Analysis of Concordance Between Next-Generation Sequencing Assessment of Microsatellite Instability and Immunohistochemistry-Mismatch Repair From Solid Tumors.

Purpose: The new CAP guideline published in August 2022 recommends using immunohistochemistry (IHC) to test for mismatch repair defects in gastroesophageal (GE), small bowel (SB), or endometrial carcinoma (EC) cancers over next-generation sequencing assessment of microsatellite instability (NGS-MSI) for immune checkpoint inhibitor (ICI) therapy eligibility and states there is a preference to use IHC over NGS-MSI in colorectal carcinoma (CRC).

Methods: We assessed the concordance of NGS-MSI and IHC-MMR from a very large cohort across the spectrum of solid tumors.

Results: Of the over 190,000 samples with both NGS-MSI and IHC-MMR about 1,160 were initially flagged as discordant.

Fetal Type Morphologies Suggest the Presence of DICER1 Hotspot Mutations in Non-small Cell Lung Cancer.

Germline and somatic pathogenic variants (PVs) in DICER1 , encoding a miRNA biogenesis protein, are associated with a wide variety of highly specific pathologic entities. The lung tumors pleuropulmonary blastoma, pulmonary blastoma (PB), and well-differentiated fetal lung adenocarcinoma (WDFLAC) are all known to harbor DICER1 biallelic variants (loss of function and/or somatic hotspot missense mutations), and all share pathologic features reminiscent of the immature lung. However, the role of DICER1 PVs in non-small cell lung cancer (NSCLC) is relatively unknown.

Pan-tumor survey of ROS1 fusions detected by next-generation RNA and whole transcriptome sequencing.

Background: Two ROS1 tyrosine kinase inhibitors have been approved for ROS1 fusion positive (ROS1+) non-small cell lung cancer (NSCLC) tumors. We performed a pan-tumor analysis of the incidence of ROS1 fusions to assess if more ROS1+ patients who could benefit from ROS1 TKIs could be identified.

Methods: A retrospective analysis of ROS1 positive solid malignancies identified by targeted RNA sequencing and whole transcriptome sequencing of clinical tumor samples performed at Caris Life Science (Phoenix, AZ).

Pan-tumor survey of RET fusions as detected by next-generation RNA sequencing identified RET fusion positive colorectal carcinoma as a unique molecular subset.

Background: RET fusions are driver alterations in cancer and are most commonly found in non-small cell lung cancer and well-differentiated thyroid cancer. However, RET fusion have been reported in other solid tumors.

Material And Methods: A retrospective analysis of RET+ solid malignancies identified by targeted RNA sequencing and whole transcriptome sequencing of clinical tumor samples performed at Caris Life Science (Phoenix, AZ).

Reversion Mutations in Patients Treated with Poly ADP-Ribose Polymerase (PARP) Inhibitors or Platinum Agents.

: Reversion mutations in , resulting in restoration of the open reading frame, have been identified as a mechanism of resistance to platinum-based chemotherapy or PARP inhibition. We sought to explore the incidence of reversion mutations in different tumor types. : We retrospectively analyzed molecular profiling results from primary and/or metastatic tumor samples submitted by multiple institutions.

Characterization and modeling of a thermoplastic elastomer tissue simulant under uniaxial compression loading for a wide range of strain rates.

Characterization and modeling of the mechanical behavior of biological tissues are critical to many biomedical related applications. For research and development, various soft materials have often been used as a tissue substitute. Among them, the mineral oil-based synthetic polymer styrene-ethylene-butylene-styrene (SEBS) gel has gained some popularity due to its superior mechanical and physical properties.

Comprehensive Analysis of R-Spondin Fusions and RNF43 Mutations Implicate Novel Therapeutic Options in Colorectal Cancer.

Purpose: Gene fusions involving R-spondin (RSPOfp) and RNF43 mutations have been shown to drive Wnt-dependent tumor initiation in colorectal cancer. Herein, we aimed to characterize the molecular features of RSPOfp/RNF43 mutated (mut) compared with wild-type (WT) colorectal cancers to gain insights into potential rationales for therapeutic strategies.

Experimental Design: A discovery cohort was classified for RSPOfp/RNF43 status using DNA/RNA sequencing and IHC.

Prognostic Values of G-Protein Mutations in Metastatic Uveal Melanoma.

Uveal melanoma is the most common primary ocular malignancy in adults, characterized by gene mutations in G protein subunit alpha q () and G protein subunit alpha 11 (). Although they are considered to be driver mutations, their role in MUM remains elusive. We investigated key somatic mutations of MUM and their impact on patients' survival after development of systemic metastasis (Met-to-Death).

Identification of Novel α and Fusions in NSCLC Plus Additional Novel Fusions in Other Solid Tumors by Whole Transcriptome Sequencing.

Introduction: A novel fusion has recently been identified in NSCLC. We surveyed a large tumor database comprehensively profiled by whole transcriptome sequencing to investigate the incidence and distribution of fusions among various solid tumors.

Methods: Tumor samples submitted for clinical molecular profiling at Caris Life Sciences (Phoenix, AZ) that underwent whole transcriptome sequencing (NovaSeq [Illumina, San Diego, CA]) were retrospectively analyzed for fusion events.

Predicted Immunogenicity of CDK12 Biallelic Loss-of-Function Tumors Varies across Cancer Types.

CDK12 biallelic inactivation is associated with a distinct genomic signature of focal tandem duplications (FTDs). Gene fusions resulting from FTDs increase neoantigen load, raising interest in CDK12 as a biomarker of response to immune checkpoint inhibitors. Despite evidence of FTDs in multiple CDK12-altered cancer types, notably prostate and ovarian, report of fusion-associated neoantigen load is limited to prostate cancer.

Eosinophilic vacuolated tumor (EVT) of kidney demonstrates sporadic TSC/MTOR mutations: next-generation sequencing multi-institutional study of 19 cases.

A distinct renal tumor has recently been described as "high-grade oncocytic renal tumor" and "sporadic renal cell carcinoma with eosinophilic and vacuolated cytoplasm". The Genitourinary Pathology Society (GUPS) consensus proposed a unifying name "eosinophilic vacuolated tumor" (EVT) for this emerging entity. In this multi-institutional study, we evaluated 19 EVTs, particularly their molecular features and mutation profile, using next-generation sequencing.

Tumour mutational burden, microsatellite instability, and actionable alterations in metastatic colorectal cancer: Next-generation sequencing results of TRIBE2 study.

Background: We performed a comprehensive genomic profiling of tumour samples from metastatic colorectal cancer (mCRC) patients enrolled in the TRIBE2 study to assess the concordance among different techniques to evaluate mismatch repair (MMR) and microsatellite instability (MSI) status, to characterize tumours according to the tumour mutational burden (TMB) and explore the clinical relevance of different TMB cutpoints, and to investigate the prevalence of alterations actionable with targeted approaches or immune checkpoint inhibitors.

Material And Methods: Tumour samples of 296 (44%) of 679 enrolled patients underwent 592-gene DNA next-generation sequencing (NGS). MMR status was assessed by immunohistochemistry (MMR-IHC), and MSI status was assessed by NGS (MSI-NGS).

TERT Gene Fusions Characterize a Subset of Metastatic Leydig Cell Tumors.

Objective: Metastatic Leydig cell tumors (LCT) are rare, difficult-to-treat malignancies without known underlying molecular-genetic events. An index case of metastatic LCT showed an LDLR-TERT gene fusion upon routine genetic profiling for detection of therapeutic targets, which was then followed by an investigation into a cohort of additional LCTs.

Patients And Methods: Twenty-nine LCT (27 male and 2 female patients) were profiled using next-generation sequencing and immunohistochemistry.

Poroid adnexal skin tumors with YAP1 fusions exhibit similar histopathologic features: A series of six YAP1-rearranged adnexal skin tumors.

Background: Adnexal skin tumors are diagnostically challenging with few known molecular signatures. Recently, however, YAP1-MAML2 and YAP1-NUTM1 fusions were identified in poroid adnexal skin tumors.

Methods: Herein, we subjected eight poroid adnexal skin tumors (three poromas and five porocarcinomas) to fusion gene analysis by whole transcriptome sequencing and next-generation DNA sequencing analysis.

Molecular Profiling Reveals Limited Targetable Biomarkers in Neuroendocrine Carcinoma of the Cervix.

Neuroendocrine carcinoma of the cervix (NEC) is a rare and highly aggressive cervical malignancy. Given that no targeted therapy has been approved specifically to NEC, we investigated the presence of novel, potentially targetable biomarkers in a large cohort of NEC. Sixty-two NEC were molecularly profiled for biomarkers of targeted therapies including antibody-drug conjugates [delta-like canonical notch ligand 3 (DLL3), a trophoblast cell surface antigen 2 (TROP-2), and folate receptor 1 (FOLR1)], NTRK1-3 gene fusions, and immune checkpoint inhibitors [programmed death-ligand 1 (PD-L1), tumor mutational burden, and microsatellite instability] using immunohistochemistry and DNA/RNA next-generation sequencing assays.

Population bias in somatic measurement of microsatellite instability status.

Microsatellite instability (MSI) is a key secondary effect of a defective DNA mismatch repair mechanism resulting in incorrectly replicated microsatellites in many malignant tumors. Historically, MSI detection has been performed by fragment analysis (FA) on a panel of representative genomic markers. More recently, using next-generation sequencing (NGS) to analyze thousands of microsatellites has been shown to improve the robustness and sensitivity of MSI detection.

Predictive mechanics-based model for depth of cut (DOC) of waterjet in soft tissue for waterjet-assisted medical applications.

The use of waterjet technology is now prevalent in medical applications including surgery, soft tissue resection, bone cutting, waterjet steerable needles, and wound debridement. The depth of the cut (DOC) of a waterjet in soft tissue is an important parameter that should be predicted in these applications. For instance, for waterjet-assisted surgery, selective cutting of tissue layers is a must to avoid damage to deeper tissue layers.

Novel targetable biomarkers in clear cell carcinoma of the breast uncovered by molecular profiling: A study of nine cases.

We profiled nine pure clear cell carcinomas of the breast using massively parallel DNA and RNA sequencing (NGS), in situ hybridization (ISH), and immunohistochemistry (IHC). All cases were primary mammary clear cell carcinomas that were diagnosed in female patients (mean age: 53.4 years; range: 31-69 years).