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Evaluation of the gene fusion landscape in early onset sporadic rectal cancer reveals association with chromatin architecture and genome stability

Oncogene volume 43, pages 2449–2462 (2024)Cite this article

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Abstract

Gene fusions represent a distinct class of structural variants identified frequently in cancer genomes across cancer types. Several gene fusions exhibit gain of oncogenic function and thus have been the focus of development of efficient targeted therapies. However, investigation of fusion landscape in early-onset sporadic rectal cancer, a poorly studied colorectal cancer subtype prevalent in developing countries, has not been performed. Here, we present a comprehensive landscape of gene fusions in EOSRC and CRC using patient derived tumor samples and data from The Cancer Genome Atlas, respectively. Gene Ontology analysis revealed enrichment of unique biological process terms associated with 5′- and 3′- fusion partner genes. Extensive network analysis highlighted genes exhibiting significant promiscuity in fusion formation and their association with chromosome fragile sites. Investigation of fusion formation in the context of global chromatin architecture unraveled a novel mode of gene activation that arose from fusion between genes located in orthogonal chromatin compartments. The study provides novel evidence linking fusions to genome stability and architecture and unearthed a hitherto unidentified mode of gene activation in cancer.

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Fig. 1: Spectrum of GF events identified in EOSRC and TCGA-CRC.
Fig. 2: GF network in EOSRC.
Fig. 3: Overlap between GF breakpoints and CFS.
Fig. 4: Association between chromatin architecture and GFs.
Fig. 5: Alteration in the expression levels of 3'-fusion partners.
Fig. 6: Validating transcript level changes of 3'-fusion partners from A-B GFs.
Fig. 7: Schematic representing activation of 3′ partner gene in A–B GFs.

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Data availability

All the raw sequencing data generated in this study has been submitted to the GEO database with accession ID GSE253106. The list of all primers used has been provided in table S5. Custom R codes used for generating figures can be accessed from the Github repository (https://github.com/asmitagpta/crc_genomics).

Code availability

Custom R codes used for generating figures can be accessed from the Github repository (https://github.com/asmitagpta/crc_genomics).

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Acknowledgements

The authors acknowledge Mandla Vasanth Kumar for his assistance in carrying out RT-PCR. A.G. received funding from the Women Scientist Scheme – A, Department of Science and Technology (DST-WOSA), Government of India and the National Postdoctoral Fellowship (NPDF) scheme, Science and Engineering Research Board (SERB), Department of Science and Technology, Government of India. The authors thank Dr Pratyusha Bala for designing the RNA-Seq experiments and the Sophisticated Equipment Facility (SEF), CDFD, for Sanger Sequencing. The authors thank Dr Sara Anisa George, Laboratory of Molecular Oncology, Centre for DNA Fingerprinting and Diagnostics, Hyderabad, India, Dr Jaya S Tyagi, Department of Biotechnology, All India Institute of Medical Sciences, N. Delhi, India and Dr J Gowrishankar, Indian Institute of Science, Education and Research, Mohali, India, for critical reading of the manuscript.

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    Asmita Gupta, Sumedha Avadhanula & Murali Dharan Bashyam

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M.D.B. and A.G. conceived the study; A.G. performed the computational analyses; A.G. and S.A. performed RT-PCR and RT-qPCR assays. A.G. and M.D.B. compiled and analyzed the data. A.G. and M.D.B. wrote and revised the manuscript.

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Correspondence to Murali Dharan Bashyam.

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Gupta, A., Avadhanula, S. & Bashyam, M.D. Evaluation of the gene fusion landscape in early onset sporadic rectal cancer reveals association with chromatin architecture and genome stability. Oncogene 43, 2449–2462 (2024). https://doi.org/10.1038/s41388-024-03088-z

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