Virginia Tech Molecular Diagnostics Lab

Molecular characterization of tumors informs diagnostic classification, prognostic assessment, and, in a subset of cases, therapy selection. The Cancer Genomics program at the MDL provides analytically validated clinical assays for defined indications, supports assays undergoing validation, and maintains research-use platforms that extend the analytical reach of the laboratory. Each category is presented on its own terms.

Comprehensive genomic profiling (CGP) refers to the simultaneous evaluation of multiple classes of genomic alteration in a single assay, typically by targeted next-generation sequencing. The scope of a specific CGP assay is defined by its panel content, the specimen types accepted, and the alteration classes covered by analytical validation. 

Genomic alteration classes

Single-nucleotide variants (SNVs). Single-base substitutions in DNA, classified by predicted functional consequence and clinical significance.

Small insertions and deletions (indels). Short additions or losses of nucleotides within coding or regulatory regions.

Copy-number alterations (CNAs). Gains or losses of gene or chromosomal segments, potentially reflecting oncogene amplification or tumor-suppressor loss.

Gene fusions. Joining of segments of two genes to form a chimeric transcript, recurrent in several tumor types.

Structural variants. Larger rearrangements including inversions, translocations, and complex events. Detection may require dedicated approaches beyond short-read targeted sequencing.

Microsatellite instability (MSI). A signature of impaired DNA mismatch repair, relevant as a biomarker in several tumor types.

Tumor mutational burden (TMB). The number of somatic mutations per megabase within the sequenced region.

Each alteration class is reported clinically only within the scope of a validated assay. Detection on a research-use platform does not constitute a clinical finding.

How molecular findings are used

Diagnostic classification. Specific alterations contribute to the classification of certain hematologic and solid-tumor entities under contemporary pathology frameworks.

Prognosis. In defined settings, particular alterations carry prognostic weight.

Clinical-trial eligibility. Molecular findings can align a patient with an available trial.

Therapy selection. In defined tumor types and clinical contexts, specific alterations inform decisions about targeted therapy as determined by the treating clinician.

Not every alteration detected in a tumor is actionable. Many findings are of uncertain significance, some are established as benign, and the actionability of a given variant depends on tumor type, prior treatment, and current evidence.

The evidentiary hierarchy

The reporting framework distinguishes four levels, and these are held as separate steps.

Analytical result.  The observation returned by the assay, a variant call at a specified position, at a specified allele frequency, with defined quality metrics.

Molecular interpretation.  The classification of that observation with respect to pathogenicity, oncogenic potential, and current biological understanding.

Potential clinical relevance.  The extent to which the interpreted molecular finding may bear on diagnosis, prognosis, trial eligibility, or therapy in the clinical context under consideration.

Clinical decision.  The action taken by the treating clinician, informed by the molecular result and integrated with pathology, imaging, and the patient's clinical circumstances. Molecular findings must be interpreted within the patient's clinical and pathological context. The laboratory issues a report; the treating clinician makes clinical decisions. 

Limitations of genomic testing

•    Coverage is defined by the assay panel. Alterations outside the panel are not assessed.

•    Detection is bounded by analytical sensitivity, tumor content, and specimen quality.

•    Not every detected alteration has established clinical significance.

•    Variants of uncertain significance may be reported without direct clinical implication at the time of testing.

•    Absence of a detected alteration does not exclude an alteration below the limit of detection or outside the assay's scope.

•    Molecular findings inform, but do not determine, clinical outcomes.

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