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

Veiga, Diogo Troggian; Nesta, Alex; Zhao, Yuqi; Mays, Anne Deslattes; Huynh, Richie; Rossi, Robert J.; Wu, Te-Chia; Palucka, Karolina; Anczuków, Olga; Beck, Christine R.; Banchereau, Jacques

doi:10.1126/sciadv.abg6711

Cited by 37 publications

(33 citation statements)

References 65 publications

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“…Moreover, the cancer-specific SEs identified by long-read sequencing in breast cancer also showed the same length bias (fig. S1B), further confirming the length-dependent splicing changes in cancer (22). Together, our results revealed a previously unnoticed feature of splicing alteration in cancer, in which the short exons are more sensitive to be dysregulated regardless of the cancer types, analytic pipelines, and patient populations.…”

Section: Significant Length Biases In Cancer-associated Alternative E...supporting

confidence: 80%

A widespread length-dependent splicing dysregulation in cancer

Zhang

Mao

et al. 2022

Sci. Adv.

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Dysregulation of alternative splicing is a key molecular hallmark of cancer. However, the common features and underlying mechanisms remain unclear. Here, we report an intriguing length-dependent splicing regulation in cancers. By systematically analyzing the transcriptome of thousands of cancer patients, we found that short exons are more likely to be mis-spliced and preferentially excluded in cancers. Compared to other exons, cancer-associated short exons (CASEs) are more conserved and likely to encode in-frame low-complexity peptides, with functional enrichment in GTPase regulators and cell adhesion. We developed a CASE-based panel as reliable cancer stratification markers and strong predictors for survival, which is clinically useful because the detection of short exon splicing is practical. Mechanistically, mis-splicing of CASEs is regulated by elevated transcription and alteration of certain RNA binding proteins in cancers. Our findings uncover a common feature of cancer-specific splicing dysregulation with important clinical implications in cancer diagnosis and therapies.

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Section: Significant Length Biases In Cancer-associated Alternative E...supporting

confidence: 80%

A widespread length-dependent splicing dysregulation in cancer

Zhang

Mao

et al. 2022

Sci. Adv.

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“…Using the same approach, another study also reported 17 to 55% of novel isoforms in human breast cancer samples (Veiga et al, 2022). These studies, together with ours, indicate long-read sequencing is better approach for discovering novel isoforms and being able to better annotate animal genomes.…”

Section: Discussionsupporting

confidence: 69%

“…The human genome is considered to be better-annotated than farm animals’, while 36.4% of full-length transcripts identified by long-read Iso-Seq methods are classified as “novel” in human cortex tissue (Leung et al, 2021). Using the same approach, another study also reported 17 to 55% of novel isoforms in human breast cancer samples (Veiga et al, 2022). These studies, together with ours, indicate long-read sequencing is better approach for discovering novel isoforms and being able to better annotate animal genomes.…”

Section: Discussionmentioning

confidence: 93%

A comprehensive prediction of transcript isoforms in 19 chicken tissues by Oxford Nanopore long-read sequencing

Guan

Halstead

Islas‐Trejo

et al. 2022

Preprint

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To comprehensively identify and annotate transcript isoforms in the chicken genome, we generated Nanopore long-read sequencing data from a diverse set of 19 chicken tissues comprising 68 samples collected from experimental line 6 × line 7 F1 adult males and females. More than 23.8 million reads with mean read length of 790 bases and average quality of 18.2 were generated. The annotation and subsequent filtering resulted in identification of 55,382 transcripts with mean length of 1,700 bases at 40,547 loci, representing ∼1.4 transcripts per locus. Among them, we predicted 30,967 potential coding transcripts at 19,461 loci and 16,495 potential lncRNA transcripts at 15,512 loci. Compared to reference annotations, we found 52% of annotated transcripts could partially to fully match while 47% were novel and potentially transcribed from lncRNA loci. Based on our annotation, we quantified transcript expression across tissues and found brain tissues (i.e. cerebellum, cortex) expressed highest number of transcripts and loci. The further tissue specificity revealed that ∼22% of the transcripts displaying tissue specificity. Of them, the reproductive tissues (i.e. testis, ovary) contained the most tissue-specific transcripts. Despite sequencing 68 transcriptomes derived from 19 tissues, still ∼20% of Ensembl reference loci were not detected. This suggests that including additional samples from different cell types, developmental and physiological conditions, is needed to fully annotate the chicken genome. The application of Nanopore sequencing transcriptomes in this study demonstrated the usefulness of long-read data in discovering additional novel loci (e.g., lncRNA loci) and resolving complex transcripts (e.g., the longest transcript for the TTN locus).

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“…5d]. We verified that isoforms containing the deleted exon are expressed in a recent dataset comprised of 30 breast cancer samples 67 . Additionally, this deletion spans six regulatory elements annotated in the Open Regulatory Annotation dataset 68 .…”

Section: Temrs Contribute To Variation In Functional Regions Of Human...mentioning

confidence: 90%

Transposable element-mediated rearrangements are prevalent in human genomes

Balachandran

Walawalkar

Flores

et al. 2022

Preprint

Self Cite

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Transposable elements constitute about half of human genomes, and their role in generating human variation through retrotransposition is broadly studied and appreciated. Structural variants mediated by transposons, which we call transposable element-mediated rearrangements (TEMRs), are less well studied, and the mechanisms leading to their formation as well as their broader impact on human diversity are poorly understood. Here, we identify 493 unique TEMRs across the genomes of three individuals. While homology directed repair is the dominant driver of TEMRs, our sequence-resolved TEMR resource allows us to identify complex inversion breakpoints, triplications or other high copy number polymorphisms, and additional complexities. TEMRs are enriched in genic loci and can create potentially important risk alleles such as a deletion in TRIM65, a known cancer biomarker and therapeutic target. These findings expand our understanding of this important class of structural variation, the mechanisms responsible for their formation, and establish them as an important driver of human diversity.

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

Cited by 37 publications

References 65 publications

A widespread length-dependent splicing dysregulation in cancer

A widespread length-dependent splicing dysregulation in cancer

A comprehensive prediction of transcript isoforms in 19 chicken tissues by Oxford Nanopore long-read sequencing

Transposable element-mediated rearrangements are prevalent in human genomes

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