Tabular foundation model predicts alternative lengthening of telomeres (ALT) and identifies SMARCAL1 as a target in ALT-driven cancers

Abstract Alternative lengthening of telomeres (ALT) is a telomerase-independent pathway used by aggressive cancers to maintain their replicative immortality. Because ALT is absent from normal human cells, it is an appealing target for cancer therapy, but the lack of ability to determine ALT status at scale has hindered target discovery. Here, we developed ALTitude, a tabular foundation model-based method that infers ALT from cell line whole-genome sequencing data, without need for paired germline sequences. We deployed ALTitude across the Cancer Dependency Map, doubling the number of known ALT+ cancer models. Systematic integration of ALTitude with CRISPR-Cas9 screens yielded the selective dependency on SMARCAL1 in ALT+ cell lines, where we show it stabilizes the ALT phenotype. Acute depletion of SMARCAL1 leads to G2/M arrest, mitotic catastrophe, and cell death. These data provide a valuable resource for studying ALT-related genomic features and present SMARCAL1 as a therapeutically relevant drug target for ALT+ malignancies. Competing Interest Statement The authors have declared no competing interest.