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New mRNA Cancer Drivers Revealed in Chronic Lymphocytic Leukemia

NEW YORK (GenomeWeb) – New evidence has emerged today showing that the inactivation or alteration of cancer suppressor genes can take place even if DNA itself remains unaltered.

Reporting in Nature, investigators demonstrated that changes in mRNA due to a process called intronic polyadenylation (IPA) can drive development of some cancers by altering gene expression in a way that interferes with the proper functioning of tumor suppression mechanisms.

Led by Memorial Sloan Kettering Cancer Center molecular biologist Christine Mayr, the study involved sequencing normal and cancerous cells from a small cohort of patients with chronic lymphocytic leukemia, which revealed that IPA-driven mRNA changes do take place, and that — at least in this cancer type — can occur much more frequently than corresponding mutations in DNA.

A known molecular mechanism for cancer development and spread is the inactivation of tumor suppressor genes, which encode various tools the body uses to keep its cells from turning cancerous.

But evidence is building that the hobbling of tumor suppressors can take place not just due to changes in the DNA itself, but by alterations in messenger RNAs, which act as a go-between, translating the DNA code into its intended function in the body.

The implication of such findings is that cancer diagnostics that look only at DNA could be missing important molecular information about the forces driving the disease.

"Current cancer diagnostic efforts predominantly focus on the sequencing of DNA to identify mutations," Mayr said in a statement. "Our study demonstrates that cancer-gained changes in mRNA processing can essentially mimic the effects of somatic mutations in DNA, pointing to the need to look past DNA for answers to questions about what causes the disease."

In the study, Mayr and her colleagues used an RNA sequencing method they developed to examine normal and malignant B cells from 59 CLL patients. They found that the patients showed widespread tumor suppressor inactivation in mRNA even without a corresponding DNA alteration

According to the investigators, IPA truncated mRNAs in the CLL cohort predominantly affected genes with tumor-suppressive functions. In some cases (genes such as DICER and FOXN3) this appeared to result in the translation of truncated proteins which lack the tumor-suppressive effect that they would have in their full-length form. In several other cases (CARD11, MGA and CHST11) the altered proteins even acted in an oncogenic manner.

Overall, the team concluded that the inactivation of tumor-suppressor genes by aberrant mRNA processing appears to be significantly more prevalent in CLL, at least based on this cohort, than functional loss of these genes via DNA mutations.

The authors also reported that they saw truncated tumor-suppressor proteins not just for known tumor-suppressor genes but also in previously unrecognized or relatively understudied sequences.

Although the current study was in CLL, mRNA tumor drivers are likely not limited to this cancer, the authors wrote. The team has also found them in cases of T cell acute lymphocytic leukemia, for example. And other groups have reported similar findings in breast cancer.

In the case of CLL, the authors wrote that the findings help explain the puzzling fact that CLL cells have relatively few known DNA mutations.

According to the investigators, most CLL patients have either a single alteration or a normal karyotype. In light of this paucity of cancer drivers on the DNA level, the MSKCC authors wrote that the mRNA changes they investigated could potentially help scientists better understand the genesis and progression of the disease in greater numbers of patients.

Regardless, the team wrote that the results, coupled with growing evidence in other cancers, suggests that genetic testing that is limited to DNA may risk missing important information about the mechanisms that drive a cancer or that may be exploited to defeat it.