scholarly journals Targeted next generation sequencing identifies functionally deleterious germline mutations in novel genes in early-onset/familial prostate cancer

PLoS Genetics ◽  
2018 ◽  
Vol 14 (4) ◽  
pp. e1007355 ◽  
Author(s):  
Paula Paulo ◽  
Sofia Maia ◽  
Carla Pinto ◽  
Pedro Pinto ◽  
Augusta Monteiro ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Next Generation Sequencing ◽  
Early Onset ◽  
Germline Mutations ◽  
Next Generation ◽  
Novel Genes ◽  
Targeted Next Generation Sequencing ◽  
Generation Sequencing

Pilot study of clinical targeted next generation sequencing for prostate cancer: Consequences for treatment and genetic counseling.

2016 ◽  
Vol 34 (2_suppl) ◽  
pp. 251-251
Author(s):  
Heather H. Cheng ◽  
Nola Klemfuss ◽  
Robert B. Montgomery ◽  
Celestia S. Higano ◽  
Michael Thomas Schweizer ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Clinical Trial ◽  
Next Generation Sequencing ◽  
Pilot Study ◽  
Germline Mutations ◽  
Next Generation ◽  
Targeted Next Generation Sequencing ◽  
Targeted Ngs ◽  
High Penetrance ◽  
Generation Sequencing

251 Background: Targeted next generation sequencing (NGS) panels for identification of actionable mutations are increasingly used in oncology for therapeutic decision-making, but have yet to be widely used for prostate cancer.To determine the utility of applying a targeted next generation sequencing to prostate cancer management, we conducted a pilot study using the clinical molecular diagnostic assay, UW-OncoPlex, on primary and metastatic tumors from patients with prostate cancer. Methods: Patients receiving treatment for prostate cancer by a medical oncologist were eligible. After providing informed consent, tumor DNA was extracted from formalin-fixed, paraffin-embedded (FFPE)primary tumors and/or metastatic biopsies. Extracted DNA was analyzed using UW-OncoPlex, a targeted NGS panel designed to assess genomic alterations in 234 cancer-associated genes (PMID: 24189654). Results were discussed at a monthly multidisciplinary precision tumor board prior to communicating results to patients. Results: Forty patients consented to the study and 31 (78%) had reportable results. Findings included frequently observed prostate cancer genomic aberrations, including: TMPRSS2-ERG fusions and copy-number alterations of PTEN, TP53, FOXA1, AR, and SPOP. We also observed potentially actionable alterations in BRAF, MAP2K1 (MEK1), PIK3R1, MET, FGFR1, and FGFR3, which inform future treatment and clinical trial considerations. Notably, 8/31 (25%) patients had suspected high penetrance germline mutations, including in BRCA2 (N = 3), TP53 (N = 2), ATM (N = 1), and CHEK2 (N = 2). These 8 individuals were referred to medical genetics and 7 of 8 mutations were confirmed to be germline. One patient was found to have a hypermutated phenotype associated with bi-allelic MSH6 mutation and microsatellite instability. Conclusions: Targeted NGS panel testing may be useful in informing future treatment approaches and clinical trial selection for patients with prostate cancer. In addition, we observed a high proportion of cases with suspected high-penetrance germline mutations and immediate actionability through referral to medical genetics.

Targeted Next-Generation Sequencing in Men with Metastatic Prostate Cancer: a Pilot Study

2018 ◽  
Vol 13 (4) ◽  
pp. 495-500 ◽  
Author(s):  
Pedro C. Barata ◽  
Prateek Mendiratta ◽  
Brandie Heald ◽  
Stefan Klek ◽  
Petros Grivas ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Next Generation Sequencing ◽  
Pilot Study ◽  
Metastatic Prostate Cancer ◽  
Next Generation ◽  
Targeted Next Generation Sequencing ◽  
Generation Sequencing

Next generation sequencing of primary prostate cancer tumors to reveal potentially actionable opportunities for clinical management: The UNC experience.

2019 ◽  
Vol 37 (7_suppl) ◽  
pp. 305-305
Author(s):  
Daniel James Crona ◽  
Anthony Drier ◽  
Jing Daisy Zhu ◽  
Emily Fox Bell ◽  
Margaret Rose Sketch ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Next Generation Sequencing ◽  
Copy Number Variations ◽  
Precision Oncology ◽  
Next Generation ◽  
Targeted Next Generation Sequencing ◽  
Formalin Fixed Paraffin ◽  
Primary Prostate Cancer ◽  
Formalin Fixed Paraffin Embedded ◽  
Generation Sequencing

305 Background: The Strata trial (NCT03061305) is a multi-institutional precision oncology collaboration structured as an observational protocol that aims to match patients to genomically-guided therapies. Methods: Selected University of North Carolina (UNC) metastatic prostate cancer (mPC) patients were enrolled on this IRB-approved study. Formalin fixed paraffin-embedded primary tumor specimens, without matched germline controls, were sent for targeted next generation sequencing (NGS) to detect actionable variants, including: mutations in 87 genes, copy number variations in 31 genes, and gene fusions in 46 gene drivers. mPC-related genes of particular interest included: AR, ATM, BRCA1/2, ERG, MSH2, MSH6, PTEN, RB1, and TP53. Results: Of the 92 cases sequenced, 5 [5%] failed testing. Of the 87 mPC patients (median age 69 years [47-86]) enrolled: 53 [61%] were white, 28 [32%] were black, 1 [1%] was Asian, and 5 [6%] declined to be identified. NGS data revealed 106 variants in 27 genes: 62 patients (71%) had at least one variant, 21 (24%) had 2 variants, 7 (8%) had 3 variants, and 4 (3%) had 4 variants. Among the 62 patients with at least 1 identified variant, TMPRSS2-ERG fusion occurred most frequently (50%), followed by TP53 (40%), and PTEN (16%). 6% of all sequenced patients had variants in DNA damage repair genes including ATM (3%), BRCA2 (2%) and MSH2 (1%). One patient had a SLC45A3-ERG fusion combined with PTEN deep deletion, which has been associated with a more aggressive phenotype. One patient with a microsatellite-instability high tumor was treated with pembrolizumab. Conclusions: The UNC experience shows that a high proportion of primary prostate cancer tumors from mPC patients have genomic variants, and one patient was treated based on these data. Limited actionability may reflect the landscape of currently FDA approved mPC treatments, and available clinical trials. It may also be due to a short follow-up, and these data could inform treatment planning upon progression.

scholarly journals The Genetic Germline Background of Single and Multiple Primary Melanomas

2021 ◽  
Vol 7 ◽  
Author(s):  
Simona De Summa ◽  
Antonia Lasorella ◽  
Sabino Strippoli ◽  
Giuseppe Giudice ◽  
Gabriella Guida ◽  
...  
Keyword(s):  
Next Generation Sequencing ◽  
Cell Cycle Control ◽  
Germline Mutations ◽  
Next Generation ◽  
Targeted Next Generation Sequencing ◽  
Multiple Genes ◽  
Multiple Primary ◽  
Small Cohort ◽  
Sequencing Platforms ◽  
Generation Sequencing

Background:Melanoma has a complex molecular background and multiple genes are involved in its development and progression. The advent of next generation sequencing platforms has enabled the evaluation of multiple genes at a time, thus unraveling new insights into the genetics of melanoma. We investigated a set of germline mutations able to discriminate the development of multiple primary melanomas (MPM) vs. single site primary melanomas (SPM) using a targeted next generation sequencing panel.Materials and Methods:A total of 39 patients, 20 with SPM and 19 with MPM, were enrolled in our study. Next generation analysis was carried out using a custom targeted sequencing panel that included 32 genes known to have a role in several carcinogenic pathways, such as those involved in DNA repair, pigmentation, regulation of kinases, cell cycle control and senescence.Results:We found a significant correlation between PIK3CA:p.I391M and MPMs, compared to SPMs,p= 0.031 and a trend for the association between CYP1B1: p.N453S and SPMs, compared to MPMs (p= 0.096). We also found that both subgroups shared a spectrum of 9 alterations in 8 genes (CYP1B1: p.N453S, BAP1: p.C39fs, PIK3CA: p.I391M, CDKAL1: c.1226_1227TG, POLE: p.V1161fs, OCA2: p.R419Q, OCA2: p.R305W, MC1R: p.V60L, MGMT: p.L115F), which suggested that these genes may play a role in melanoma development.Conclusions:In conclusion, despite the small cohort of patients, we found that germline mutations, such as those of PIK3CAand CYP1B1, might contribute to the differential development of SPM and MPM.

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