Results of the analysis undermine anew long-held beliefs that cells with metastatic potential originate solely from the original or primary site of a cancer, according to the scientists who performed the study.
“The idea that metastatic tumors can seed and establish other metastatic tumors in patients is different from traditional theories that the primary tumor is solely responsible for disseminating cancer cells with metastatic potential,” says William Isaacs, Ph.D., the William Thomas Gerrard, Mario Anthony Duhon and Jennifer and John Chalsty Professor of Urology at the Johns Hopkins Brady Urological Institute and a member of The Johns Hopkins Kimmel Cancer Center. “The new genomic information lends more support to the idea that treatments for metastatic cancers should be a combination of therapies that target a variety of genetic pathways.”
Data used in the analysis, described in a report of the work online April 1 in Nature, were generated from a novel set of samples, collected in a Johns Hopkins autopsy program for patients with prostate cancer from 1995 through 2004. The new work comprised extensive genome sequencing and bioinformatics analysis of tumor samples by scientists at the Wellcome Trust Sanger Institute, University of Tampere in Finland and members of the International Cancer Genome Consortium, who found that the genetic makeup of cells within metastatic prostate tumors matched the makeup of new tumors from other metastatic sites.
Specifically, the investigators used a catalog of the genetic code of 51 tumors removed from 10 men who died from prostate cancer and were autopsied at The Johns Hopkins Hospital, as well as a sample of normal tissue from each of them.
Whole-genome sequencing on the samples showed that “even though a single cell begins the metastatic process, the disease becomes very heterogeneous as it spreads throughout the body over time, both between and among individuals. In individual patients, each metastatic site becomes an entity unto itself,” says Isaacs, who also is a professor of oncology at the Johns Hopkins University School of Medicine.
The scientists found that five of the 10 men had patterns of mutations across several metastatic lesions, suggesting that these lesions were derived from not one but multiple metastatic sites. In seven of the men, the metastatic tumors were genetically more similar to each other than to the primary tumor.
The current findings expand on results of a Johns Hopkins-led study of autopsy samples published in Nature Medicine in 2009, conducted by scientist G. Steven Bova, M.D., who was then at Johns Hopkins and is now at the University of Tampere in Finland. That study showed similar patterns of genetic similarities across metastatic sites. The current study provides more detail and insight into the metastatic process, says Isaacs.
Isaacs says the current study relied on a novel set of tissue samples obtained from metastatic prostate cancer patients who, along with their families, agreed to be autopsied when they ultimately died from the disease. “Nearly every tissue and bone in the body was biopsied, and Dr. Bova and the autopsy team collected thousands of samples from these men who generously donated their tissues to science,” says Isaacs.
Bova, Isaacs and their team at Johns Hopkins began the autopsy program in 1994 at a time when there was little access to metastatic prostate cancer tissue and when genome sequencing technology did not exist. “These samples, along with their annotations, are even more valuable now since we can use them in very sophisticated genetic studies such as the current one,” says Isaacs. “The contributions these men made will hopefully produce more illuminating results that will pave the way for better treatment and prevention of prostate cancer.”