Genome-wide SNP-based Profiling of Loss of Heterozygosity Reveals Distinct Molecular Subgroup-specific Patterns in Gastrointestinal Stromal Tumors (GIST)

Purpose: Gastrointestinal stromal tumors (GIST) are molecularly heterogeneous neoplasms defined by mutually exclusive driver alterations (KIT, PDGFRA, SDH, BRAF, RAS and NF1). However, driver mutations alone do not fully explain their biological and clinical variability. Chromosomal imbalances and loss of heterozygosity (LOH) may represent an additional layer of tumor characterization. We developed a single-nucleotide polymorphism (SNP)-based next-generation sequencing (NGS) panel enabling genome-wide LOH assessment from formalin-fixed paraffin-embedded tissue. Materials and methods: Forty-nine GIST cases molecularly classified by targeted NGS (KIT n=19, PDGFRA n=9, SDH-deficient n=8, NF1 n=7, quadruple wild type [qWT] n=6) were analyzed. LOH was inferred from variant allele frequency patterns across 1,826 genome-wide SNPs. Results: Chromosome 14 was the most commonly affected (63%), followed by chromosomes 22 (45%), 15 (41%), 21 (27%), and 13 (20%). Loss of chromosome arm 1p occurred in 43% of tumors. Distinct subgroup-specific patterns emerged: KIT-mutant GIST exhibited the highest degree of genomic instability, whereas both SDH-deficient tumors and PDGFRA-mutant GIST displayed minimal chromosomal instability. NF1-mutant tumors showed recurrent single-arm chromosome 17 LOH. qWT GISTs were heterogeneous, including one case with extensive chromosomal instability. Conclusions: Genome-wide SNP-based LOH profiling reveals distinct, subgroup-specific patterns of chromosomal imbalance in GIST and may serve as a feasible complementary approach to driver mutation analysis for refined molecular characterization and potential future clinical utility.