Through an international collaboration, researchers have produced an extensive characterization of adrenocortical carcinoma, a rare endocrine cancer with limited treatment options. They found that the disease has three DNA methylation–driven subtypes with distinct clinical outcomes, and is prone to genomic instability.

Researchers from 39 institutions in six countries have joined forces to extensively characterize adrenocortical carcinoma (ACC), a rare endocrine cancer that affects just two in every million people worldwide. ACC is often diagnosed at an advanced stage, so its 5-year survival rate ranges from 6% to 13%. Standard treatments for metastatic disease—chemotherapy, radiation, and the hormone-blocking agent mitotane—are palliative and have remained unchanged since the 1970s.

The analysis, part of The Cancer Genome Atlas, was led by Thomas Giordano, MD, PhD, and Gary Hammer, MD, PhD, at the University of Michigan in Ann Arbor; and Roel Verhaak, PhD, at The University of Texas MD Anderson Cancer Center in Houston.

The team used several molecular platforms to scrutinize 91 tumors, including whole-exome and RNA sequencing, and DNA methylation profiling (Cancer Cell 2016;29:723–36). They found that 8% of the samples harbored inactivating PRKAR1A mutations—“a new twist in the story,” Giordano says, given that alterations in this gene were thought to occur only in benign adrenal disease. They also observed loss of ZNRF3 in almost 20% of cases, resulting in constitutive activation of Wnt signaling.

“We knew Wnt signaling is important in adrenal cancer biology'some tumors have an initiating mutation in the β-catenin gene [CTNNB1], which correlates with poor survival,” Hammer explains. “This discovery that ZNRF3 is a critical mediator adds another level of complexity to Wnt pathway activation.” Small-molecule inhibitors of Porcupine, an enzyme that processes Wnt ligands, are in phase I clinical trials for various cancers, he adds, and “we're looking forward to testing their efficacy in ACCs lacking ZNRF3.”

Additionally, the researchers noted that a sizeable proportion of ACCs displayed evidence of profound genomic instability—often whole-genome doubling, which was associated with more aggressive disease and decreased survival. Why this happens so frequently “is an open mechanistic question,” Giordano says.

By clustering their data, the researchers pinpointed three ACC subtypes with different DNA methylation levels: low, intermediate, and high. Statistical analyses showed distinct clinical outcomes'the corresponding tumor recurrence and/or metastasis rates were 7%,56%, and 96%. The median progression-free survival was not reached in the first subtype; in the intermediate- and high-methylation subtypes, it was 38 months and 8 months, respectively.

“It looks like DNA methylation is a major driver [of the different subtypes],” Giordano observes, “so we're looking to develop this signature into a full, analytically valid prognostic assay.” Currently, ACCs are classified as low- or high-grade based on mitotic activity under the microscope, “which isn't all that informative,” he adds. “A three-group classification would enable more confident treatment decisions.”

Ultimately, “we view our study as more of a hypothesis generator,” Hammer says, “and although it's a long road ahead, I think we have the first steps to facilitating targeted therapy development for ACC.”

“There's much to do, to better understand all our observations,” Giordano agrees, “but the fact that clinical outcome is linked means we're at least barking up the right tree.” –Alissa Poh

For more news on cancer research, visit Cancer Discovery online at