When a young person develops cancer, doctors most often assume that genetics are the reason, because the patient hasn’t lived long enough to accumulate environmental damage. But it’s been hard to find the faulty DNA behind many tumors. Now, using new genomic technology, scientists have discovered a novel explanation for some testicular cancers, the most common cause of cancer in men under 35. Rather than being triggered by a single gene mutation, the tumors are caused by too many or too few copies of a gene in a person’s cells. These “copy number variations” have been linked to other conditions such as autism, but never before to cancer.
“This is a very exciting and interesting and, to be honest, important observation in the world of cancer susceptibility,” says Stephen Chanock, the chief of translational genomics at the National Cancer Institute in Bethesda, Maryland, who was not involved in the study.
It’s normal for people to have different copy number variations (CNVs) throughout their genome. But when certain genes are copied too many or too few times, it can lead to disease. In addition to autism, CNVs have been linked to congenital heart defects and epilepsy. Researchers at Memorial Sloan-Kettering Cancer Center in New York City, led by oncologist Zsofia Stadler, suspected that CNVs could also play a role in some cancers, particularly those that appear early in life and are therefore less likely to have environmental components.
So the team tested 116 people with early-onset testicular cancer, breast cancers not explained by known mutations, or early-onset colorectal cancer. While the testicular cancer patients averaged 29 years old, the other patients were older, since early-onset disease has a later cut-off for those types of cancers. Instead of looking for point mutations—changes to part of a gene—they studied whether entire genes were repeated an unusual number of times. They compared the results with data from disease-free family members of the patients as well as healthy, unrelated controls to home in on CNVs unique to the cancer patients. While the colorectal and breast cancer patients had no unusual CNVs, 7% of those with early-onset testicular germ cell tumors—which are the vast majority of all testicular cancer cases—had a CNV that had developed de novo, that is not inherited directly from their parents but the result of a change to a sperm or egg cell. The CNVs appeared at different places in the genome and while some were extra copies of a gene, others were fewer copies than usual. But all were considered rare CNVs, not found in healthy people, the researchers report online today in The American Journal of Human Genetics.
“What we think this might mean is that these de novo, new, genetic changes may be more relevant to early onset cancers with an impact on fertility,” says Stadler, since testicular cancers more often occur during reproductively active years than the other cancer types. In the past, men who developed early-onset testicular cancer often had no offspring as a result of the treatment they received, although the odds that they will are better now. This means genetic abnormalities would rarely be passed between generations, instead more often developing anew for each patient.
It’s still unclear whether testicular cancer is more often caused by de novo mutations instead of inherited ones when compared with other cancer types, says Chanock. But the study provides vital clues about the risk factors for some cancers. “I suspect as we dig deeper into sequencing and family studies, we’ll see more and more CNVs representing a portion of the genetic architecture that explains diseases,” he says.
For now, Stadler’s team wants to focus on the regions in which it found altered gene numbers to see how the CNVs affect gene and protein functions. It also wants to perform more detailed sequencing on the tumor biopsies from testicular cancer patients with CNVs. The discovery won’t immediately change the way the cancer is treated, Stadler says, but it will provide a jumping off point for more work on the disease.