Researchers from across the globe have joined together to improve understanding about one of the most rare -- and lethal -- types of cancer.

Teams from 39 institutions in Europe, North America, South America and Australia collected and analyzed 91 samples of adrenocortical carcinoma.

They performed a comprehensive genomic analysis as part of The Cancer Genome Atlas Research Network.

The results of this collaboration, published in Cancer Cell, newly identify several genes that drive adrenal cancer.

In fact, the analysis uncovered double the number of genetic drivers already known to fuel adrenal cancer, a disease which affects less than two people per million annually, and is seen more commonly in children under age 5 and adults ages 30-40 with an overall five-year survival rate is 20 to 35 percent.

"This data has implications for diagnosing and predicting outcomes of adrenal cancer. It also allows us to probe deep into the biology of the disease to understand how these new gene mutations contribute to adrenal cancer progression and formation," says senior author Gary D. Hammer, M.D., Ph.D., the Millie Schembechler Professor of Adrenal Cancer at the University of Michigan Comprehensive Cancer Center.

Scientists examined 91 ACC tumor specimens from four continents, and observed "massive" DNA loss followed by whole genome doubling (WGD).

WGD occurs when tumor cells acquire an extra copy of their entire genome.

The researchers found that WGD was associated with aggressive clinical course, suggesting that it could be a hallmark of disease progression.

They speculate that tumor growth could be slowed if they could prohibit WGD in future pre-clinical studies.

"Our results represent the most complete characterization of ACC tissues and may indicate a key to successful targeted therapy for this disease," said Roeland Verhaak, Ph.D., associate professor of Bioinformatics and Computational Biology. "The study findings illustrate how molecular data, combined with traditional clinical assessment, might inform therapeutic decisions and lead to significant advances in patient outcomes."

"It speaks to the power of collaboration with rare cancers. It's very difficult to do advanced genomics without collaboration, especially in a disease in which the number of patients is so small," says Thomas Giordano M.D, Giordano, the Henry Clay Bryant Professor of Pathology at U-M, and senior author on the paper.

The study revealed several interesting findings.

One of the most exciting mutations is in ZNRF3, which the researchers found to be lost in up to 20 percent of the adrenal cancers studied.

The study also confirmed that mutations involved in benign adrenal disease play a role in adrenal cancer.

Another key finding was that many adrenal tumours undergo whole genome doubling -- a phenomenon in which each chromosome in the gene replicates and creates a second copy.

This reflects instability of the cancer genome, which is particularly prominent in adrenal cancer.

"We suspect that understanding the biology of how that happens and the consequences of that event will ultimately help us define and discover new therapies," Hammer says.

Researchers identified three distinct subtypes of adrenal cancer based on their molecular alterations.

The subtypes were linked to different outcomes, suggesting a way to use molecular biomarkers to identify those patients likely to have more aggressive disease, and to more precisely match therapy with disease biology.

"Our understanding of ACC pathogenesis is incomplete and new therapies are needed," said Verhaak. "While standard clinical assessments are informative for patient management, molecular information may be able to more precisely predict patient outcome and direct optimal care."

Source: Cancer Cell