Assessing copy number aberrations and copy neutral loss of heterozygosity across the genome as best practice: An evidence based review of clinical utility from the cancer genomics consortium (CGC) working group for myelodysplastic syndrome, myelodysplastic/myeloproliferative and myeloproliferative neoplasms

Multiple studies have demonstrated the utility of chromosomal microarray (CMA) testing to identify clinically significant copy number alterations (CNAs) and copy-neutral loss-of-heterozygosity (CN-LOH) in myeloid malignancies. However, guidelines for integrating CMA as a standard practice for diagnostic evaluation, assessment of prognosis and predicting treatment response are still lacking. CMA has not been recommended for clinical work-up of myeloid malignancies by the WHO 2016 or the NCCN 2017 guidelines but is a suggested test by the European LeukaemiaNet 2013 for the diagnosis of primary myelodysplastic syndrome (MDS). The Cancer Genomics Consortium (CGC) Working Group for Myeloid Neoplasms systematically reviewed peer-reviewed literature to determine the power of CMA in (1) improving diagnostic yield, (2) refining risk stratification, and (3) providing additional genomic information to guide therapy. In this manuscript, we summarize the evidence base for the clinical utility of array testing in the workup of MDS, myelodysplastic/myeloproliferative neoplasms (MDS/MPN) and myeloproliferative neoplasms (MPN). This review provides a list of recurrent CNAs and CN-LOH noted in this disease spectrum and describes the clinical significance of the aberrations and how they complement gene mutation findings by sequencing. Furthermore, for new or suspected diagnosis of MDS or MPN, we present suggestions for integrating genomic testing methods (CMA and mutation testing by next generation sequencing) into the current standard-of-care clinical laboratory testing (karyotype, FISH, morphology, and flow)

Assessing copy number abnormalities and copy-neutral loss-of-heterozygosity across the genome as best practice in diagnostic evaluation of acute myeloid leukemia: An evidence-based review from the cancer genomics consortium (CGC) myeloid neoplasms working group

Structural genomic abnormalities, including balanced chromosomal rearrangements, copy number gains and losses and copy-neutral loss-of-heterozygosity (CN-LOH) represent an important category of diagnostic, prognostic and therapeutic markers in acute myeloid leukemia (AML). Genome-wide evaluation for copy number abnormalities (CNAs) is at present performed by karyotype analysis which has low resolution and is unobtainable in a subset of cases. Furthermore, examination for possible CN-LOH in leukemia cells is at present not routinely performed in the clinical setting. Chromosomal microarray (CMA) analysis is a widely available assay for CNAs and CN-LOH in diagnostic laboratories, but there are currently no guidelines how to best incorporate this technology into clinical testing algorithms for neoplastic diseases including AML. The Cancer Genomics Consortium Working Group for Myeloid Neoplasms performed an extensive review of peer-reviewed publications focused on CMA analysis in AML. Here we summarize evidence regarding clinical utility of CMA analysis in AML extracted from published data, and provide recommendations for optimal utilization of CMA testing in the diagnostic workup. In addition, we provide a list of CNAs and CN-LOH regions which have documented clinical significance in diagnosis, prognosis and treatment decisions in AML

A harmonized meta-knowledgebase of clinical interpretations of somatic genomic variants in cancer

Precision oncology relies on accurate discovery and interpretation of genomic variants, enabling individualized diagnosis, prognosis and therapy selection. We found that six prominent somatic cancer variant knowledgebases were highly disparate in content, structure and supporting primary literature, impeding consensus when evaluating variants and their relevance in a clinical setting. We developed a framework for harmonizing variant interpretations to produce a meta-knowledgebase of 12,856 aggregate interpretations. We demonstrated large gains in overlap between resources across variants, diseases and drugs as a result of this harmonization. We subsequently demonstrated improved matching between a patient cohort and harmonized interpretations of potential clinical significance, observing an increase from an average of 33% per individual knowledgebase to 57% in aggregate. Our analyses illuminate the need for open, interoperable sharing of variant interpretation data. We also provide a freely available web interface () for exploring the harmonized interpretations from these six knowledgebases

CIViCdb 2022: evolution of an open-access cancer variant interpretation knowledgebase

CIViC (Clinical Interpretation of Variants in Cancer; civicdb.org) is a crowd-sourced, public domain knowledgebase composed of literature-derived evidence characterizing the clinical utility of cancer variants. As clinical sequencing becomes more prevalent in cancer management, the need for cancer variant interpretation has grown beyond the capability of any single institution. CIViC contains peer-reviewed, published literature curated and expertly-moderated into structured data units (Evidence Items) that can be accessed globally and in real time, reducing barriers to clinical variant knowledge sharing. We have extended CIViC’s functionality to support emergent variant interpretation guidelines, increase interoperability with other variant resources, and promote widespread dissemination of structured curated data. To support the full breadth of variant interpretation from basic to translational, including integration of somatic and germline variant knowledge and inference of drug response, we have enabled curation of three new Evidence Types (Predisposing, Oncogenic and Functional). The growing CIViC knowledgebase has over 300 contributors and distributes clinically-relevant cancer variant data currently representing >3200 variants in >470 genes from >3100 publications

Trinucleotide repeats in DNA replication and gene expression.

Trinucleotide repeats in DNA replication and gene expression

MYC Amplification in Angiosarcoma Arising from an Arteriovenous Graft Site

Angiosarcoma arising in association with an arteriovenous graft (AVG) or fistula is a unique clinicopathologic scenario that appears to be gaining recognition in the literature. Among reported cases, none has described high-level MYC gene amplification, a genetic aberration that is increasingly unifying the various clinicopathologic subdivisions of angiosarcoma. We therefore report the MYC gene status in a case of angiosarcoma arising at an AVG site

Cytogenetics Is a Science, Not a Technique! Why Optical Genome Mapping Is So Important to Clinical Genetic Laboratories

Karyotyping is a technique that has been used in clinical cytogenetic laboratories for more than 40 years [...

A Unique “Composite” PTLD with Diffuse Large B-Cell and T/Anaplastic Large Cell Lymphoma Components Occurring 17 Years after Transplant

Posttransplant lymphoproliferative disorder (PTLD) comprises a spectrum ranging from polyclonal hyperplasia to aggressive monoclonal lymphomas. The majority of PTLDs are of B-cell origin while T-cell PTLDs and Hodgkin lymphoma-like PTLDs are uncommon. Here, we report a unique case of a 56-year-old man in whom a lymphoma with two distinct components developed as a duodenal mass seventeen years following a combined kidney-pancreas transplant. This PTLD, which has features not previously reported in the literature, consisted of one component of CD20 positive and EBV negative monomorphic diffuse large B-cell lymphoma. The other component showed anaplastic morphology, expressed some but not all T-cell markers, failed to express most B-cell markers except for PAX5, and was diffusely EBV positive. Possible etiologies for this peculiar constellation of findings are discussed and the literature reviewed for “composite-like” lymphomas late in the posttransplant setting

Congenital B-lymphoblastic leukemia with a cryptic MLL rearrangement and post-treatment evolution to mixed phenotype acute leukemia

Congenital leukemia is a rare event with a poor prognosis. We report a case of congenital leukemia with a cryptic rearrangement of MLL demonstrable only with RT-PCR. Interestingly, with treatment, the patient showed lineage plasticity of the leukemia with the development of monocytic lineage blasts after presenting with B-cell lineage blasts. This was heralded by the development of a new clonal cytogenetic abnormality. This case highlights the primitive nature of the leukemic cells in congenital leukemia, and emphasizes that RT-PCR for MLL rearrangements may identify a subset of cases which are otherwise negative by karyotyping, FISH, and chromosomal microarrays