Gene Mutation May Signal Indolent Thymus Cancer

A single mutation in the transcription factor GTF2I may help differentiate fast-growing cancers of the thymus that require aggressive treatment from slow-growing ones that don't require extensive therapy, according to a study published in Nature Genetics.

Conducted by researchers from Georgetown Lombardi Comprehensive Cancer Center in Washington, DC, and the NCI, the study involved thymic epithelial tumors (TET), which are subdivided into thymomas and thymic carcinomas; thymomas are further classified into types A, AB, B1, B2, and B3 based on histological features. All begin in the epithelial cells of the thymus, a lymphatic system organ where T cells mature. Together, they account for only 0.2% to 1.5% of all cancers.

“In addition to being rare, there is an insufficient characterization of the genetic abnormalities in these tumors,” says the study's senior investigator Guiseppe Giaccone, MD, PhD, associate director for clinical research at Georgetown. “Having a GTF2I mutation as a marker could be important for diagnostic and therapeutic purposes.”

Using next-generation sequencing, investigators analyzed 28 TETs and identified a “strikingly prevalent” missense mutation in GTF2I in the relatively indolent type A and AB thymomas. Next, they assessed the frequency of GTF2I mutations in 274 TETs, detecting GTF2I mutations in 82% of type A and 74% of type AB thymomas.

The frequency of the mutation decreased markedly in the more aggressive TETs—the B1, B2, and B3 thymoma subtypes and thymic carcinomas—with just 8% of thymic carcinomas harboring the mutation.

In contrast, thymic carcinomas, which are typically more aggressive, carried a higher number of mutations of known cancer genes, including TP53, CYLD, CDKN2A, BAP1, and PBRM1.

“The results were very surprising because GTF2I is a transcription factor that has not been linked to cancer before,” says Giaccone, adding that, “There are very few tumors that are characterized by one specific genetic abnormality.”

Identifying a marker of non-aggressive disease could affect treatment regimens. Currently, patients with TETs may have radiation and/or chemotherapy in addition to, or instead of, surgery, depending on the presumed aggressiveness of the cancer. Giaccone says this is controversial because many thymomas are indolent, leading to concerns about overtreatment.

To assess patient outcomes and gauge the predictive value of GTF2I mutations, the researchers examined survival data from 204 patients. They found that the prognosis for patients whose thymomas carried the GTF2I mutation was significantly better than for those carrying wild-type GTF2I (96% versus 70% 10-year-survival, respectively). Survival rates were also better for the three patients with thymic carcinoma who carried the GTF2I mutation than for those who didn't.

Due to the rarity of these cancers, Giaccone admits more research is needed. “We are currently developing cell lines from these tumors and developing in vivo models,” he says. “Our goal is to clarify whether, in fact, this mutant gene may improve prognosis by keeping tumors from becoming more aggressive.”