Homologous recombination pathway gene variants identified by tumor-only sequencing assays in lung carcinoma patients.

Background: The homologous recombination (HR) repair pathway plays a key role in double-stranded DNA break repair, and germline HR pathway gene variants are associated with increased risk of several cancers, including breast and ovarian cancer. HR deficiency is also a therapeutically targetable phenotype.

Methods: Somatic (tumour-only) sequencing was performed on 1,109 cases of lung tumors, and the pathological data were reviewed to filter for lung primary carcinomas.

Optimization of Sources of Circulating Cell-Free DNA Variability for Downstream Molecular Analysis.

Circulating cell-free DNA (ccfDNA) is used increasingly as a cancer biomarker for prognostication, as a correlate for tumor volume, or as input for downstream molecular analysis. Determining optimal blood processing and ccfDNA quantification are crucial for ccfDNA to serve as an accurate biomarker as it moves into the clinical realm. Whole blood was collected from 50 subjects, processed to plasma, and used immediately or frozen at -80°C.

TP53 Mutation and Extraneural Metastasis of Glioblastoma: Insights From an Institutional Experience and Comprehensive Literature Review.

Extraneural metastases of glioblastoma (GBM), although rare, are becoming an increasingly recognized occurrence. Currently, the biological mechanism underlying this rare occurrence is not understood. To explore the potential genomic drivers of extraneural metastasis in GBM, we present the molecular features of 4 extraneural metastatic GBMs, along with a comprehensive review and analysis of previously reported cases that had available molecular characterization.

Molecular Neuropathology in Practice: Clinical Profiling and Integrative Analysis of Molecular Alterations in Glioblastoma.

Molecular profiling of glioblastoma has revealed complex cytogenetic, epigenetic, and molecular abnormalities that are necessary for diagnosis, prognosis, and treatment. Our neuro-oncology group has developed a data-driven, institutional consensus guideline for efficient and optimal workup of glioblastomas based on our routine performance of molecular testing. We describe our institution's testing algorithm, assay development, and genetic findings in glioblastoma, to illustrate current practices and challenges in neuropathology related to molecular and genetic testing.

Analytical Validation of a Highly Sensitive, Multiplexed Chronic Myeloid Leukemia Monitoring System Targeting BCR-ABL1 RNA.

This study describes the analytical performance of the QuantideX qPCR BCR-ABL IS Kit, the first Food and Drug Administration-cleared assay designed to monitor breakpoint cluster region-Abelson tyrosine-protein kinase 1 (BCR-ABL1) fusion transcripts isolated from peripheral blood specimens from patients with chronic myeloid leukemia. This multiplex real-time quantitative RT-PCR assay amplifies both e13a2 and e14a2 Major BCR-ABL1 transcripts and the reference target ABL1. The test results are provided in international scale (IS) values by incorporating armored RNA-based calibrators that have defined IS values tied directly to the World Health Organization BCR-ABL1 Primary Reference Materials, without the necessity of determining and maintaining conversion factors.

Copy number alterations determined by single nucleotide polymorphism array testing in the clinical laboratory are indicative of gene fusions in pediatric cancer patients.

Gene fusions resulting from structural rearrangements are an established mechanism of tumorigenesis in pediatric cancer. In this clinical cohort, 1,350 single nucleotide polymorphism (SNP)-based chromosomal microarrays from 1,211 pediatric cancer patients were evaluated for copy number alterations (CNAs) associated with gene fusions. Karyotype or fluorescence in situ hybridization studies were performed in 42% of the patients.

Whole Chromosome 7 Gain Predicts Higher Risk of Recurrence in Pediatric Pilocytic Astrocytomas Independently From KIAA1549-BRAF Fusion Status.

The most frequent genetic alteration identified in pediatric pilocytic astrocytomas and pilomyxoid variant is the KIAA1549-BRAF fusion, which typically results from a 2.0 Mb tandem duplication in chromosome band 7q34. Less frequent abnormalities include fusion genes,BRAF, FGFR, KRAS, and NF1 point mutations, and whole chromosome gains.

Clonal evolution and clinical significance of copy number neutral loss of heterozygosity of chromosome arm 6p in acquired aplastic anemia.

Acquired aplastic anemia (aAA) results from the T cell-mediated autoimmune destruction of hematopoietic stem cells. Factors predicting response to immune suppression therapy (IST) or development of myelodysplastic syndrome (MDS) are beginning to be elucidated. Our recent data suggest most patients with aAA treated with IST develop clonal somatic genetic alterations in hematopoietic cells.

Biology and Treatment of Rhabdoid Tumor.

Rhabdoid tumor is a rare, highly aggressive malignancy that primarily affects infants and young children. These tumors typically arise in the brain and kidney, although extrarenal, non-central nervous system tumors in almost all soft-tissue sites have been described. SMARCB1 is a member of the SWI/SNF chromatin-remodeling complex and functions as a tumor suppressor in the vast majority of rhabdoid tumors.

Emergence of clonal hematopoiesis in the majority of patients with acquired aplastic anemia.

Acquired aplastic anemia (aAA) is a nonmalignant disease caused by autoimmune destruction of early hematopoietic cells. Clonal hematopoiesis is a late complication, seen in 20-25% of older patients. We hypothesized that clonal hematopoiesis in aAA is a more general phenomenon, which can arise early in disease, even in younger patients.

Disrupting LIN28 in atypical teratoid rhabdoid tumors reveals the importance of the mitogen activated protein kinase pathway as a therapeutic target.

Atypical teratoid rhabdoid tumor (AT/RT) is among the most fatal of all pediatric brain tumors. Aside from loss of function mutations in the SMARCB1 (BAF47/INI1/SNF5) chromatin remodeling gene, little is known of other molecular drivers of AT/RT. LIN28A and LIN28B are stem cell factors that regulate thousands of RNAs and are expressed in aggressive cancers.

Chromosome band 7q34 deletions resulting in KIAA1549-BRAF and FAM131B-BRAF fusions in pediatric low-grade Gliomas.

The majority of pediatric low-grade gliomas (LGGs) are characterized by constitutive activation of the mitogen-activated protein kinase (MAPK) pathway through various mechanisms including BRAF mutations, inactivation of NF1, and KIAA1549-BRAF and FAM131B-BRAF fusions. The KIAA1549-BRAF fusion typically results from a 2.0 Mb tandem duplication in chromosome band 7q34.

Diagnostic application of high resolution single nucleotide polymorphism array analysis for children with brain tumors.

Single nucleotide polymorphism (SNP) array analysis is currently used as a first tier test for pediatric brain tumors at The Children's Hospital of Philadelphia. The results from 100 consecutive patients are summarized in the present report. Eighty-seven percent of the tumors had at least one pathogenic copy number alteration.

Single nucleotide polymorphism array analysis of bone marrow failure patients reveals characteristic patterns of genetic changes.

The bone marrow failure syndromes (BMFS) are a heterogeneous group of rare blood disorders characterized by inadequate haematopoiesis, clonal evolution, and increased risk of leukaemia. Single nucleotide polymorphism arrays (SNP-A) have been proposed as a tool for surveillance of clonal evolution in BMFS. To better understand the natural history of BMFS and to assess the clinical utility of SNP-A in these disorders, we analysed 124 SNP-A from a comprehensively characterized cohort of 91 patients at our BMFS centre.

Common polymorphic deletion of glutathione S-transferase theta predisposes to acquired aplastic anemia: Independent cohort and meta-analysis of 609 patients.

Acquired aplastic anemia (AA) is a rare life-threatening bone marrow failure syndrome, caused by autoimmune destruction of hematopoietic stem and progenitor cells. Epidemiologic studies suggest that environmental exposures and metabolic gene polymorphisms contribute to disease pathogenesis. Several case-control studies linked homozygous deletion of the glutathione S-transferase theta (GSTT1) gene to AA; however, the role of GSTT1 deletion remains controversial as other studies failed to confirm the association.

A conserved tissue-specific homeodomain-less isoform of MEIS1 is downregulated in colorectal cancer.

Colorectal cancer is one of the most common cancers in developed nations and is the result of both environmental and genetic factors. Many of the genetic lesions observed in colorectal cancer alter expression of homeobox genes, which encode homeodomain transcription factors. The MEIS1 homeobox gene is known to be involved in several hematological malignancies and solid tumors and recent evidence suggests that expression of the MEIS1 transcript is altered in colorectal cancer.

Identification of Mom12 and Mom13, two novel modifier loci of Apc (Min) -mediated intestinal tumorigenesis.

Colorectal cancer is a heterogeneous disease resulting from a combination of genetic and environmental factors. The C57BL/6J (B6) Apc (Min/+) mouse develops polyps throughout the gastrointestinal tract and has been a valuable model for understanding the genetic basis of intestinal tumorigenesis. Apc (Min/+) mice have been used to study known oncogenes and tumor suppressor genes on a controlled genetic background.

The armadillo repeat domain of Apc suppresses intestinal tumorigenesis.

The adenomatous polyposis coli (APC) gene is known to act as a tumor suppressor gene in both sporadic and hereditary colorectal cancer by negatively regulating WNT signaling. Familial adenomatous polyposis (FAP) patients develop intestinal polyps due to the presence of a single germline mutation in APC. The severity of the FAP phenotype is a function of the position of the APC mutation, indicating a complex role for APC that extends beyond the canonical WNT pathway.