Abstract 519P
Background
NGS technology has impacted precision medicine with identification of clinically relevant alterations. Significant number of Variant of Unknown Significance (VUS) are also identified accounting 20-40% with no clinical data. Utility of VUS in clinical setting is challenging but possible role in oncogenesis cannot be ruled out and necessitates systematic analysis of VUS. Present study evaluated spectrum of VUS present across different solid tumours.
Methods
The study included 4250 FFPE tissues (January 2021-June 2024) from lung (n=2047), gastrointestinal (GI; n=1081), Head-Neck (HN; n=348), urological (Uro; n=167), central nervous system (CNS; n=161), soft tissue sarcomas (SFT: n=92), breast (n=87), pediatric (n=31) and adult hematological cancers (n=26). Cases were subjected to NGS using Sophia Solid Tumor Plus Solution. Data analysis was performed using Sophia DDM. Variants were reported as per ACMG/AMP guidelines for Tier based classification.
Results
Total 3900 cases were interpretable and 77.6% were mutant. Of 5263 variants reported, 36.8% were Tier I, 51.4% Tier II and 11.7% Tier III. Atleast 1 VUS was observed in 11.8% cases and 1 unique VUS was identified in 87.2% of genes tested. Of all, 75.1% VUS were present with Tier I/II. Highest VUS were reported in pediatric (35.7%) followed adult hematological (26.6%), uro (20.0%), SFT (16.1%), CNS (16.3%), gynecological (14.4%), GI (12.1%), lung (10.5%), HN (9.8%) and breast tumors (8.9%). Within VUS cohort, 55% cases showed single VUS whereas 17.6% and 2.6% showed 2 and >2 VUS. Top 5 variants were TP53 (30.3%), CDKN2A (13.8%), SMAD4 (5.9%), BRCA2 (4.2%) and BRCA1(4.0%). Almost 33-73% variants affecting FOXL2, BRCA2, MET, CDKN2A, BRCA1 were reported as VUS; however, known driver oncogenes such as KRAS, EGFR, NRAS, BRAF, PIK3CA, TERT, KIT, GNAS, CTNNB1, HRAS showed lower frequency of VUS (<10%).
Conclusions
The present study reported 11.7% VUS among all solid tumors tested. This is lower than reported because of use of targeted panels as compared to clinical exome and CGP. These VUS are mostly reported in non-classical oncogenic genes. Hence, detailed analysis of regions affected, variant database and in-silico functional analysis may help reclassify VUS into potentially oncogenic variants.
Clinical trial identification
Editorial acknowledgement
Legal entity responsible for the study
Molecular Pathology, Tata Memorial Hospital.
Funding
Has not received any funding.
Disclosure
All authors have declared no conflicts of interest.