Somatic or Germline? Enhancing Tumor Profiling Accuracy

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Correct genomic profiling is crucial for scientific decision-making and optimizing therapy suggestions. Tumor-only sequencing has been adopted by many laboratories to information precision oncology approaches; nonetheless, a serious limitation of this method is its lack of ability to differentiate true somatic mutations from germline variants with certainty. It’s estimated that as much as one-third of mutations recognized via tumor-only sequencing could also be false-positive germline modifications, together with these in actionable genes.¹

Matched tumor-normal sequencing is an efficient technique involving the paired evaluation of a tumor pattern and a traditional pattern from the identical particular person.^{1– 4} When variants current within the regular pattern are used as a filter towards the tumor pattern, tumor-specific variants may be recognized with a excessive diploma of confidence. Variants discovered at low frequencies within the regular pattern may be reliably labeled as false positives if they aren’t considerably enriched within the tumor.

Sophia Genetics GEN May 2025 sponsored content Figure — Determine tailored from Mandelker, D, & Ceyhan-Birsoy, O. (2020)²

Whereas an important perform of matched tumor-normal sequencing is to establish and retain somatic mutations, it additionally serves different necessary capabilities. These embody:

Decreasing false positives attributable to pattern variability and sequencing artifacts

Samples can exhibit variability attributable to elements akin to environmental influences, organic processes, and pattern dealing with. Matched tumor-normal sequencing gives a built-in baseline of background noise ensuing from these elements, or from introduction of sequencing artifacts, which may be filtered out.

Within the case of formalin-fixed, paraffin-embedded (FFPE) samples, extracted DNA is commonly fragmented and of a decrease high quality than recent tissue samples. Matched tumor-normal sequencing gives a comparability that helps distinguish true alterations from noise ensuing from degradation of the DNA, enhancing sensitivity.

Decreasing false positives from clonal hematopoiesis of indeterminate potential (CHIP) variants

Cell-free DNA (cfDNA) obtained from liquid biopsy samples contains DNA from tumor cells in addition to a big quantity of DNA from white blood cells. In lots of people, particularly those that are older, these phenotypically regular blood cells include acquired mutations subsequently elevated in relative frequency attributable to clonal growth. These CHIP variants can usually happen in the identical genes related to blood cancers like leukemia. Nevertheless, whereas they’re indicative of an elevated danger of creating a blood most cancers sooner or later, they aren’t more likely to be related to the tumor being analyzed.

Sequencing matched white blood cells as a traditional management can efficiently distinguish somatic mutations that drive tumorigenesis from somatic mutations arising from the conventional strategy of clonal hematopoiesis.⁴ Each ESMO and AMP suggestions specify that matched white blood cell sequencing ought to be used for interpretation of somatic variants in cfDNA testing.^5,6

Streamlining germline variant evaluation

The flexibility to differentiate between somatic and germline variants has the extra good thing about streamlining evaluation of germline variants which have further implication for a affected person’s scientific care, most notably in offering details about future illness danger that may be managed partially via surveillance, in addition to permitting for testing of relations who may additionally be in danger for illness.

All in favour of leveraging a matched tumor-normal method on your scientific analysis? We have now collaborated with Memorial Sloan Kettering Most cancers Heart (MSK) to decentralize their best-in-class next-generation sequencing (NGS) assays—MSK-ACCESS^® for liquid biopsy and MSK-IMPACT^® for complete genomic profiling—by way of the SOPHiA DDM™ Platform. Establishments worldwide can improve their analysis with an easy-to-adopt matched tumor-normal workflow, bettering somatic detection charge for sturdy precision oncology insights.

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