Long-read Sequencing Reveals Repeat Expansions and Large Structural Variants in Oral Squamous Cell Carcinoma

Previous genomic studies have predominantly analyzed oral squamous cell carcinoma (OSCC) in conjunction with other head and neck squamous cell carcinomas (HNSCC), constraining our comprehension of OSCC-specific structural variants (SVs). Here, we performed long-read whole-genome sequencing on 16 paired OSCC tumor and blood samples to elucidate the biological functions of somatic SVs. We identified a total of 5775 high-confidence somatic SVs, including five recurrent simple repeat expansions (SREs). Notably, one SRE located within the promoter region of the OBI1 gene is present in 45% of OSCC samples. Knocking out this SRE in the HSC4 cell line significantly reduces the expression of OBI1, resulting in decreased proliferative and migratory capacities compared to wild-type cells. Furthermore, we found that the frequently amplified region 11q13 in HNSCC is prone to large-scale somatic SVs, affecting the expression of ANO1, FADD, and CTTN, thereby confirming the association of SVs in this region with OSCC development. Our study provides novel insights into the role of somatic SVs in OSCC, especially with respect to SREs and large-scale SVs in critical genomic regions, thereby enhancing our comprehension of the molecular pathogenesis of OSCC.