Genomic characteristics of deleterious BRCA1 and BRCA2 alterations and associations with baseline clinical factors in patients with metastatic castration-resistant prostate cancer (mCRPC) enrolled in TRITON2.

5031 Background: The phase 2 TRITON2 study (NCT02952534) is evaluating the PARP inhibitor rucaparib in patients with mCRPC who have a deleterious germline or somatic alteration in BRCA ( BRCA1 or BRCA2) or 1 of 13 other DNA damage repair genes. Here we present analyses of tumor genomics and baseline clinical characteristics in mCRPC patients with a deleterious alteration in BRCA. Methods: Plasma (baseline) and tissue (archival or baseline) samples from patients with a deleterious alteration in BRCA were analyzed using Foundation Medicine next-generation sequencing assays. The alterations and zygosity of the alterations that were detected, as well as the somatic/germline status from Color Genomics testing, were summarized. Associations between genomic alterations, DNA yield, allele frequency, and baseline clinical characteristics were investigated. Results: Results are shown in the Table for a cohort of 40 BRCA2 and 5 BRCA1 patients enrolled in TRITON2 (Abida W et al. Presented at ESMO 2018. Abst 793PD). A biallelic alteration was observed in 21 of the 22 BRCA2 patients (95%) for whom alteration zygosity could be determined. Among the 5 BRCA1 patients, 1 alteration was monoallelic and 4 were of unknown zygosity. Co-occurring alterations in cancer-related or DNA damage repair genes were observed in many patients with BRCA alterations. At baseline, cell-free DNA (cfDNA) yield correlated positively with the sum of target lesions (STL; P= 0.04), but not with prostate-specific antigen (PSA) levels ( P= 0.86). No correlation was observed between allele frequency of the BRCA alteration baseline STL ( P= 0.68) or PSA levels ( P= 0.97). Conclusions: Patients with a BRCA mutation enrolled in TRITON2 demonstrate a profile of genomic alterations consistent with that of prior studies of patients with mCRPC. Plasma cfDNA profiling showed a correlation between baseline cfDNA yield and measurable tumor burden, but not baseline PSA. Clinical trial information: NCT02952534. [Table: see text]

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Antitumor Activity of a Novel Tyrosine Kinase Inhibitor AIU2001 Due to Abrogation of the DNA Damage Repair in Non-Small Cell Lung Cancer Cells

International Journal of Molecular Sciences ◽

10.3390/ijms20194728 ◽

2019 ◽

Vol 20 (19) ◽

pp. 4728 ◽

Cited By ~ 2

Author(s):

Hwani Ryu ◽

Hyun-Kyung Choi ◽

Hyo Jeong Kim ◽

Ah-Young Kim ◽

Jie-Young Song ◽

...

Keyword(s):

Lung Cancer ◽

Dna Damage ◽

Tyrosine Kinase ◽

Small Molecule ◽

Parp Inhibitor ◽

Dna Damage Repair ◽

Class Iii ◽

Damage Repair ◽

Repair Genes

Class III receptor tyrosine kinase (RTK) inhibitors targeting mainly FLT3 or c-KIT have not been well studied in lung cancer. To identify a small molecule potentially targeting class III RTK, we synthesized novel small molecule compounds and identified 5-(4-bromophenyl)-N-(naphthalen-1-yl) oxazol-2-amine (AIU2001) as a novel class III RKT inhibitor. In an in vitro kinase profiling assay, AIU2001 inhibited the activities of FLT3, mutated FLT3, FLT4, and c-KIT of class III RTK, and the proliferation of NSCLC cells in vitro and in vivo. AIU2001 induced DNA damage, reactive oxygen species (ROS) generation, and cell cycle arrest in the G2/M phase. Furthermore, AIU2001 suppressed the DNA damage repair genes, resulting in the ‘BRCAness’/‘DNA-PKness’ phenotype. The mRNA expression level of STAT5 was downregulated by AIU2001 treatment and knockdown of STAT5 inhibited the DNA repair genes. Our results show that compared to either drug alone, the combination of AIU2001 with a poly (ADP-ribose) polymerase (PARP) inhibitor olaparib or irradiation showed synergistic efficacy in H1299 and A549 cells. Hence, our findings demonstrate that AIU2001 is a candidate therapeutic agent for NSCLC and combination therapies with AIU2001 and a PARP inhibitor or radiotherapy may be used to increase the therapeutic efficacy of AIU2001 due to inhibition of DNA damage repair.

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Use of Circulating Tumor DNA for the Clinical Management of Metastatic Castration-Resistant Prostate Cancer: A Multicenter, Real-World Study

Journal of the National Comprehensive Cancer Network ◽

10.6004/jnccn.2020.7663 ◽

2021 ◽

Vol 19 (8) ◽

pp. 905-914

Author(s):

Baijun Dong ◽

Liancheng Fan ◽

Bin Yang ◽

Wei Chen ◽

Yonghong Li ◽

...

Keyword(s):

Prostate Cancer ◽

Dna Damage ◽

Cox Regression ◽

Dna Damage Repair ◽

Chinese Patients ◽

Castration Resistant Prostate Cancer ◽

Genomic Alterations ◽

Castration Resistant ◽

Damage Repair ◽

Repair Genes

Background: This study aimed to describe the aberrations of DNA damage repair genes and other important driving genes in Chinese patients with metastatic castration-resistant prostate cancer (mCRPC) using circulating tumor (ctDNA) sequencing and to evaluate the associations between the clinical outcomes of multiple therapies and key genomic alterations in mCRPC, especially DNA damage repair genes. Patients and Methods: A total of 292 Chinese patients with mCRPC enrolled from 8 centers. Multigene targeted sequencing was performed on 306 ctDNA samples and 23 matched tumor biopsies. The frequency of genomic alterations were compared with the Stand Up to Cancer–Prostate Cancer Foundation (SU2C-PCF) cohort. The Kaplan-Meier method was used to evaluate progression-free survival (PFS) following standard systemic treatments for mCRPC. Cox regression analyses were performed to determine prognostic factors associated with PFS resulting from treatments for mCRPC. Results: In total, 33 of 36 (91.7%) mutations were found consistently between ctDNA and paired biopsy samples. The most common recurrent genomic alterations were found in AR (34.6%), TP53 (19.5%), CDK12 (15.4%), BRCA2 (13%), and RB1 (5.8%). The frequency of CDK12 alterations (15.4%) in our cohort was significantly higher than that in Western populations (5%–7%). AR amplification and TP53 and/or RB1 alterations were associated with resistance to abiraterone or docetaxel. Patients with a CDK12 defect showed rapid disease progression after abiraterone treatment. However, the clinical outcome after docetaxel treatment was similar between patients with and without CDK12 defects. In multivariate Cox regression analysis, a CDK12 defect was significantly associated with inferior PFS after abiraterone treatment. Patients with a BRCA2 defect showed marked response to both PARP inhibitors and platinum-based chemotherapy. Conclusions: Our study explored the genomic landscape of Chinese patients with mCRPC at different treatment stages using minimally invasive methods and evaluated the clinical implications of the driver genomic alterations on patients’ response to the most widely used therapies for mCRPC. We observed a significantly higher alteration frequency of CDK12 in our cohort compared with the SU2C-PCF cohort.

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Clinical Impact of Somatic Variants in Homologous Recombination Repair-Related Genes in Ovarian High-Grade Serous Carcinoma

Cancer Research and Treatment ◽

10.4143/crt.2019.207 ◽

2020 ◽

Vol 52 (2) ◽

pp. 634-644 ◽

Cited By ~ 4

Author(s):

Min Chul Choi ◽

Sohyun Hwang ◽

Sewha Kim ◽

Sang Geun Jung ◽

Hyun Park ◽

...

Keyword(s):

Dna Damage ◽

Homologous Recombination ◽

Parp Inhibitor ◽

Dna Damage Repair ◽

Disease Free Survival ◽

Serous Carcinoma ◽

High Grade ◽

Repair Gene ◽

Damage Repair ◽

Repair Genes

PurposeIn this study, we investigated the frequencies of mutations in DNA damage repair genes including BRCA1, BRCA2, homologous recombination genes and TP53 gene in ovarian high-grade serous carcinoma, alongside those of germline and somatic BRCA mutations, with the aim of improving the identification of patients suitable for treatment with poly(ADP-ribose) polymerase inhibitors.Materials and MethodsTissue samples from 77 Korean patients with ovarian high-grade serous carcinoma were subjected to next-generation sequencing. Pathogenic alterations of 38 DNA damage repair genes and TP53 gene and their relationships with patient survival were examined. Additionally, we analyzed BRCA germline variants in blood samples from 47 of the patients for comparison.ResultsBRCA1, BRCA2, and TP53 mutations were detected in 28.6%, 5.2%, and 80.5% of the 77 patients, respectively. Alterations in RAD50, ATR, MSH6, MSH2, and FANCA were also identified. At least one mutation in a DNA damage repair gene was detected in 40.3% of patients (31/77). Germline and somatic BRCA mutations were found in 20 of 47 patients (42.6%), and four patients had only somatic mutations without germline mutations (8.5%, 4/47). Patients with DNA damage repair gene alterations with or without TP53mutation, exhibited better disease-free survival than those with TP53 mutation alone.ConclusionDNA damage repair genes were mutated in 40.3% of patients with high-grade serous carcinoma, with somatic BRCA mutations in the absence of germline mutation in 8.5%. Somatic variant examination, along with germline testing of DNA damage repair genes, has potential to detect additional candidates for PARP inhibitor treatment.

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Platinum-based chemotherapy in metastatic prostate cancer with alterations in DNA damage repair genes.

Journal of Clinical Oncology ◽

10.1200/jco.2019.37.15_suppl.5038 ◽

2019 ◽

Vol 37 (15_suppl) ◽

pp. 5038-5038

Author(s):

Jose Mauricio Mota ◽

Ethan Barnett ◽

Jones Nauseef ◽

Konrad Hermann Stopsack ◽

Andreas Georg Wibmer ◽

...

Keyword(s):

Prostate Cancer ◽

Dna Damage ◽

Parp Inhibitor ◽

Dna Damage Repair ◽

Castration Resistant Prostate Cancer ◽

Castration Resistant ◽

Damage Repair ◽

Platinum Based Chemotherapy ◽

Before And After ◽

Repair Genes

5038 Background: Platinum-based chemotherapy has shown palliative and radiographic benefit in small unselected studies of metastatic castration-resistant prostate cancer (mCRPC). Alterations in DNA damage repair genes (DDRmut), which occur in ~25% of patients with mCRPC, may sensitize to platinum-based chemotherapy, and may aid in the selection of patients for this therapy. We sought to evaluate the efficacy of platinum-based chemotherapy in DDRmut mCRPC. Methods: We performed a retrospective review of patients with prostate cancer who underwent tumor genomic profiling and received platinum-based chemotherapy. Deleterious alterations in a panel including BRCA2, BRCA1, ATM, FANCA, CDK12 or PALB2 were classified as DDRmut. Absence of deleterious alterations in those genes was classified as DDRwt. MSI-H cases were excluded from analysis. Electronic charts, PSA values, and scans were reviewed to assess for outcomes. Results: From October 2013 to July 2018, 109 patients with mCRPC received platinum-based chemotherapy. 64/109 had prior taxane progression and were PARP inhibitor (PARPi) naïve at the time of platinum-based chemotherapy. DDRmut was found in 16/64 (25%) of patients ( BRCA2, n = 6; ATM, n = 2; CDK12, n = 4; FANCA, n = 4; PALB2, n = 1). Visceral metastasis occurred in 4/16 (25%) of DDRmut patients and in 22/48 (46%) of DDRwt patients. PSA50 responses were more common among DDRmut (8/15 evaluable = 53%, 95% CI, 30-75%) than among DDRwt patients (5/42 evaluable = 12%, 95% CI, 5-25%). Time on platinum-based chemotherapy tended to be longer in the DDRmut group (median 3.1 vs 1.8 months; HR 0.73, 95% CI 0.42-1.26). Of 8 DDRmut patients ( BRCA2, n = 6; BRCA1, n = 1; ATM, n = 2) who received platinum-based chemotherapy after progression on a PARPi, 3/7 evaluable patients (43%) had RECIST response or stable disease, and 2/7 evaluable patients (29%) had a PSA50 response. Of 4 patients with ATM deleterious mutations, none had a radiographic or PSA50 response to platinum-based chemotherapy. Conclusions: Platinum-based chemotherapy showed activity in DDRmut mCRPC patients before and after PARPi treatment.

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P57.04 Mutations of DNA Damage Repair Genes in Lung Adenocarcinoma and Their Association with Actionable Alterations

Journal of Thoracic Oncology ◽

10.1016/j.jtho.2021.01.948 ◽

2021 ◽

Vol 16 (3) ◽

pp. S534-S535

Author(s):

Z. Yu ◽

S. Dang ◽

J. Zhang ◽

J. Duan ◽

S. Chen ◽

...

Keyword(s):

Dna Damage ◽

Lung Adenocarcinoma ◽

Dna Damage Repair ◽

Damage Repair ◽

Repair Genes

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DISTRIBUTION OF DNA DAMAGE REPAIR GENE POLYMORPHISM hOGG1, XRCC1 and p53 AMONG SICKLE CELL DISEASE PATIENTS IN INDIA

Mediterranean Journal of Hematology and Infectious Diseases ◽

10.4084/mjhid.2015.046 ◽

2015 ◽

Vol 7 ◽

pp. e2015046 ◽

Cited By ~ 1

Author(s):

Sudhansu Sekhar Nishank

Keyword(s):

Oxidative Stress ◽

Dna Damage ◽

Sickle Cell Disease ◽

Gene Polymorphisms ◽

Clinical Effect ◽

Dna Damage Repair ◽

Cell Disease ◽

Repair Gene ◽

Damage Repair ◽

Repair Genes

Background– Defect in DNA damage repair genes due to oxidative stress predispose the humans to malignancies. There are many cases of association of malignancies with sickle cell disease patients (SCD) throughout the world, the molecular cause of which has never been investigated. DNA damage repair genes such as hOGG1, XRCC1 and p53 play significant role in repair of DNA damage during oxidative stress but the distribution and clinical effect of these genes are not known till date in SCD patients who are associated with oxidative stress related clinical complications. Objective – The aim of the study was to characterize the distribution and clinical effect of DNA damage gene polymorphisms p53 (codon 72 Arg> Pro), hOGG1 (codon 326 Ser>Cyst) and XRCC1 (codons 194 Arg>Trp, codon 280 Arg> His, codon 399 Arg> Gln) among SCD patients of central India. Methods- A case control study of 250 SCD patients and 250 normal individuals were investigated by PCR-RFLP techniques. Result- The prevalence of mutant alleles of hOGG1 gene, XRCC1 codon 280 Arg>His were found to be significantly high among SCD patients as compared to controls. However, SCD patients did not show clinical association with any of these DNA repair gene polymorphisms. Conclusion- This indicates that hOGG1, p53 and XRCC1 gene polymorphisms may not have any clinical impact among SCD patients in India.

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Changes in DNA Damage Repair Gene Expression and Cell Cycle Gene Expression Do Not Explain Radioresistance in Tamoxifen-Resistant Breast Cancer

Oncology Research Featuring Preclinical and Clinical Cancer Therapeutics ◽

10.3727/096504019x15555794826018 ◽

2020 ◽

Vol 28 (1) ◽

pp. 33-40 ◽

Cited By ~ 3

Author(s):

Annemarie E. M. Post ◽

Johan Bussink ◽

Fred C. G. J. Sweep ◽

Paul N. Span

Keyword(s):

Breast Cancer ◽

Gene Expression ◽

Cell Cycle ◽

Dna Damage ◽

Dna Damage Repair ◽

Cross Resistance ◽

Damage Repair ◽

Breast Cancer Cohort ◽

Tamoxifen Resistant ◽

Repair Genes

Tamoxifen-induced radioresistance, reported in vitro, might pose a problem for patients who receive neoadjuvant tamoxifen treatment and subsequently receive radiotherapy after surgery. Previous studies suggested that DNA damage repair or cell cycle genes are involved, and could therefore be targeted to preclude the occurrence of cross-resistance. We aimed to characterize the observed cross-resistance by investigating gene expression of DNA damage repair genes and cell cycle genes in estrogen receptor-positive MCF-7 breast cancer cells that were cultured to tamoxifen resistance. RNA sequencing was performed, and expression of genes characteristic for several DNA damage repair pathways was investigated, as well as expression of genes involved in different phases of the cell cycle. The association of differentially expressed genes with outcome after radiotherapy was assessed in silico in a large breast cancer cohort. None of the DNA damage repair pathways showed differential gene expression in tamoxifen-resistant cells compared to wild-type cells. Two DNA damage repair genes were more than two times upregulated (NEIL1 and EME2), and three DNA damage repair genes were more than two times downregulated (PCNA, BRIP1, and BARD1). However, these were not associated with outcome after radiotherapy in the TCGA breast cancer cohort. Genes involved in G1, G1/S, G2, and G2/M phases were lower expressed in tamoxifen-resistant cells compared to wild-type cells. Individual genes that were more than two times upregulated (MAPK13) or downregulated (E2F2, CKS2, GINS2, PCNA, MCM5, and EIF5A2) were not associated with response to radiotherapy in the patient cohort investigated. We assessed the expression of DNA damage repair genes and cell cycle genes in tamoxifen-resistant breast cancer cells. Though several genes in both pathways were differentially expressed, these could not explain the cross-resistance for irradiation in these cells, since no association to response to radiotherapy in the TCGA breast cancer cohort was found.

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Abstract 1389: Exploiting inherent DNA damage repair defects in IDH1/2 mutated gliomas with the CNS penetrant PARP inhibitor, pamiparib

10.1158/1538-7445.am2020-1389 ◽

2020 ◽

Author(s):

Christopher Hong ◽

Amrita Sule ◽

Jason Beckta ◽

Ranjini Sundaram ◽

Ranjit Bindra

Keyword(s):

Dna Damage ◽

Parp Inhibitor ◽

Dna Damage Repair ◽

Damage Repair

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Altered expression of DNA damage repair genes in the brain tissue of mice conceived by in vitro fertilization

MHR Basic science of reproductive medicine ◽

10.1093/molehr/gaaa010 ◽

2020 ◽

Vol 26 (3) ◽

pp. 141-153

Author(s):

Minhao Hu ◽

Yiyun Lou ◽

Shuyuan Liu ◽

Yuchan Mao ◽

Fang Le ◽

...

Keyword(s):

Dna Methylation ◽

Dna Damage ◽

Brain Tissue ◽

Dna Damage Repair ◽

Damage Repair ◽

Gene And Protein Expression ◽

The Brain ◽

Repair Genes

Abstract Our previous study revealed a higher incidence of gene dynamic mutation in newborns conceived by IVF, highlighting that IVF may be disruptive to the DNA stability of IVF offspring. However, the underlying mechanisms remain unclear. The DNA damage repair system plays an essential role in gene dynamic mutation and neurodegenerative disease. To evaluate the long-term impact of IVF on DNA damage repair genes, we established an IVF mouse model and analyzed gene and protein expression levels of MSH2, MSH3, MSH6, MLH1, PMS2, OGG1, APEX1, XPA and RPA1 and also the amount of H2AX phosphorylation of serine 139 which is highly suggestive of DNA double-strand break (γH2AX expression level) in the brain tissue of IVF conceived mice and their DNA methylation status using quantitative real-time PCR, western blotting and pyrosequencing. Furthermore, we assessed the capacity of two specific non-physiological factors in IVF procedures during preimplantation development. The results demonstrated that the expression and methylation levels of some DNA damage repair genes in the brain tissue of IVF mice were significantly changed at 3 weeks, 10 weeks and 1.5 years of age, when compared with the in vivo control group. In support of mouse model findings, oxygen concentration of in vitro culture environment was shown to have the capacity to modulate gene expression and DNA methylation levels of some DNA damage repair genes. In summary, our study indicated that IVF could bring about long-term alterations of gene and protein expression and DNA methylation levels of some DNA damage repair genes in the brain tissue and these alterations might be resulted from the different oxygen concentration of culture environment, providing valuable perspectives to improve the safety and efficiency of IVF at early embryonic stage and also throughout different life stages.

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