Researchers led by scientists at Dana-Farber Cancer Institute identified unique genomic changes that may be integral to testicular cancer development and explain why the great majority are highly curable with chemotherapy -- unlike most solid tumors. The findings, which may shed light on factors in other cancers that influence their sensitivity to chemotherapy, was featured on the cover of last week’s Nature.
Germ cell tumors are growths that arise from reproductive cells (germ cells produce sperm and eggs), most commonly in the testes. Approximately 8,720 new cases are expected in the U.S. in 2016 with about 380 deaths. Although rare, primary testicular germ cell tumors are the most common solid cancers in young men. Tumors are generally highly sensitive to chemotherapy, and 80 percent of patients with germ cell tumors can be cured with standard chemotherapy, even when the cancer has metastasized. However, a significant number become chemotherapy-resistant, and about 10 percent of patients with metastatic germ cell tumors die as a result.
Previous studies of the genomes of testicular tumors revealed mutations and chromosome damage, but haven't pinpointed specific alterations or events linked to chemosensitivity or resistance. Scientists led by Eliezer Van Allen, MD, of Dana-Farber and the Broad Institute of MIT and Harvard, and Christopher Sweeney, MBBS, of Dana-Farber decided to conduct a comprehensive search for the critical genomic and molecular features of these cancers. The team analyzed samples of 59 tumors from 49 patients treated between 1997 and 2014 at Dana-Farber/Brigham and Women's Cancer Center (DF/BWCC). The samples were sequenced for the whole-exome DNA and RNA transcriptome, with the findings correlated to clinical outcomes data. Although mutated genes are the main drivers of many cancers, no single gene was discovered that really explains the formation of testicular cancers.
The more surprising insights came when they analyzed the sequence data for copy number variation, looking for extra or missing pieces of DNA in the tumor genome. One feature of the tumors that had been previously reported was a gain of extra DNA copies on one arm of chromosome 12, in a segment labeled 12p. The new study revealed widespread genetic rearrangement in the cancer cells with many having multiple parts of the genome having gain of one parental allele while simultaneously losing a copy of the other parental allele -- a type of chromosomal damage called reciprocal loss of heterozygosity (RLOH). This abnormality maybe linked to the development of germ cell tumors and cause them to be sensitive to chemotherapy, but exactly how it does so remains to be discovered.
The analysis revealed another feature of the chemosensitive germ cell tumors possessed intact copies of the p53 tumor suppressor gene, which is often inactivated or lost in cancer cells. Moreover, the researchers discovered that in contrast to most types of cancer, which have evolved strategies for blocking the cell's orders to self-destruct, testicular tumor cells are already highly "primed” for self-destruction by apoptosis. This be account for the high susceptibleness to chemotherapy by most testicular tumors, although the mechanism remains undetermined.
By studying drug-resistant germ tumor cells across the entire treatment course, the scientists found that as the cancers progressed, they showed increases in chromosomal abnormalities seen in all the tumors. The cells of the germ cell tumors also became more "differentiated" -- a trait that's usually associated with less-aggressive cancers; this observation remains a puzzle, the authors said, but may explain the resistance of these tumors to chemotherapy. An important next step in this research will be understanding what drives the RLOH events, and exploring whether therapeutics can block that factor or reverse the path to drug resistance.
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