It’s the oncological version of the groin attack, but unlike the groin attacks seen in America’s Funniest Home Videos, it’s no laughing matter. The “it” in this case is testicular cancer’s extreme sensitivity to chemotherapy. Given the potentially grave consequences of testicular cancer, the effectiveness of a chemotherapeutic groin attack does not inspire guffaws or even sympathetic winces, but rather expressions of grim satisfaction—and a determination to learn whether other types of cancer could also be made to suffer chemotherapy’s blows so badly.
To learn why testicular cancer is, in most cases, highly curable with chemotherapy, scientists based at the Dana-Farber Cancer Institute examined the genomic features of germ-cell tumors (GCTs), which are derived from germ cells and occur most frequently in testes. Genomic features identified in previous studies included mutations and chromosome damage, but none of these studies managed to pinpoint specific alterations or events linked to chemosensitivity or resistance.
The Dana-Farber scientists, along with colleagues from the Broad Institute and Harvard, plowed ahead, churning though whole-exome and transcriptome data. They sequenced samples of precursor, primary (testicular and mediastinial), and chemoresistant metastatic human GCTs taken from 49 patients treated between 1997 and 2014 at Dana-Farber/Brigham and Women's Cancer Center.
After correlating their sequencing results with clinical outcomes data, the scientists realized that they could not attribute the formation of testicular cancers to any one gene. Instead, they found a diverse set of features, a “convergence of cancer genomics, mitochondrial priming, and GCT evolution.”
Details appeared November 30 in the journal Nature, in an article entitled, “Genomic Evolution and Chemoresistance in Germ-Cell Tumours.” Besides describing the genomic signature that drives testicular tumors, the article emphasizes that these tumors are highly “primed” to self-destruct.
“[We] show that the primary somatic feature of GCTs is highly recurrent chromosome arm level amplifications and reciprocal deletions (reciprocal loss of heterozygosity), variations that are significantly enriched in GCTs compared to 19 other cancer types,” wrote the authors of the Nature paper. “These tumours also acquire KRAS mutations during the development from precursor to primary disease.”
Previous studies had found that testicular tumors are characterized by a gain of extra DNA copies on one arm of chromosome 12, in a segment labeled 12p. In the new study, however, the scientists found there were many chromosomal changes, with multiple parts of the genome having a 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).
The gain and loss of DNA copies shows that the tumors' chromosomes “are profoundly deranged,” said Dana-Farber’s Eliezer Van Allen, M.D., one of the current study’s senior authors. This abnormality, he added, represents “a hallmark feature we hadn't noticed before.” It may be linked to the development of GCTs and cause them to be sensitive to chemotherapy, Van Allen indicated, but exactly how it does so remains to be discovered.
The study revealed another feature of chemosensitive GCTs: “Primary testicular GCTs are uniformly wild type for TP53.” In other words, these GCTs possess intact copies of the p53 gene, which directs cells to make a tumor-suppressor protein that clamps down on renegade cells so they can't form tumors. Many cancers contain mutated or lost p53 genes, indicating they have lost this protective factor.
“In addition,” the study’s authors continued, “by functional measurement of apoptotic signalling (BH3 profiling) of fresh tumour and adjacent tissue, we find that primary TGCTs [testicular GCTs] have high mitochondrial priming that facilitates chemotherapy-induced apoptosis.” That is, testicular tumor cells are already poised on the brink of self-destruction.
Apoptosis, also known as programmed cell death, is the body's quality-control process that gets rid of unneeded and dangerously abnormal cells. Many cancers have evolved strategies for blocking the cell's orders to self-destruct. The study results suggest that most testicular tumors may be highly susceptible to chemotherapy because their cells are already highly “primed” for apoptotic death, although why this is so hasn't been determined.
In another part of the study, the scientists studied 13 GCT samples taken from five patients over time, spanning from before they underwent treatment to after the tumors became drug-resistant. As the cancers progressed, they showed increases in chromosomal abnormalities seen in all the tumors. The cells of the GCTs 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.
More than 80% of patients with GCTs are cured, even when the cancer has metastasized. However, a significant number become chemotherapy-resistant, and about 10% of patients with metastatic GCTs die as a result. In 2016, about 8720 new cases of testicular cancer are expected in the United States, with about 380 deaths.
Because of their rarity, GCTs haven't been studied as intensively as other forms of cancer, and research funding is more scarce, noted Dana-Farber’s Christopher Sweeney, the study’s other senior author. The new study, he said, “gives us insights into GCT biology that haven't been found to this degree and provide a strong base to explore these very interesting findings further.”