Changes

The laboratory should be consistent in the analysis, interpretation, and reporting of microarray results. The laboratory should have a record of and be familiar with the microarray coverage, including known cancer-associated genes and regions, benign and/or common population CNVs, and common genetic disorders caused by genomic CNVs and/or LOH.

The laboratory should be consistent in the analysis, interpretation, and reporting of microarray results. The laboratory should have a record of and be familiar with the microarray coverage, including known cancer-associated genes and regions, benign and/or common population CNVs, and common genetic disorders caused by genomic CNVs and/or LOH.

The laboratory should establish the methods for microarray result analysis and interpretation using the following recommendations.

The laboratory should establish the methods for microarray result analysis and interpretation using the following recommendations.

Analysis and interpretation of microarray data from a neoplastic disorder should take into account the working diagnosis, the clinical information provided, and other disorders in the differential diagnosis. The indication or working diagnosis may prove to be incorrect after the diagnostic workup is complete; thus, the laboratory should be aware of other disorders that may be in the differential.

Analysis and interpretation of microarray data from a neoplastic disorder should take into account the working diagnosis, the clinical information provided, and other disorders in the differential diagnosis. The indication or working diagnosis may prove to be incorrect after the diagnostic workup is complete; thus, the laboratory should be aware of other disorders that may be in the differential.

The laboratory should be familiar with recurrent, clonal aberrations associated with particular diagnoses. In addition, the laboratory should be familiar with specific genes known to be pathogenic or to contribute to the pathogenesis of a particular disorder. The medical literature should be used to stay abreast of current disease-specific genetic aberrations, as well as the diagnostic, prognostic, and therapeutic significance of aberrations.

The laboratory should be familiar with recurrent, clonal aberrations associated with particular diagnoses. In addition, the laboratory should be familiar with specific genes known to be pathogenic or to contribute to the pathogenesis of a particular disorder. The medical literature should be used to stay abreast of current disease-specific genetic aberrations, as well as the diagnostic, prognostic, and therapeutic significance of aberrations.

The size of a CNV is relevant, as larger CNVs encompassing multiple genes are more likely to have a clinical impact; however, very small CNVs that interrupt or delete an established cancer-associated gene may be clinically significant. A single laboratory-established CNV size cutoff or threshold for determination of inclusion of a CNV in a clinical report should not be used as the sole determinant of a call. The laboratory should establish methods for detection of clinically significant CNVs that fall below laboratory-established thresholds, particularly in regions of known cancer-associated genes.

The size of a CNV is relevant, as larger CNVs encompassing multiple genes are more likely to have a clinical impact; however, very small CNVs that interrupt or delete an established cancer-associated gene may be clinically significant. A single laboratory-established CNV size cutoff or threshold for determination of inclusion of a CNV in a clinical report should not be used as the sole determinant of a call. The laboratory should establish methods for detection of clinically significant CNVs that fall below laboratory-established thresholds, particularly in regions of known cancer-associated genes.

The genomic content of the CNV should be carefully examined for genes relevant to disorders in the differential diagnosis, gene-rich sequences, or genes known to have a clinical association. CNVs encompassing known oncogenes or tumor suppressor genes may have significance, although the implications of the CNV for the particular disorder or patient being studied may not be clear based on current literature.

The genomic content of the CNV should be carefully examined for genes relevant to disorders in the differential diagnosis, gene-rich sequences, or genes known to have a clinical association. CNVs encompassing known oncogenes or tumor suppressor genes may have significance, although the implications of the CNV for the particular disorder or patient being studied may not be clear based on current literature.

Thresholds or minimal criteria to identify clinically important ROHs consistent with LOH (LOH or AOH) should be established. ROHs associated with parental consanguinity or uniparental disomy should be distinguished from acquired LOH. Distinction of acquired versus constitutional AOH may be facilitated by detection of the clonal aberration in affected tissue (acquired LOH) and/or detection (or not) of the aberration in unaffected tissue (constitutional LOH). Homozygosity in a region that contains a tumor suppressor gene may be associated with an inherited cancer predisposition syndrome. Constitutional analysis should be recommended as appropriate.

Thresholds or minimal criteria to identify clinically important ROHs consistent with LOH (LOH or AOH) should be established. ROHs associated with parental consanguinity or uniparental disomy should be distinguished from acquired LOH. Distinction of acquired versus constitutional AOH may be facilitated by detection of the clonal aberration in affected tissue (acquired LOH) and/or detection (or not) of the aberration in unaffected tissue (constitutional LOH). Homozygosity in a region that contains a tumor suppressor gene may be associated with an inherited cancer predisposition syndrome. Constitutional analysis should be recommended as appropriate.

Public databases and the medical literature should be used in determining the significance of CNVs. Available databases include (all last accessed 26 January 2013) the following:

Public databases and the medical literature should be used in determining the significance of CNVs. Available databases include (all last accessed 26 January 2013) the following:

     Database of Genomic Variants (http://projects.tcag.ca/variation/),

 

     Online Mendelian Inheritance in Man (http:www.ncbi.nlm.nih.gov/omim/),

     <li>Database of Genomic Variants (http://projects.tcag.ca/variation/),</li>

     DECIPHER (http:www.sanger.ac.uk/research/areas/),

     <li>Online Mendelian Inheritance in Man (http:www.ncbi.nlm.nih.gov/omim/),</li>

     dbVar—database of Structural Variation (http:www.ncbi.nlm.nih.gov/dbvar),

     <li>DECIPHER (http:www.sanger.ac.uk/research/areas/),</li>

     dbGaP—database of Genotypes and Phenotypes (http:www.ncbi.nlm.nih.gov/gap),

     <li>dbVar—database of Structural Variation (http:www.ncbi.nlm.nih.gov/dbvar),</li>

     Memorial Sloan-Kettering Cancer Center (http://cbio.mskcc.org/CancerGenes),

     <li>dbGaP—database of Genotypes and Phenotypes (http:www.ncbi.nlm.nih.gov/gap),</li>

     The Cancer Genome Anatomy Project (http:www.ncbi.nlm.nih.gov/ncicgap/),

     <li>Memorial Sloan-Kettering Cancer Center (http://cbio.mskcc.org/CancerGenes),</li>

     UCSC Genome Bioinformatics (http://genome.ucsc.edu/cgi-bin/hgGateway),

     <li>The Cancer Genome Anatomy Project (http:www.ncbi.nlm.nih.gov/ncicgap/),</li>

     The Cancer Genome Atlas (http://cancergenome.nih.gov/),

     <li>UCSC Genome Bioinformatics (http://genome.ucsc.edu/cgi-bin/hgGateway),</li>

     Ensembl (http://uswest.ensembl.org/Homo_sapiens/Gene/Summary),

     <li>The Cancer Genome Atlas (http://cancergenome.nih.gov/),</li>

     The International Standards for Cytogenomics Arrays Consortium (https://www.iscaconsortium.org/), and

     <li>Ensembl (http://uswest.ensembl.org/Homo_sapiens/Gene/Summary),</li>

     Wellcome Trust Sanger Institute (http://www.sanger.ac.uk/genetics/CGP/cosmic/).

     <li>The International Standards for Cytogenomics Arrays Consortium (https://www.iscaconsortium.org/), and</li>

     <li>Wellcome Trust Sanger Institute (http://www.sanger.ac.uk/genetics/CGP/cosmic/).</li>

 

Laboratories should document pathogenic CNVs, CNVs of uncertain significance, benign CNVs, and CNVs thought or determined to be constitutional. The intralaboratory data should be used along with external data as a reference for interpretation of data from new studies.

Laboratories should document pathogenic CNVs, CNVs of uncertain significance, benign CNVs, and CNVs thought or determined to be constitutional. The intralaboratory data should be used along with external data as a reference for interpretation of data from new studies.

Using the guidelines outlined above for systematic investigation of a CNV for clinical significance, it is recommended that the interpreting laboratory geneticist use the following categories for reporting. Consistent terminology will facilitate unambiguous communication of clinical significance. Taking into account that tumors may be genetically complex, it may not be feasible to provide a detailed interpretation of every CNV and/or AOH region detected. In such cases, a narrative to describe variants and their clinical significance and interpretation should be provided to communicate the desired information. When feasible, the laboratory should provide details of specific CNV and AOH anomalies.

Using the guidelines outlined above for systematic investigation of a CNV for clinical significance, it is recommended that the interpreting laboratory geneticist use the following categories for reporting. Consistent terminology will facilitate unambiguous communication of clinical significance. Taking into account that tumors may be genetically complex, it may not be feasible to provide a detailed interpretation of every CNV and/or AOH region detected. In such cases, a narrative to describe variants and their clinical significance and interpretation should be provided to communicate the desired information. When feasible, the laboratory should provide details of specific CNV and AOH anomalies.

Acquired. The CNV is a documented clinically significant and/or disease-associated clonal genetic aberration.

''Acquired.'' The CNV is a documented clinically significant and/or disease-associated clonal genetic aberration.

Constitutional. Microarray analysis will inevitably reveal common benign and rare constitutional CNVs. Rare constitutional CNVs should be noted and investigated for clinical significance, e.g., cancer-predisposing gene aberration and/or deletion or duplication associated with a known constitutional syndrome. Evaluation and reporting of constitutional CNVs should follow the guidelines set forth in the American College of Medical Genetics and Genomics Standards and Guidelines for interpretation and reporting of constitutional CNVs.30

''Constitutional.'' Microarray analysis will inevitably reveal common benign and rare constitutional CNVs. Rare constitutional CNVs should be noted and investigated for clinical significance, e.g., cancer-predisposing gene aberration and/or deletion or duplication associated with a known constitutional syndrome. Evaluation and reporting of constitutional CNVs should follow the guidelines set forth in the American College of Medical Genetics and Genomics Standards and Guidelines for interpretation and reporting of constitutional CNVs.30

This category may include CNVs that are not known to be associated with disease but meet the reporting criteria established by the laboratory. A CNV in this category is not clearly pathogenic, and there is insufficient evidence for an unequivocal determination of clinical significance. The laboratory should interpret novel CNVs in light of the available clinical and/or pathological information and current literature. Reporting CNVs of uncertain significance is at the discretion of the laboratory. If reported, they may be categorized as follows:

This category may include CNVs that are not known to be associated with disease but meet the reporting criteria established by the laboratory. A CNV in this category is not clearly pathogenic, and there is insufficient evidence for an unequivocal determination of clinical significance. The laboratory should interpret novel CNVs in light of the available clinical and/or pathological information and current literature. Reporting CNVs of uncertain significance is at the discretion of the laboratory. If reported, they may be categorized as follows:

Uncertain clinical significance, acquired, likely pathogenic. Many neoplastic disorders have well-recognized and/or well-characterized aberrations. However, microarray resolution may reveal uncharacterized CNVs. If reported, the discussion should avoid speculation as to the pathogenicity or clinical significance of the CNV without supporting evidence.

''Uncertain clinical significance, acquired, likely pathogenic.'' Many neoplastic disorders have well-recognized and/or well-characterized aberrations. However, microarray resolution may reveal uncharacterized CNVs. If reported, the discussion should avoid speculation as to the pathogenicity or clinical significance of the CNV without supporting evidence.

Examples: (i) A CNV described in a single case report of a similar neoplasm. (ii) A CNV with a gene in the interval that has potential or relevant function as an oncogene or tumor suppressor gene or that belongs to another known gene family that has an association with neoplastic processes but not the neoplastic process being studied. (iii) A CNV that appears related to the clonal neoplastic process being studied by having a similar log2 ratio as the clonal process being studied but is not a recognized aberration. Evolution and heterogeneity of a clonal neoplastic process is common. Microarray is likely to reveal new, but uncharacterized, aberrations that may be reported in this category.

Examples: (i) A CNV described in a single case report of a similar neoplasm. (ii) A CNV with a gene in the interval that has potential or relevant function as an oncogene or tumor suppressor gene or that belongs to another known gene family that has an association with neoplastic processes but not the neoplastic process being studied. (iii) A CNV that appears related to the clonal neoplastic process being studied by having a similar log2 ratio as the clonal process being studied but is not a recognized aberration. Evolution and heterogeneity of a clonal neoplastic process is common. Microarray is likely to reveal new, but uncharacterized, aberrations that may be reported in this category.

Collection of the data of CNVs of uncertain significance is encouraged to build a database for intralaboratory reference, for correlation with clinical parameters, and for sharing in publications. The eventual understanding of the clinical significance will depend on accumulation of sufficient information and correlation with clinical features.

Collection of the data of CNVs of uncertain significance is encouraged to build a database for intralaboratory reference, for correlation with clinical parameters, and for sharing in publications. The eventual understanding of the clinical significance will depend on accumulation of sufficient information and correlation with clinical features.

Uncertain clinical significance, likely constitutional. Refer to the American College of Medical Genetics and Genomics Standards and Guidelines for interpretation and reporting of constitutional CNVs.30

''Uncertain clinical significance, likely constitutional.'' Refer to the American College of Medical Genetics and Genomics Standards and Guidelines for interpretation and reporting of constitutional CNVs.30

Uncertain clinical significance, not otherwise specified. A CNV that meets the laboratory parameters for reporting but has no features to categorize it further.

''Uncertain clinical significance, not otherwise specified.'' A CNV that meets the laboratory parameters for reporting but has no features to categorize it further.

Benign. Reporting of benign CNVs is at the discretion of the laboratory. The laboratory should be familiar with common benign CNVs, stay current with the literature, and interpret results with this knowledge. This category will include: (i) CNVs reported in multiple peer-reviewed publications or curated databases as a benign variant and (ii) CNVs without relevant genetic content that meet criteria for reporting. It should be recognized, however, that cancer-associated anomalies that occur in known variant regions might not be benign.

''Benign.'' Reporting of benign CNVs is at the discretion of the laboratory. The laboratory should be familiar with common benign CNVs, stay current with the literature, and interpret results with this knowledge. This category will include: (i) CNVs reported in multiple peer-reviewed publications or curated databases as a benign variant and (ii) CNVs without relevant genetic content that meet criteria for reporting. It should be recognized, however, that cancer-associated anomalies that occur in known variant regions might not be benign.

== Reporting Guidelines for Microarray Analysis of Neoplastic Disorders ==

== Reporting Guidelines for Microarray Analysis of Neoplastic Disorders ==