Format

Send to

Choose Destination
Nature. 2018 Sep;561(7721):127-131. doi: 10.1038/s41586-018-0465-8. Epub 2018 Aug 27.

Widespread intronic polyadenylation inactivates tumour suppressor genes in leukaemia.

Author information

1
Cancer Biology and Genetics Program, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
2
Computational and Systems Biology Program, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
3
Tri-I Program in Computational Biology and Medicine, Weill Cornell Graduate College, New York, NY, USA.
4
Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
5
Cancer Biology and Genetics Program, Memorial Sloan Kettering Cancer Center, New York, NY, USA. mayrc@mskcc.org.

Abstract

DNA mutations are known cancer drivers. Here we investigated whether mRNA events that are upregulated in cancer can functionally mimic the outcome of genetic alterations. RNA sequencing or 3'-end sequencing techniques were applied to normal and malignant B cells from 59 patients with chronic lymphocytic leukaemia (CLL)1-3. We discovered widespread upregulation of truncated mRNAs and proteins in primary CLL cells that were not generated by genetic alterations but instead occurred by intronic polyadenylation. Truncated mRNAs caused by intronic polyadenylation were recurrent (n = 330) and predominantly affected genes with tumour-suppressive functions. The truncated proteins generated by intronic polyadenylation often lack the tumour-suppressive functions of the corresponding full-length proteins (such as DICER and FOXN3), and several even acted in an oncogenic manner (such as CARD11, MGA and CHST11). In CLL, the inactivation of tumour-suppressor genes by aberrant mRNA processing is substantially more prevalent than the functional loss of such genes through genetic events. We further identified new candidate tumour-suppressor genes that are inactivated by intronic polyadenylation in leukaemia and by truncating DNA mutations in solid tumours4,5. These genes are understudied in cancer, as their overall mutation rates are lower than those of well-known tumour-suppressor genes. Our findings show the need to go beyond genomic analyses in cancer diagnostics, as mRNA events that are silent at the DNA level are widespread contributors to cancer pathogenesis through the inactivation of tumour-suppressor genes.

Comment in

PMID:
30150773
PMCID:
PMC6527314
DOI:
10.1038/s41586-018-0465-8
[Indexed for MEDLINE]
Free PMC Article

Supplemental Content

Full text links

Icon for Nature Publishing Group Icon for PubMed Central
Loading ...
Support Center