Researchers Find Early-Onset Testicular Cancer May Occur from Spontaneous Genetic Mutations

Pictured: Kenneth Offit & Zsofia Stadler

Kenneth Offit, Chief of the Clinical Genetics Service (left), and medical oncologist Zsofia K. Stadler

Although it is clear that genetic mutations contribute to cancer risk, researchers have been unable to pinpoint the genetic cause of most cancers arising at a young age in people without a family history of the disease. Now Memorial Sloan Kettering researchers have found that some early-onset testicular cancers may result from spontaneous, or de novo, genetic changes. These de novo mutations are not inherited from either parent, but arise in either the egg or sperm cell or sometime during embryonic development.

The mutations occur in the form of copy number variations (CNVs), in which one or more DNA segments are duplicated or deleted. Though previous research has demonstrated an association between de novo CNVs and autism, the new study, published in the August 10 issue of the American Journal of Human Genetics, is the first to suggest that these types of DNA changes may also be linked to cancer susceptibility.

“We now have the first evidence that de novo CNVs could be linked to cancer predisposition,” says medical oncologist Zsofia K. Stadler, who led the study. In addition to improving understanding of the genetic origins of testicular cancer, the authors indicate that similar spontaneous changes may be critical to understanding the origin of other pediatric cancers.

CNVs and Testicular Cancer

Because de novo CNVs have been found in higher rates in children with certain disorders, including autism and schizophrenia, the Memorial Sloan Kettering team suspected that these types of genetic changes might also play a role in cancers that occur in younger people.

The researchers looked for CNVs in 116 people with early-onset testicular cancers (diagnosed at or before age 35), breast cancers (diagnosed at or before age 45), and colorectal cancers (diagnosed at or before age 50). Comparing the DNA of these people with the DNA of their unaffected parents, scientists found that 7 percent of the men with testicular cancer had de novo CNVs. None of the patients with breast or colorectal cancer had these DNA changes.

“We have always known that even in cancer-prone families, the mutations had to start somewhere,” says Kenneth Offit, Chief of the Clinical Genetics Service and the study’s senior author. “In this study, we appear to have pinpointed the spontaneous origin of genetic changes in the most common cancer occurring in young men.”

The researchers propose that de novo changes might be more relevant to cancers that affect people before their reproductive years, as in many men with testicular cancer. In these cases, genetic abnormalities have rarely been passed between generations, and instead develop anew for each person. In contrast, breast and colorectal cancers, even if they affect a person early in life, usually arise after the age of reproduction, which could partly explain the lower frequency of de novo mutations in these cancers.

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Future Research

For the next stage of research, Memorial Sloan Kettering investigators will focus on the DNA regions where CNVs were found in order to understand how these changes are affecting the function of genes and proteins.

In addition, they are using advanced genetic sequencing technology to look for additional de novo changes — apart from CNVs — in survivors of childhood malignancies. This approach, called next-generation sequencing, can scan the entire genome to detect the tiniest of mutations, where a single DNA base (the commonly known T, C, G, and A that make up the “letters” of DNA) differs between child and parent.

“I think we’re going to find these kinds of genetic changes in several early-onset cancers,” Dr. Stadler says. “With newer sequencing technology, we will be able to identify other rare alterations affecting cancer risk that were previously impossible to detect.”

This research was supported in part by funding from the Starr Cancer Consortium, The Society of MSKCC, and the Damon Runyon Cancer Research Foundation.

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I have a question. My 1st husband passed away from testicular cancer (2nd recurrance). We have 2 beautiful girls. What are the chances they carry a gene and can they get tested for carrying a gene for testicular cancer to pass on to their boys? I've read that a mother can pass a gene if hereditary.

I lost a friend to testicular cancer in 1995. He went to a general oncologist, who did not specialize in testicular cancer. He went 3 years before it spread to his liver and killed him? Should he have gone to a testicular cancer specialist? WAS TC curable in the early 1990's. Are you using more advanced treatments now? What are some of the major advancements that were not availabe in 1992. He was in his 30's when he died. Way to young.

My husband passed away in December 2011 from Stage 3c non-seminoma testicular cancer. Our son conceived in June of 2007 was diagnosed with autism. Is Memorial Sloan Kettering aware of or conducting any research studies with regard to the incidences of autistic children born to men diagnosed with testicular cancer?

Angela, thank you for your comment. We consulted with Dr. Stadler, and she responds:

To date, there is no known link between autism and development of testicular cancer. While there is a lot of research being performed with respect to the possibility of a genetic etiology of autism, we are not actively conducting any such studies given our primary focus on cancer at MSKCC.

My 16 year old son was diagnosed with stage 4 germ cell cancer in September. His doctors are not planning surgery at this point because he had “dozens & dozens of tumors in his liver, lungs, & lymph nodes in his abdomen. He is being treated with Bleomysin, Etoposide & Cisplatin.
He was diagnosed at age 4 with mild autism. I don’t know if there is any connection. I am interested in your genetic testing that is being offered.

Dear Melinda, we’re very sorry to hear about your son’s diagnosis. There have been some studies that have suggested a link between autism and certain cancers, but the connections are not clear. If you are interested in speaking with a clinical geneticist at MSK you can call 646-888-4050 or go to… for more information. Thank you for your comment and best wishes to you.