A comprehensive long-read isoform analysis platform and sequencing resource for breast cancer

Author:

Veiga Diogo F. T.1ORCID,Nesta Alex12,Zhao Yuqi1ORCID,Mays Anne Deslattes1ORCID,Huynh Richie1ORCID,Rossi Robert1ORCID,Wu Te-Chia1ORCID,Palucka Karolina1ORCID,Anczukow Olga123ORCID,Beck Christine R.123ORCID,Banchereau Jacques1ORCID

Affiliation:

1. The Jackson Laboratory for Genomic Medicine, Farmington, CT 06032 USA.

2. Department of Genetics and Genome Sciences, University of Connecticut Health Center, Farmington, CT 06030, USA.

3. Institute for Systems Genomics, University of Connecticut Health Center, Farmington, CT 06030, USA.

Abstract

Tumors display widespread transcriptome alterations, but the full repertoire of isoform-level alternative splicing in cancer is unknown. We developed a long-read (LR) RNA sequencing and analytical platform that identifies and annotates full-length isoforms and infers tumor-specific splicing events. Application of this platform to breast cancer samples identifies thousands of previously unannotated isoforms; ~30% affect protein coding exons and are predicted to alter protein localization and function. We performed extensive cross-validation with -omics datasets to support transcription and translation of novel isoforms. We identified 3059 breast tumor–specific splicing events, including 35 that are significantly associated with patient survival. Of these, 21 are absent from GENCODE and 10 are enriched in specific breast cancer subtypes. Together, our results demonstrate the complexity, cancer subtype specificity, and clinical relevance of previously unidentified isoforms and splicing events in breast cancer that are only annotatable by LR-seq and provide a rich resource of immuno-oncology therapeutic targets.

Publisher

American Association for the Advancement of Science (AAAS)

Subject

Multidisciplinary

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