Surana, P.; Obusan, M.; Davuluri, R. V.

Most of the human genome is transcribed into diverse isoforms whose tissue specificity is profoundly disrupted in cancer, yet isoform-level dysregulation remains poorly characterized across solid tumors. Here, we introduce STPCaT (Solid Tumors Pan-Cancer Transcriptome), an isoform-centric analysis extending TransTEx to systematically classify transcript expression across TCGA solid tumors and GTEx normal tissues. STPCaT reveals a striking collapse of normal tissue-specific programs in cancer, accompanied by the emergence of two dominant expression groups: cancer-high (CanHigh) and normal-high (NorHigh) isoforms. We uncover a large repertoire of previously unannotated Cancer-Testis Antigens (CTAs), the majority of which are absent from existing CTA databases, with broad relevance across multiple cancers, including gliomas. In pan-gliomas, consensus clustering and random-forest feature selection identify compact, highly discriminative isoform signatures that robustly stratify low-grade and glioblastomas with up to 97 to 98% accuracy using as few as five transcripts. These signatures recapitulate canonical glioma biology and highlight pathways linked to migration, development, and vesicle trafficking. Independent validation in the GLASS consortium cohort demonstrates cohort-specific trends that partially recapitulate primary findings, reflecting known biological heterogeneity across patient populations. Together, STPCaT provides a scalable, isoform-resolved resource for tumor stratification, CTA discovery, and precision oncology applications across solid tumors.