Publications by authors named "Ashkan Bigdeli"

3 Publications

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Negative prognostic impact of epidermal growth factor receptor copy number gain in young adults with isocitrate dehydrogenase wild-type glioblastoma.

J Neurooncol 2019 Nov 21;145(2):321-328. Epub 2019 Sep 21.

Division of Hematology and Oncology, Department of Medicine, University of Pennsylvania, 10th Floor, South Pavilion, 3400 Civic Center Blvd, Philadelphia, PA, 19104, USA.

Purpose: Young adults with isocitrate-dehydrogenase wild-type (IDH-WT) glioblastoma (GBM) represent a rare, understudied population compared to pediatric high-grade glioma, IDH-mutant GBM, or IDH-WT GBM in older patients. We aimed to explore the prognostic impact of epidermal growth factor receptor copy number gain (EGFR CN gain), one of the most common genetic alterations in IDH-WT glioma, in young adults with IDH-WT GBM.

Methods: We performed a retrospective cohort study of patients 18-45 years old with newly diagnosed, IDH-WT GBM whose tumors underwent next-generation sequencing at our institution between 2014 and 2018. The impact of EGFR CN gain on time to tumor progression (TTP) and overall survival (OS) was assessed. A validation cohort of patients 18-45 years old with IDH-WT GBM was analyzed from The Cancer Genome Atlas (TCGA).

Results: Ten of 28 patients (36%) from our institution had EGFR CN gain, which was associated with shorter TTP (median 6.5 vs. 11.9 months; p = 0.06) and OS (median 16.3 vs. 23.5 months; p = 0.047). The negative prognostic impact of EGFR CN gain on OS persisted in a multivariate model (HR 6.40, 95% CI 1.3-31.0, p = 0.02). In the TCGA cohort (N = 43), EGFR CN gain was associated with shorter TTP and worse OS, although these did not reach statistical significance (TTP, median 11.5 vs. 14.4 months, p = 0.18; OS, median 23.6 vs. 27.8 months; p = 0.18).

Conclusions: EGFR CN gain may be associated with inferior outcomes in young adults with newly diagnosed, IDH-WT GBM, suggesting a potential role for targeting EGFR in this population.
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http://dx.doi.org/10.1007/s11060-019-03298-6DOI Listing
November 2019

Validation of a next-generation sequencing oncology panel optimized for low input DNA.

Cancer Genet 2018 12 19;228-229:55-63. Epub 2018 Sep 19.

Hospital of the University of Pennsylvania, Division of Precision and Computational Diagnostics, Department of Pathology & Laboratory Medicine, 3020 Market Street, Suite 220, Philadelphia, PA 19104, United States. Electronic address:

One caveat of next-generation sequencing (NGS)-based clinical oncology testing is the high amount of input DNA required. We sought to develop a focused NGS panel that could capture hotspot regions in relevant genes requiring 0.5-10 ng input DNA. The resulting Penn Precision Panel (PPP) targeted 20 genes containing clinically significant variants relevant to many cancers. One hundred twenty-three samples were analyzed, including 83 solid tumor specimens derived from FFPE. Various input quantities of DNA (0.5-10 ng) were amplified with content-specific PCR primer pools, then sequenced on a MiSeq instrument (Illumina, Inc.) via paired-end, 2 × 186 base pair reads to an average read depth of greater than 6500x. Variants were detected using an in-house analysis pipeline. Clinical sensitivity and specificity were assessed using results from our previously validated solid tumor NGS panel; sensitivity of the PPP is 96.75% (387/400 variants) and specificity is 99.9% (8427/8428 base pairs). Variant allele frequencies (VAFs) are highly concordant across both assays (r = 0.98 p < 0.0001). The PPP is a robust, clinically validated test optimized for low-yield solid tumor specimens, capturing a high percentage of clinically relevant variants found by larger commercially available NGS panels while using only 0.5-10 ng of input DNA.
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http://dx.doi.org/10.1016/j.cancergen.2018.08.004DOI Listing
December 2018

Classes of ITD Predict Outcomes in AML Patients Treated with FLT3 Inhibitors.

Clin Cancer Res 2019 01 4;25(2):573-583. Epub 2018 Sep 4.

Department of Pathology and Laboratory Medicine, University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania.

Purpose: Recurrent internal tandem duplication (ITD) mutations are observed in various cancers including acute myeloid leukemia (AML), where ITD mutations in tyrosine kinase receptor FLT3 are associated with poor prognostic outcomes. Several FLT3 inhibitors (FLT3i) are in clinical trials for high-risk -ITD-positive AML. However, the variability of survival following FLT3i treatment suggests that the mere presence of -ITD mutations might not guarantee effective clinical response. Motivated by the heterogeneity of -ITD mutations, we investigated the effects of -ITD structural features on the response of AML patients to treatment. We developed the HeatITup (HEAT diffusion for Internal Tandem dUPlication) algorithm to identify and quantitate ITD structural features including nucleotide composition. Using HeatITup, we studied the impact of ITD structural features on the clinical response to FLT3i and induction chemotherapy in -ITD-positive AML patients.

Results: HeatITup accurately identifies and classifies ITDs into newly defined categories of "typical" or "atypical" based on their nucleotide composition. A typical ITD's insert sequence completely matches the wild-type whereas an atypical ITD's insert contains nucleotides exogenous to the wild-type . Our analysis shows marked divergence between typical and atypical ITD mutation features. Furthermore, our data suggest that AML patients carrying typical -ITDs benefited significantly more from both FLT3i and induction chemotherapy treatments than patients with atypical -ITDs.

Conclusions: These results underscore the importance of structural discernment of complex somatic mutations such as ITDs in progressing toward personalized treatment of AML patients, and enable researchers and clinicians to unravel ITD complexity using the provided software..
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http://dx.doi.org/10.1158/1078-0432.CCR-18-0655DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6335170PMC
January 2019