We just got back from three busy days at the Molecular Pathology (AMP) conference in friendly San Antonio, Texas. Keeping up the Golden Helix conference momentum for the year, we had 3-4 in-booth demonstrations a day covering our CNV calling, variant interpretation, and data warehousing products for NGS-based genetic tests. And in short, NGS based tests for cancer and germline applications were the dominant topic at AMP. My impression after three days of conversations, talks and poster sessions is that pathology labs have embraced NGS based tests for genomic profiling of tumors and are now moving past the routine interpretation of
Germline and Somatic Variant CNV Calling and Variant Interpretation Discussed
It’s clear that pathology labs have momentum as a key part of the cancer diagnosis process. As labs adopt Next Generation Sequencing for the profiling of the genomic mutations for diagnostic, prognostic and therapeutic guidance, they are also expanding their test portfolio to leverage their sequencing and variant interpretation capabilities. During our in-booth scheduled and spontaneous one-on-one demos, I demonstrated our deep-diving variant interpretation capabilities to assistant and automate the ACMG guidelines for germline variant interpretation. The in-silico analysis for function prediction, splice site disruption and conversation are universally of interest to any variant interpretation workflow. The user-friendliness display of VSClinical and its aggregation of variant annotations were frequently commented on.
Similarly, the Golden Helix method to call CNVs from hybrid captured NGS panel data was of particular interest. Common CNVs such as the EGFR exon 19 amplification are must-call mutations when doing tumor profiling, and the ability to use the existing NGS data to make these calls can be a considerable cost savings over having a secondary PCR or MLPA assays as part of the test.
Large Insertions, Deletions and Complex Variants are of Clinical Significance
One thing that struck me while attending some of the early bird sessions and reading through the posters is the limitations of variant callers to call larger insertions/deletions and complex variants. For germline tests, this hasn’t been a major focus given the generally high diagnosis rates of whole exome sequencing. But in tumors, these “extreme” variants occur at a higher frequency and are being missed by standard bioinformatic pipelines.
Examples of somatic insertions of 50bp and deletions of 100bp and even 1,000bp where provided in case studies, yet these variants are nearly always missed by standard alignment and variant calling strategies. BWA will fail to align many reads harboring the evidence for these larger indels, and variant callers like GATK, even with their local indel re-alignment corrections will fail to call with reliability indels larger than 25 to 35bp. For labs willing to develop custom pipelines, the preferred strategy is to use specialized re-alignment passes and then merge the results of two to three specialized or in-house built variant callers to catch these variants. With our recently announced Phase II SBIR grant for development methods for calling complex NGS variants of clinical relevance, this class of difficult to call variants will be of particular interest and influential to our research.
Interpreting Somatic Variants Requires a Plethora of Resources and Annotation Sources
My closing thoughts is that as more and more labs look to bring on NGS tests for molecular profiling of tumors, there is a strong desire for the aggregation of the many disparate yet meaningful resources for the interpreting somatic variants.
I will be covering some of these annotation sources in my webcast this Wednesday, so be sure to register! Ultimately, the adoption of precision medicine is accelerated as more tests come on-line by labs that have accurate and efficient workflows in place to do their variant analysis, and we look forward to innovating in close collaboration with our customers to enable this capability.
