Haplotype-Aware Detection of SERPINA1 Variants by Nanopore Sequencing.

被引量：- 发表：1970

Comparison of Results from Two Commercially Available In-House Tissue-Based Comprehensive Genomic Profiling Solutions: Research Use Only AVENIO Tumor Tissue Comprehensive Genomic Profiling Kit and TruSight Oncology 500 Assay.

被引量：- 发表：1970

Tailored Digital PCR Follow-Up of Rare Fusion Transcripts after Initial Detection through RNA Sequencing in Hematological Malignancies.

Minimal residual disease (MRD) monitoring plays a pivotal role in the management of hematologic malignancies. Well-established molecular targets, such as PML::RARA, CBFB::MYH11, or RUNX1::RUNX1T1, are conventionally tracked by quantitative RT-PCR. Recently, a broader landscape of fusion transcripts has been unveiled through transcriptomic analysis. These newly discovered fusion transcripts may emerge as novel molecular markers for MRD quantification. In this study, we compared a targeted RNA-sequencing (RNA-seq) approach (FusionPlex) with a whole-transcriptomic strategy (Advanta RNA-Seq XT) for fusion detection in a training set of 21 samples. We evidenced a concordance of 100% for the detection of known fusions, and showed a good correlation for gene expression quantification between the two techniques (Spearman r = 0.77). Additionally, we prospectively evaluated the identification of fusions by targeted RNA-seq in a real-life series of 126 patients with hematological malignancy. At least one fusion transcript was detected for 60 patients (48%). We designed tailored digital PCR assays for 11 rare fusions, and validated this technique for MRD quantification with a limit of detection of <0.01%. The combination of RNA-seq and tailored digital PCR may become a new standard for MRD evaluation in patients lacking conventional molecular targets.

被引量：- 发表：1970

Genotype and Phenotype Correlation of the TPMT∗8 Allele in Thiopurine Metabolism.

Thiopurine 6-mercaptopurine (6-MP) is metabolized by thiopurine methyl transferase (TPMT). TPMT genetic variation results in some individuals having reduced or absent TPMT enzyme activity. If these individuals take a full thiopurine dose, life-threatening adverse events can occur. Testing identifies patients with reduced or absent TPMT activity and is recommended before initiation of therapy. The TPMT∗8 allele, defined by c.644G>A (p.Arg215His), is common among individuals of African ancestry (approximately 2.3% minor allele frequency) but is not included in genotyping recommendations due to its uncertain function. Here, a clinical TPMT enzyme activity assay was used to assess TPMT activity in red blood cells from 982 patients, including those with ∗1/∗8 (n = 22), ∗3A/∗8 (n = 1), and ∗3C/∗8 (n = 1) TPMT diplotypes. The average production of 6-methylmercaptopurine (primary TPMT product measured clinically) was 3.08 ± 0.16 nmol/mL per hour for ∗1/∗8 individuals, compared with 3.77 ± 0.03 nmol/mL per hour for normal metabolizers (P = 0.0001) and 2.39 ± 0.06 nmol 6-methylmercaptopurine/mL per hour for intermediate metabolizers (P < 0.0001). Individuals with a TPMT∗1/∗8 diplotype displayed reduced 6-MP metabolism between that of normal metabolizers and intermediate metabolizers, suggesting that TPMT∗8 is a reduced function allele.

被引量：- 发表：1970

Purity Independent Subtyping of Tumors (PurIST) Pancreatic Cancer Classifier: Analytic Validation of a 16-RNA Expression Signature Distinguishing Basal and Classical Subtypes.

The two major molecular subtypes of pancreatic adenocarcinoma reportedly have differential response to FOLFIRINOX-based therapy. To promote rapid assignment of basal versus classical subtypes, an array-based single-sample classifier assay was developed and applied to 74 formalin-fixed, paraffin-embedded biopsy or resection specimens of known subtype based on transcriptomics. The Purity Independent Subtyping of Tumors (PurIST) algorithm assigns subtype based on relative expression of 16 RNAs counted by RNA sequencing (RNAseq) versus more practical array-based NanoString nCounter Elements XT technology. Subtype calls were largely concordant between RNAseq and array methods (72/74, 97% agreement). Compared with the lengthy RNAseq protocol, the array-based assay takes just 3 working days to analyze, permitting rapid reporting of tumor subtype. In conclusion, the PurIST pancreatic cancer classifier has robust performance to classify pancreatic adenocarcinoma into basal versus classical subtypes. Clinical validation studies are underway to evaluate outcome in patients whose standard-of-care chemotherapy regimen is selected on the basis of rapid subtype assignment (NCT04683315).

被引量：- 发表：1970