24. Tissue-based sequencing for laboratory diagnosis of Somatic Mosaic Disorders

Abstract

<h3>Background</h3> Post-zygotic genetic variants in cancer genes cause a group of syndromic and non-syndromic conditions termed somatic mosaic disorders (SMD). Tissue-based deep sequencing is becoming the diagnostic method of choice given the diverse variant allele fractions (VAF) involved. We report the diagnostic yield of high-depth tissue-based next-generation sequencing (NGS) in 57 patients with SMD. <h3>Methods</h3> We retrospectively identified patients referred for testing with clinical diagnosis of SMD (e.g., CLOVES) or characteristic clinical manifestations. 35 patients were tested with a 124 gene solid tumor panel at 500-1000x coverage. Beginning in 2021, 22 patients were tested with a 29 gene SMD panel. Testing was predominantly performed on formalin-fixed paraffin-embedded (FFPE) tissue. <h3>Results</h3> An AMP/ASCO/CAP tier I/II variant was reported in 25/57 (43.8%) patients, including 17/35 (48.6%) patients tested with the solid tumor panel, and 8/22 (36.3%) tested with the SMD panel (p=0.37). Six patients had a variant of unknown significance at VAF consistent with mosaicism. Diagnosed disorders were related to PIK3CA (n=15), KRAS (3), GNAQ (2), AKT1, BRAF, GNA11, GNAS, MAP2K1, PTEN. The median VAF was 9% (4-80%), and 24/26 tier I/II variants are reported in COSMIC. 9/18 patients with prior germline genetic testing received a new diagnosis. 11/21 diagnosed patients who are following at our center are receiving targeted therapies. <h3>Conclusion</h3> Patients with SMDs can benefit from molecular diagnoses when clinical, radiologic and pathologic findings are inconclusive. In a significant proportion of patients, high-depth NGS of lesional tissue can reveal somatic mosaic alterations at low allelic fractions amenable to targeted therapy.