral blood samples from 432 patients were collected in our center and evaluated on specific germline alterations. This study was approved by the Medical Ethics Committee of West China Second University Hospital, Sichuan University (Ethical Lot Number 20200076). Results: The most observed mutated genes were FANCD2 (47%), BRCA1 (27%), BRCA2 (27%), ERCC5 (18%) and RECQL4 (17%). The frequency of missense mutation was higher than other mutation types in most genes, except FANCD2, TSC2 and PHOX2B. Deleterious DDR gene mutations and deleterious homologous recombination repair gene mutations were detected in 346 patients (80.1%) and 240 patients (55.6%), respectively. The most observed genes with deleterious mutation were BRCA1 (18.5%), BRCA2 (12.5%), ERCC5 (6%), MLH1 (5.8%), PALB2 (3.7%) and ERCC4 (3.7%). The prevalence of BRCA2 deleterious mutations is higher than other studies (patients mainly from Eastern China), and so are the mismatch repair genes. Furthermore, we pointed out that deleterious mutations of FNACD2 and RECQL4 are potential ovarian cancer susceptibility genes and may predispose carriers to ovarian cancer. Conclusions: Our study presented here showed the germline DDR gene mutation spectrum of ovarian cancer patients in Southwest China, which is different from other regions of China in some genes. And we found germline FANCD2 and RECQL4 deleterious mutations were likely ovarian cancer susceptibility sites, which should draw more attention in patient management and genetic counseling.

PARP Inhibition, a New Therapeutic Avenue in Patients with Prostate Cancer.

Up to 25% of patients with metastatic prostate cancer present with germline or somatic DNA damage repair alterations, some of which are associated with aggressive disease and poor outcomes. New data have brought poly(ADP-ribose) polymerase (PARP) inhibitors into sharp focus in the treatment of metastatic castrate-resistant prostate cancer (mCRPC). Olaparib improved survival after at least one new hormonal therapy (NHT) in a cohort of patients harboring BRCA1, BRCA2 or ATM mutations in the PROfound trial, while rucaparib, talazoparib and niraparib demonstrated compelling activity in phase II trials. While patients with prostate cancer and BRCA1 or BRCA2 mutations may derive greatest benefit of PARP inhibition, the magnitude of benefit seems much lower in the context of most other homologous recombination gene mutations. Several PARP inhibitors are currently developed in combination with conventional therapy, including chemotherapy, NHT, and alpha-particle emitters, at different disease stages. Herein, we review the rationale for PARP inhibition in patients with prostate cancer, discuss the impact of PARP inhibitors on outcomes, and explore underlying challenges for future developments.

Evolving real-world patterns of practice in metastatic castration-sensitive prostate cancer (mCSPC): The genitourinary research consortium (GURC) national multicenter cohort study.

86 Background: Treatment options for patients with mCSPC have rapidly evolved with the introduction of androgen receptor axis targeted therapies (ARATs) and chemotherapy. The GURC cohort study is a phase 4, multicentre, non-interventional, longitudinal cohort study of Canadian men with advanced prostate cancer. We prospectively examined the evolving real world management and treatment patterns of patients with mCSPC, with a focus on treatment intensification beyond ADT and germline DNA damage repair (DDR) testing. Methods: Clinical management patterns, baseline patient characteristics, germline DDR alteration status, treatment intensification with ARATs (abiraterone acetate [AA], apalutamide [Apa], enzalutamide [Enza]) and chemotherapy within the mCSPC cohort were analyzed. Results: 204 patients with mCSPC were enrolled from 2018 to 2021 across 25 Canadian sites. The median age was 71 (range 64 - 77), median PSA at study entry was 24, 88% (158/180) of patients had de novo mCSPC, 69% (110/204) of patients had a Gleason Score &gt; 7, and 4% (2/49) of the patients who received a germline testing harbored a germline DDR alteration (BRCA2 = 1, MUTYH/MEN1 = 1). The distribution of high and low volume mCSPC at study entry was 62% (118/189) and 37% (71/189), respectively. Overall, patients received ADT alone 27% (51/189), AA 45% (86/189), apalutamide 17% (33/189), docetaxel 8% (15/189), and enzalutamide 3% (6/189). Treatment intensification with ARATs/docetaxel was administered to 69% [141/189]) of patients. Patients treated with ADT alone had a significantly lower volume of disease at treatment initiation (low volume rates of 49% [24/49] in ADT alone vs 33% [47/143] in treatment intensified patients, p = 0.044). Among those receiving treatment intensification with ARATs/docetaxel, time to intensification was ≤ 3 months in 78.5 % (113/144). Conclusions: This cohort study demonstrates that patients with mCSPC continue to receive ADT alone and docetaxel over time, despite an ever-increasing list of accessible ARATs. Patients receiving ADT alone appear to have lower volume of disease. Germline DDR testing is not yet comprehensively performed. This underlines the real world need to provide greater education and resources to encourage ARAT treatment and genetic testing in this setting.

PROMISE Registry: A prostate cancer registry of outcomes and germline mutations for improved survival and treatment effectiveness.

TPS191 Background: Recent updates to genetic testing recommendations and approved treatment options for prostate cancer (PCa) patients (pts) have clarified the need for comprehensive genetic registries. Germline DNA damage repair (DDR) defects are present in over 10% of pts who develop metastatic castration-resistant prostate cancer (mCRPC) while 5-10% of pts with localized PCa have germline pathogenic variants in DDR genes. NCCN guidelines have recently expanded to address genetic testing to include high risk localized, node positive and metastatic disease, in addition to family cancer history criteria. In May 2020, the FDA approved 2 PARP inhibitors for mCRPC treatment. Genetic registries can address the critical need to identify pts for recently approved targeted treatments, understand real-world effects of targeted therapies, and expand clinical trials examining less common mutations. PROMISE is a prospective genetic registry equipped to meet these needs. Methods: 5,000 PCa pts will be screened via the online study portal and at-home germline testing to identify and enroll 500 eligible pts with germline pathogenic variants, likely pathogenic variants, and variants of uncertain significance (VUS) in the genes of interest: ATM, ATR, BRCA1, BRCA2, BRIP1, CHEK2, FAM175A, GEN1, HOXB13, MRE11A, MLH1, MSH2, MSH6, NBN, PALB2, PMS2, PTEN, RAD51C, RAD51D, TP53 and XRCC2. Additional genes may be added as evidence emerges. Eligible pts must be assigned male at birth and have documented PCa through tissue biopsy, and/or PSA &gt;100ng/dL, and/or radiographic evidence of disease. Pts with or without prior genetic testing, including those with known pathogenic variants, are encouraged to enroll. Exclusion criteria are: inability or unwillingness to provide information for eligibility and incomplete inclusion criteria. Following germline testing, all pts will be offered genetic counseling and periodic newsletters with updates on treatments and clinical trials. Every 6 months, eligible pts will complete a patient-reported outcome (PRO) survey (EORTC QLQ-C30) and updated medical records will be obtained for clinical data abstraction. Eligible pts will enter long-term follow-up. The primary endpoint is the creation of a prospective genetic registry of PCa pts. Additional endpoints include: frequency of pathogenic or likely pathogenic germline variants of interest, recruitment of a control group with a VUS in the genes of interest, association between disease characteristics and germline testing results, comparison of PROs between disease subpopulations, longitudinal outcomes, and overall survival. Study duration will be 20 years (active recruitment: 5 years, follow-up: 15 years). PROMISE is recruiting at 10 US sites and has 282 subjects enrolled in the screening phase to date. PROMISE is sponsored and managed by the Prostate Cancer Clinical Trials Consortium. Clinical trial information: NCT04995198.

Self-DNA Exposure Induces Developmental Defects and Germline DNA Damage Response in Caenorhabditis elegans.

Simple SummaryAll organisms, from bacteria to mammals, activate responses protecting themselves from dangers represented by outsider invaders and damages. Inappropriately localised self-DNA is one of the molecular clues detected as a danger and triggering defence reactions that may lead to chronic activation of inflammatory conditions. In this study, we investigate if dietary delivered self-DNA is detrimental in a simple metazoan model organism, the nematode Caenorhabditis elegans. Adverse effects were observed in the progenies of worms exposed to self-DNA integrated into their bacterial diet. The presence of self-DNA in the food significantly decreased egg deposition, induced high embryo death, and negatively affected larval development. The findings, on the one side, raise interesting questions on the basic molecular mechanisms involved in response to extracellular self-DNA. On the other side, the observed phenomenon suggests possible applications for the biocontrol of parasitic nematodes by appropriate delivery of their self-DNA in their growing environment.All organisms, from bacteria to mammals, sense and respond to foreign nucleic acids to fight infections in order to survive and preserve genome integrity across generations. The innate immune system is an evolutionarily conserved defence strategy. Complex organisms have developed various cellular processes to respond to and recognise not only infections, i.e., pathogen-associated molecular patterns (PAMPs), but also to sense injury and tissue dysfunctions, i.e., damage-associated molecular patterns (DAMPs). Mis-localized self-DNA can be sensed as DAMP by specific DNA-sensing pathways, and self-DNA chronic exposure can be detrimental to the organisms. Here, we investigate the effects of dietary delivered self-DNA in the nematode Caenorhabditis elegans. The hermaphrodite worms were fed on Escherichia coli genomic libraries: a C. elegans library (self) and a legume (Medicago truncatula) library (non-self). We show that the self-library diet affects embryogenesis, larval development and gametogenesis. DNA damage and activation of p53/CEP-1-dependent apoptosis occur in gonadal germ cells. Studies of self-DNA exposure in this model organism were not pursued up to now. The genetic tractability of C. elegans will help to identify the basic molecular pathways involved in such mechanisms. The specificity of the adverse effects associated with a self-DNA enriched diet suggests applications in biological pest control approaches.

Efficacy of neoadjuvant docetaxel + cisplatin chemo-hormonal therapy versus docetaxel chemo-hormonal therapy in patients with locally advanced prostate cancer with germline DNA damage repair gene alterations

Purpose:To assess the efficacy and safety of neoadjuvant docetaxel + cisplatin chemotherapy with androgen deprivation therapy for the treatment of locally advanced prostate cancer (PCa) in patients harboring germline DNA damage repair genes (gDDR) defects.Methods:We conducted a prospective observational study in patients with locally advanced PCa confirmed with gDDR defects through next-generation sequencing. All patients received either docetaxel + cisplatin (platinum-group) or docetaxel chemo-hormonal therapy (docetaxel group) followed by radical prostatectomy with extended lymphadenectomy. The primary end point was biochemical progression-free survival (bPFS) and secondary end points include postoperative pathological response and safety assessment during the study period.Results:A total of 36 patients were included in the study, among whom 14 and 22 patients received docetaxel + cisplatin and docetaxel treatment, respectively. Down-staging of Tumor (T), Nodes (N), and Metastasis (M) stages was observed in 11 (78.57%) and 9 (40.9%) patients (p = 0.041), respectively, in the docetaxel + cisplatin group and docetaxel group. The median bPFS was 7.76 months (95% CI 0.770–14.748) and not reached in the docetaxel group and docetaxel + cisplatin group, respectively. bPFS was significantly longer in the docetaxel + cisplatin group (p = 0.039) with a hazard ratio of 0.386 (95% CI 0.151–0.987, p < 0.05). Furthermore, one patient discontinued docetaxel + cisplatin after second cycle due to severe liver insufficiency which was confirmed as viral hepatitis A and no significant perioperative complications was observed in either group.Conclusion:This study suggests that cisplatin may increase docetaxel anticancer activity with tolerable safety profile in patients with locally advanced PCa carrying gDDR defects in the neoadjuvant setting, a hypothesis which will require prospective, randomized confirmation.