Comprehensive analysis of AR alterations in cell free DNA from prostate cancer patients.

2018 ◽  
Vol 36 (6_suppl) ◽  
pp. 314-314
Author(s):  
Elisa Ledet ◽  
Michael B. Lilly ◽  
Guru Sonpavde ◽  
Neeraj Agarwal ◽  
Rebecca J Nagy ◽  
...  
Keyword(s):  
Point Mutations ◽  
Treatment Strategies ◽  
Comprehensive Analysis ◽  
Repair Gene ◽  
Dna Repair Gene ◽  
Somatic Alterations ◽  
The Common ◽  
Generation Sequencing ◽  
Redwood City ◽  
Gene Alterations

314 Background: Somatic alterations identified in cfDNA may be associated with prognosis. Select AR alterations are associated with abiraterone/enzalutamide resistance in PCa. The goal was to characterize AR amplifications (amps) and somatic point mutations (muts) detected in cfDNA from PCa patients and to relate those changes to non-AR alterations detected in the cfDNA landscape. Methods: cfDNA data was obtained from a heterogeneous group of unique PCa pts who underwent Guardant360 testing (Guardant Health, Redwood City, CA). This assay includes next generation sequencing for full exonic coverage of 73 genes and amplifications in 18 genes. The AR amps/muts detected in cfDNA testing were reported. Results: Over 6,800 genomic alterations including AR amps/muts were identified in 892 PCa patients. Pts were a median age of 70 (range = 41-93) at testing. 49% (n = 436) had AR amp only, 32% (n = 283) had nonsynonymous (NS)-muts only, 18% (n = 165) had both amp and NS-muts; < 1% (n = 8) had synonymous AR muts only. AR amps had a mean absolute copy number of 3.3 (range = 1.2-165.2). Many patients had multiple AR muts; a total of 112 unique muts were identified in the AR gene, some of which are poorly characterized. The most prevalent AR muts were L702H (n = 220), T878A (n = 129), H875Y (n = 102), W742C (n = 75), W742L (n = 34), F877L (n = 19), and T878S (n = 14). The AR muts with the highest mutant allele fraction were H875Y, T878A, and L702H. Aside from AR, among these selected pts, amps/muts were identified in 74 other genes including TP53 50% (n = 449), MYC 34% (n = 301), BRAF 32% (n = 287), PIK3CA 29% (n = 259), MET 25% (n = 224), CDK6 26% (n = 229), EGFR 24% (n = 219), FGFR1 21% (n = 189), and APC 12% (n = 112). DNA repair gene alterations were detected in combination with AR alterations, BRCA2 8% (n = 69), BRCA1 5% (n = 42), and ATM 3% (n = 28). Conclusions: To our knowledge, this is the largest dataset ever reporting AR alterations in cfDNA. Both amps and muts, were frequently found in cfDNA from PCa pts. The common AR muts were L702H, T878A, H875Y and W742C/L, which are linked to resistance to abiraterone, enzalutamide or bicalutamide. Determining the association with other somatic cfDNA alterations and clinical outcomes may be critical for conceiving optimal treatment strategies.

Association of cfDNA androgen receptor amplifications with BRAF alterations in mCRPC.

2017 ◽  
Vol 35 (6_suppl) ◽  
pp. 234-234
Author(s):  
Elisa M. Ledet ◽  
Joshua Schiff ◽  
Patrick Cotogno ◽  
Charlotte Manogue ◽  
Emma M. Ernst ◽  
...  
Keyword(s):  
Point Mutations ◽  
Response To Therapy ◽  
Cancer Center ◽  
Therapeutic Implications ◽  
Heterogenous Group ◽  
Somatic Alterations ◽  
The Common ◽  
The Relationship ◽  
Larger Sample ◽  
Redwood City

234 Background: Cell free DNA (cfDNA) present in plasma of cancer pts can reflect tumoral alterations. Genomic alterations in cfDNA alter prognosis and abiraterone/enzalutamide resistance in mCRPC. The goal of this evaluation was to characterize AR amplifications (Amps) and various somatic point mutations (Muts) detected in mCRPC cfDNA and to relate those changes to other common alterations in the cfDNA landscape. Methods: A heterogenous group of 46 mCRPC patients (pts) with evidence of clinical progression from Tulane Cancer Center underwent cfDNA analysis using Guardant360 test (Guardant Health, Redwood City, CA). This evaluation included full exonic coverage of 70 genes and amplifications in 18 genes. Mutations reported herein include both known pathogenic mutations as well as mutations uncharacterized for functional importance. Results: 69.5% (n = 32) of the mCRPC pts evaluated had an AR alteration. Of the pts with AR alterations, 46.8% (n = 16) had AR Amps, 43.7% (n = 14) had AR Muts, and only 6.25% (n = 2) had both. In this cohort, AR alterations were the most commonly observed aberration. In addition to amplifications, 12 different AR Muts were detected. AR Muts included: T878A (n = 9), H875Y (n = 5), W742C (n = 4), AR L702H (n = 3), and others. To better understand the relationship between AR alteration and other commonly detected cfDNA aberrations, association between BRAF (35.5%), TP53 (46.7%), and MYC (22.2%) alterations and AR were assessed. Among these genes, TP53 alterations were all Muts and MYC alterations were all Amps. BRAF alterations were predominantly Amps (N = 15) though Muts were also detected (N = 6). Neither TP53 Muts or MYC Amps were significantly associated with AR alterations. On the other hand, BRAF alterations were significantly associated with AR Amps (p = 0.041); 60% (9/15) pts with AR Amps also had BRAF alteration (Odds ratio = 7.71, 95% CI 1.284- 46.366). Conclusions: AR alterations in cfDNA impact both disease progression and response to therapy. Co-segregation of AR and BRAF alterations may have significant prognostic and therapeutic implications. Further research and larger sample size is needed to further elucidate associations between the common somatic alterations detected in mCRPC.

scholarly journals Comprehensive analysis of the role of DNA repair gene polymorphisms on risk of glioma

2007 ◽  
Vol 17 (6) ◽  
pp. 800-805 ◽  
Author(s):  
Lara Bethke ◽  
Emily Webb ◽  
Anne Murray ◽  
Minouk Schoemaker ◽  
Christoffer Johansen ◽  
...  
Keyword(s):  
Dna Repair ◽  
Gene Polymorphisms ◽  
Comprehensive Analysis ◽  
Repair Gene ◽  
Dna Repair Gene

675 Unveiling of DNA Repair Gene Alterations in Non-Lynch Hereditary Colorectal Cancer Through Exome Sequencing

2014 ◽  
Vol 146 (5) ◽  
pp. S-119
Author(s):  
Priti Marwaha ◽  
Rosa M Xicola ◽  
Yeong C. Kim ◽  
Carrie L. Snyder ◽  
Timothy Carroll ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Dna Repair ◽  
Exome Sequencing ◽  
Hereditary Colorectal Cancer ◽  
Repair Gene ◽  
Dna Repair Gene ◽  
Gene Alterations

scholarly journals Cloning of the DNA repair gene, uvsF, by transformation of Aspergillus nidulans.

Genetics ◽  
1990 ◽  
Vol 125 (2) ◽  
pp. 341-349
Author(s):  
K Oza ◽  
E Käfer
Keyword(s):  
Dna Repair ◽  
Aspergillus Nidulans ◽  
Genomic Dna ◽  
Genomic Library ◽  
Cdna Clones ◽  
Repair Gene ◽  
Dna Repair Gene ◽  
Mutant Strains ◽  
The Common ◽  
Vector Sequences

Abstract As a first step in the cloning of the DNA repair gene uvsF of Aspergillus nidulans, uvsF pyrG double mutant strains were transformed with a genomic library which carried the complementing Neurospora pyr-4 gene in the vector. Rare pyr+ uvs+ cotransformants were obtained on media lacking pyrimidines, overlayed with MMS (methyl-methane sulfonate) to which uvsF is hypersensitive. Among MMS-resistant transformants, Southerns revealed two types which showed single bands of different sizes when BglII-digested genomic DNA was probed with the vector. Both types produced uvsF- recombinants without vector sequences in homozygous crosses, but only those with the larger band also produced haploid uvs+ progeny. Using BglII-digested genomic DNA to transform Escherichia coli, plasmids of the corresponding two sizes could be rescued. Their inserts had a short internal region in common, giving evidence of rearrangement(s). In secondary transformation of uvsF mutants, only the plasmids with the larger insert showed complementation and these were used to screen Aspergillus libraries. Three types of genomic and two overlapping cDNA clones were identified. The cDNAs hybridized not only to each other, but also to the common region of the rescued plasmids. Therefore, cDNA subclones were used to map the putative uvsF sequences to a short segment in one genomic clone. In Northerns, the complementing large plasmid hybridized to three mRNAs, while the cDNA subclone identified one of these as the probable uvsF message.

scholarly journals Genomic Characterization of Prostatic Ductal Adenocarcinoma Identifies a High Prevalence of DNA Repair Gene Mutations

2019 ◽  
pp. 1-9 ◽  
Author(s):  
Michael T. Schweizer ◽  
Emmanuel S. Antonarakis ◽  
Tarek A. Bismar ◽  
Liana B. Guedes ◽  
Heather H. Cheng ◽  
...  
Keyword(s):  
Dna Damage ◽  
Next Generation Sequencing ◽  
Mapk Pathway ◽  
Dna Damage Repair ◽  
Case Series ◽  
Next Generation ◽  
Repair Gene ◽  
Damage Repair ◽  
Dna Repair Gene ◽  
Generation Sequencing

PURPOSE Ductal prostate cancer (dPC) is a rare variant of prostatic adenocarcinoma associated with poor outcomes. Although its histopathologic features are well characterized, the underlying molecular hallmarks of this aggressive subtype are not well described. We sought to provide a comprehensive overview of the spectrum of mutations associated with dPC. METHODS Three case series across multiple institutions were assembled. All patients had a diagnosis of dPC, and histopathologic classification was confirmed by an expert genitourinary pathologist. Case series 1 included men who were prospectively enrolled in a tumor sequencing study at the University of Washington (n = 22). Case series 2 and 3 included archival samples from men treated at Johns Hopkins Hospital (n = 21) and University of Calgary (n = 8), respectively. Tumor tissue was sequenced on a targeted next-generation sequencing assay, UW-OncoPlex, according to previously published methods. The frequency of pathogenic/likely pathogenic mutations are reported. RESULTS Overall, 25 patients (49%) had at least one DNA damage repair gene alteration, including seven (14%) with a mismatch repair gene mutation and 16 (31%) with a homologous repair mutation. Germline autosomal dominant mutations were confirmed or suspected in 10 patients (20%). Activating mutations in the PI3K pathway (n = 19; 37%), WNT pathway (n = 16; 31%), and MAPK pathway (n = 8; 16%) were common. CONCLUSION This study strongly suggests that dPCs are enriched for actionable mutations, with approximately 50% of patients demonstrating DNA damage repair pathway alteration(s). Patients with dPC should be offered next-generation sequencing to guide standard-of-care treatment (eg, immune checkpoint inhibitors) or triaged toward an appropriate clinical trial (eg, poly [ADP-ribose] polymerase inhibitors).

scholarly journals Germline and somatic DNA repair gene alterations in prostate cancer

Cancer ◽  
2020 ◽  
Vol 126 (13) ◽  
pp. 2980-2985 ◽  
Author(s):  
Marc A. Dall’Era ◽  
John D. McPherson ◽  
Allen C. Gao ◽  
Ralph W. DeVere White ◽  
Jeffrey P. Gregg ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Dna Repair ◽  
Repair Gene ◽  
Dna Repair Gene ◽  
Gene Alterations

Comprehensive analysis of DNA repair gene polymorphisms and survival in patients with early stage non-small-cell lung cancer

2010 ◽  
Vol 101 (11) ◽  
pp. 2436-2442 ◽  
Author(s):  
Min Kim ◽  
Hyo-Gyoung Kang ◽  
Shin Yup Lee ◽  
Hyung Cheol Lee ◽  
Eung Bae Lee ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Dna Repair ◽  
Small Cell Lung Cancer ◽  
Gene Polymorphisms ◽  
Early Stage ◽  
Comprehensive Analysis ◽  
Small Cell ◽  
Small Cell Lung ◽  
Repair Gene ◽  
Dna Repair Gene

Detection of germline deleterious mutations in prostate cancer patients with use of a validated 30-gene sequencing assay.

2018 ◽  
Vol 36 (6_suppl) ◽  
pp. 223-223
Author(s):  
Panagiotis J. Vlachostergios ◽  
Ana M. Molina ◽  
Himisha Beltran ◽  
David M. Nanus ◽  
Scott T. Tagawa
Keyword(s):  
Prostate Cancer ◽  
Dna Repair ◽  
Family History ◽  
Positive Family History ◽  
High Susceptibility ◽  
Degree Relative ◽  
Repair Gene ◽  
Dna Repair Gene ◽  
History Of ◽  
Gene Alterations

223 Background: Germline DNA repair gene alterations in men with metastatic prostate cancer (PC) unselected for family history of malignancy occur in a greater frequency compared to localized PC and the general population. We hypothesized that assessing heritable alterations in a broader panel of high-susceptibility genes, may be relevant for detecting familial associations with other cancers in PC patients. Methods: We examined a cohort of 52 PC patients (median age 60, range 45-80) with histologically confirmed PC (17 localized, 35 metastatic). Germline DNA was isolated from blood lymphocytes or buccal swabs, and targeted next-generation sequencing was conducted with use of a previously validated panel of 30 genes associated with an elevated risk for common cancers (Color Genomics). As a reference for gene aberration frequencies we used the Exome Aggregation Consortium (ExAC) database. Results: The majority of patients (48/52, 92%) had a positive family history of cancer in any relative. Nine deleterious pathogenic mutations were identified in germline DNA samples from 8/52 (15%) patients, affecting the following genes: APC (n = 2, 3.8%), BRCA2 (n = 2, 3.8%), CHEK2 (n = 3, 5.7%), ATM (n = 1, 1.9%), RAD51D (n = 1, 1.9%). APC mutations were significantly more frequent in our cohort compared to the ExAC database (0.3%, p < 0.001). The frequency of DNA repair gene alterations (7/52, 13.5%) was also significantly higher compared to the ExAC database (0.3%, p < 0.001). The median overall survival (OS) between patients with and without germline gene alterations was similar (81.5 versus 74 months, respectively). The presence of heritable gene alterations from the 30-gene panel was significantly more frequent in patients with a positive family history of any cancer (p < 0.001) or prostate, breast, ovarian cancer (p = 0.001) in a first degree relative. Conclusions: The use of a targeted panel of high-susceptibility cancer-associated genes in PC not only confirms the enrichment of germline mutations in men with PC. It can also reveal associations of PC with other cancers which may portend implications for treatment and prognosis.

scholarly journals The interplay of cell cycle and DNA repair gene alterations in upper tract urothelial carcinoma: predictive and prognostic implications

2020 ◽  
Vol 3 (3) ◽  
pp. 153-160
Author(s):  
Panagiotis J Vlachostergios
Keyword(s):  
Cell Cycle ◽  
Urothelial Carcinoma ◽  
Checkpoint Inhibitors ◽  
Clinical Importance ◽  
Upper Tract Urothelial Carcinoma ◽  
Cell Cycle Gene ◽  
Repair Gene ◽  
Upper Tract ◽  
Dna Repair Gene ◽  
Gene Alterations

Abstract Upper tract urothelial carcinoma (UTUC) is rare but can occur sporadically outside the context of Lynch syndrome. In these cases, knowing whether non-mismatch repair (MMR), DNA damage response and repair (DDR), and cell cycle gene alterations may predict responses to chemotherapy or immunotherapy and survival is of clinical importance. This study examined the germline and somatic mutational landscape of two UTUC patients with differential responses to programmed death 1 (PD-1)/PD-ligand 1 (PD-L1) immune checkpoint inhibitors and queried three independent UTUC cohort studies for co-occurrence of key cell cycle and DDR genes, as well as for their associations with overall survival (OS). TP53 and RB1 emerged as potential determinants of shorter OS in UTUC cohort patients, regardless of concurrent DDR alterations, and if prospectively assessed in larger studies they might also explain resistance to PD-1/PD-L1 blockade despite PD-L1 expression.

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