Sloan Kettering Institute Researchers Look Beyond DNA to Identify Cancer Drivers

Bottom Line: Researchers at the Sloan Kettering Institute have found that changes in an information-carrying molecule called messenger RNA (mRNA) can inactivate the functions of tumor suppressor genes and thereby promote cancer. The findings pinpoint previously unknown drivers of the disease, indicating that cancer diagnostics need to go beyond the analysis of DNA mutations.

Background: Most people think of cancer as a disease of disorderly DNA. Mutations in the sequence of DNA alter the function of the proteins made from that DNA, leading to uncontrolled cell division. But between DNA and proteins is another layer of information, mRNA, which serves as a crucial link between the two.

Findings and Method: New findings from molecular biologist Christine Mayr, MD, PhD, and colleagues at the Sloan Kettering Institute suggest that many of the mRNAs in cancer cells produce truncated tumor-suppressor proteins which have cancer promoting functions. The changes occur not only in known tumor-suppressor genes but also in previously unrecognized ones. Because genetic tests don’t usually look at mRNA, those changes have gone undetected by cancer doctors so far. Based on these findings, cancer diagnostics may need to change to include these previously unknown cancer drivers.

Dr. Mayr’s team looked specifically at chronic lymphocytic leukemia (CLL), a type of blood cancer. Her colleague at Memorial Sloan Kettering Cancer Center, physician-scientist Omar Abdel-Wahab, MD, supplied them with blood samples from people with the condition. Using a method that Dr. Mayr’s lab developed to detect these particular mRNA changes, they found that a substantially greater number of people with CLL had an inactivation of a tumor suppressor gene at the mRNA level than those who had it at the DNA level.

These findings help explain a long-standing conundrum, which is that CLL cells have relatively few known DNA mutations. Some CLL cells lack even those known mutations. In effect, the mRNA changes that Dr. Mayr’s team discovered could account for the missing DNA mutations. Because CLL is such a slow-growing cancer and people with CLL often live for many years, it’s too early to say whether these mRNA changes are associated with a poorer prognosis.

Though Dr. Mayr’s team identified the mRNA changes in CLL, they’re likely not limited to this blood cancer. The team found them in samples of T cell acute lymphocytic leukemia too, for example. Other researchers have found them in breast cancer.

Author Comments: “Current cancer diagnostic efforts predominantly focus on the sequencing of DNA to identify mutations,” explained Dr. Mayr. “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.”

Journal: “Widespread intronic polyadenylation inactivates tumor suppressor genes in leukemia” was published in Nature on August 27, 2018. Dr. Mayr, a member of the Cancer Biology and Genetics Program at the Sloan Kettering Institute, served as senior author.

Funding: This work was funded by a National Cancer Institute grant (U01-CA164190), a Starr Cancer Foundation grant, an Innovator Award of the Damon Runyon-Rachleff Cancer Foundation and the Island Outreach Foundation (DRR-24-13), a National Institutes of Health Director’s Pioneer Award (DP1-GM123454), the Pershing Square Sohn Cancer Research Alliance, and an MSK Core grant (P30 CA008748).