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UMich Researchers Sequence DNA, RNA From Hundreds of Metastatic Tumors

NEW YORK (GenomeWeb) – An analysis of 500 metastatic tumors has found that they harbor many more mutations than primary tumors do.

Researchers from the University of Michigan performed whole-exome and whole-transcriptome sequencing on metastatic tumors from 500 adult patients. The effort was part of the Michigan Oncology Sequencing (MI-ONCOSEQ) Program that aims to identify mutations in order to guide treatment.

As they reported today in Nature, the researchers also found that a sizable portion of people with metastatic disease had germline mutations that increased their cancer risk. Additionally, they noted that metastatic tumors could be divided into two groups based upon their mRNA profiles and that those subtypes appeared linked to tumors' responses to treatment.

"Our findings emphasize the importance of getting a fresh biopsy of the metastatic tumor," Michigan's Arul Chinnaiyan said in a statement. "Tumors are evolving as part of metastasis and under therapy. We need to biopsy the metastatic tumors and then suggest therapies, rather than using archival tissue from the primary tumor."

The research team sequenced biopsies and germline DNA from 500 people with metastatic cancer. This MET500 cohort represented 20 cancer types, most commonly metastatic prostate cancer, breast cancer, and soft tissue sarcoma. The most frequent metastasis sites were liver, lymph node, lung, and bone.

On average, the researchers observed 119 somatic mutations per patient, and they noted a significant increase in mutations in metastases as compared to primary tumors for most cancer types. They attributed this increase to the cancers' aggressiveness, the longer amount of time they have to accumulate mutations, and the effects of treatment.

While they reported increased numbers of mutations, they found that only a few genes were mutated at a high rate. Most often, those mutations were in the tumor suppressor genes TP53, CDKN2A, PTEN, and RB1 or the oncogenes PIK3CA, AR, and KRAS.

Chinnaiyan and his colleagues also noticed a high rate of possibly pathogenic germline mutations among the MET500 cohort. Some 12 percent of patients harbored inherited putatively pathogenic mutations. In particular, they homed in on 63 presumed pathogenic germline mutations within their cohort. Three-quarters of these mutations were in genes involved in DNA repair like MUTYH, BRCA2, CHEK2, and BRCA1.

When they compared the frequency of these mutations in their cohort to their frequency in the nearly 53,000 people of the Exome Aggregation Consortium dataset, they found that MET500 cohort was much more likely to have presumed pathogenic germline mutations.

In a related commentary in Nature, the BioMediTech Institute's Steven Bova noted that additional studies of people with metastatic cancer are now "needed to determine whether a diagnosis of metastatic cancer should trigger more-intense evaluation of familial cancer risk than currently occurs."

When Chinnaiyan and his colleagues examined the metastases' transcriptomes, they found that they generally had increased cancer-related transcriptional programs. As compared to normal tissue, metastatic tumors had increased proliferation, stress response, and metabolism.

At the same time, they found that that the tumors clustered into to one of two subtypes, marked by mutually exclusive transcriptomic signatures. One signature was associated with inflammation and the other with proliferation.

"Not all metastases are the same," Chinnaiyan said. "Different pathways are driving them to be quite different — highly proliferative versus those that are differentiating more. This mutually exclusive aspect was a striking finding that could guide us in developing new types of therapies."

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